Friday, Dec 28, 2018

imageHIV evolution is in fact dominated by soft sweeps

Alison Feder, Pleuni Pennings, and Dmitri just posted a short follow-up piece on why we might expect soft sweeps to be the dominant mode of adaptation for HIV evolving drug resistance in response to early therapies. This article is in response to a paper by Harris et al that just came out in PLoS Genetics. Richard Neher also wrote a nice blogpost following up on the article. 

Thursday, Oct 4, 2018

imageNeanderthals and modern humans exchanged both viral diseases and genetic defenses against them

In this paper just published in Cell, a former postdoc David Enard, now an Assistant Professor at the University of Arizona EEB Department, found compelling evidence that Neanderthals passed along genetic defenses against viral diseases to modern humans when the two species interbred 50,000 years ago. This study garnered quite a bit of attention that you can see here. See in particular the NY Times write-up by Carl Zimmer and a write by Ker Than in Stanford Report.

Wednesday, Sep 26, 2018

imageAlison Feder wins the inaugural prize at the new Milner Center in Evolutionary Biology at the University of Bath

Alison Feder won the inaugural Milner Prize in evolutionary biology! She traveled to Bath to give the keynote lecture and accept the award. Made us all very proud! You can see the talk here.


Thursday, May 24, 2018

imageAlison Feder defends her thesis!

Alison Feder defended her PhD entitled "the evolutionary dynamics of rapidly adapting intra-patient pathogens through space and time". She will next join Oskar Hallatschek's lab as a Miller Fellow at UC Berkeley. Congratulations, Alison!

Thursday, September 28, 2017

imageHigh Rate of Adaptation in Proteins that interact with malaria-like parasites

Nearly half the world's population lives in areas where malaria is endemic--and that's only counting the humans. Plasmodium and related parasites (called Piroplasms) have infected all kinds of mammals for millions of years, ranging from cats to cows to coyotes. Human adaptations to malaria, including sickle cell disease, have been important in understanding the maintenance of genetic diversity within and across populations. But almost nothing is known about how malaria has shaped mammalian genomes on the timescales of species divergence.

In a paper that was just published in PLoS Genetics, a graduate student Emily Ebel, postdoctoral fellow David Enard, former graduate student Sandeep Venkataram, and a graduate student in Jonathan Pritchard's lab, Natalie Tellis, and Dmitri curated and analyzed hundreds of mammalian proteins that interact with malaria-like parasites. They found that 'parasite-interacting proteins' have accumulated adaptive substitutions across species three times faster than similar proteins that do not interact with parasites. Digging deeper, they also found that host immune proteins tend to interact with many kinds of pathogens--not just parasites, but also viruses and bacteria. Nonetheless, they show that malaria appears to havedriven its own share of host adaptation, especially in the liver and red blood cells. This large dataset of parasite-interacting proteins dramatically expands the set of candidate genes underlying human malaria susceptibility, which may help us understand how the same proteins adapt at different time scales. 

Tuesday, June 6, 2017

imageJamie Blundell is joining Cambridge as a Group Leader in the Department of Oncology

Happy to announce that former postdoc in the lab Jamie Blundell has accepted an offer to become a Group Leader in the Department of Oncology, University of Cambridge. Jamie's new lab will focus on quantifying the evolutionary dynamics that goes on inside our tissues as we age, with application to early cancer detection. He will continue to generate and analyze rich time-series data to spot signs of positive selection with the aim of detecting malignant transformations earlier. Best of luck!

If you are interested in Jamie's work while at Stanford chgeck out these two papers in particular: Levy&Blundell et al, Nature, 2015, Venkataram&Dunn et al, Cell 2016, Assaf, Petrov, & Blundell, PNAS 2015.

Monday, May 22, 2017

imageSizing up cancer with Tuba-seq

Cancer growth is a multistage, stochastic evolutionary process. To measure the divergent outcomes of tumors, we teamed up with the Winslow Lab to develop a new method that measures the growth of thousands of tumors within a single mouse using DNA barcodes, termed Tuba-seq. Tuba-seq measures tumor sizes far more precisely and rapidly than previous approaches, and demonstrates the importance of studying tumor growth as a stochastic process: we found that loss of p53, the most common mutation in human lung cancers, did not appreciably alter the median size of tumors, but instead increased the likelihood of very large, very rare tumors.

While cancer genome sequencing is identifying the genomic alterations that occur in human tumors, the consequences of most of these alterations remain unknown because the most effective approach to studying these alterations in vivo, genetically engineered mouse models, is not scalable. To overcome this challenge, we combined Tuba-seq with CRISPR/Cas9-mediated genome editing to quantified the growth effects of 11 tumor suppressor pathways that are frequently altered in human lung adenocarcinomas. We surveyed more genotypes in vivo than the entire field had measured in lung adenocarcinoma to date. 

We're really excited about Tuba-seq and are currently using it in several burgeoning projects. Check out our recent paper in Nature Methods which was led by a postdoctoral fellow in the lab, Chris McFarland, and a graduate student in the Winslow and Petrov labs, Zoe Rogers. Also take a look at the commentary in the Nature Review Genetics.

Thursday, June 1, 2017

imageAsymptotic McDonald-Kreitman (aMK) test widget

Ben Haller and Philipp Messer have just came out with a very useful on-line widget that can be used to run aMK test on line. Very cool!

Check out their paper in G3 and also the original PNAS Messer&Petrov 2013 paper that developed the aMK test. And here is the widget.

Monday, May 22, 2017

imageAlison wins the Ommen Prize in Evolutionary Medicine!

Our paper "More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1" was selected as this year's Omenn Prize winner! In the paper, we show that the dynamics through which HIV acquires drug resistance to a treatment within a patient correspond to the failure rate of that treatment across patients. The prize is awarded annually to the best article of the previous year "in any scientific journal on a topic related to evolution in the context of medicine and public health." Alison will be going to the annual meeting of the International Society of Evolution, Medicine and Public Health in Groningen in August to present the paper. Learn more about the Omenn prize, the official award announcement or read the paper here!

Monday, May 1, 2017

imageSoft Sweeps in Evolutionary Rescue

At times populations are faced with existential threats such that the population starts decreasing in size and would go all the way to extinction unless a new adaptive solution is found in time. The question of how likely such recovery - called evolutionary rescue - is under different scenarios is a subject of much research as it is important in conservation biology, where evolutionary rescue is a good thing, and in evolution of resistance of pathogens and pests to drugs and pesticides, where it is bad. In a recent Genetics paper authored by a graduate student in the lab Ben Wilson, Dmitri, and a long-term associate of the lab, professor at SF State and a former postdoc Pleuni Pennings, we ask a different question: if the rescue is to happen, is it likely to happen via a single adaptive variant increasing in frequency (hard sweep) or via many independent mutations sweeping simultaneously (soft sweep). The key insight of the paper is that if the rescue is likely to happen at all it is also like to take place via a soft sweep. The insight is even more generic than that: if something is lilely to happen it is not likely to happen only once. For instance, if something is likely to be discovered, multiple people are likely to discover it simultaneously leading to the famous Stigler's law of eponymy. If you go through IVF and really want to make sure that you do get pregnant, you are quite likely to end up with twins. And so on.

See the video that Pleuni made about the paper. And note that this theoretical result is entirely consistent with the recent paper by Alison Feder and colleague in Elife (see the video as well).

Wednesday, September 28, 2016

imageEmily Ebel receives a Seed Grant from CEHG

Emily has just been awarded a Seed Grant from Stanford CEHG (Center for Computational Evolutionary and Human Genomics) to study the malaria parasite, Plasmodium falciparumP. falciparum employs complicated mechanisms to evade the human immune system, making it difficult to prevent malaria with vaccines. The parasite genes involved in this process are known to evolve in unique and effective ways--which, unfortunately, makes them difficult to characterize. Emily will be applying new sequencing technologies including PacBio and Nanopore to tackle these key parasite genes. Congratulations Emily!



Saturday, September 10, 2016

imageDevelopment of a comprehensive genotype-to-fitness map of adaptation-driving mutations in yeast

Adaptive evolution plays a large role in generating the phenotypic diversity observed in nature, yet current methods are impractical for characterizing the molecular basis and fitness effects of large numbers of individual adaptive mutations. In a paper just published in Cell, we used a DNA barcoding approach to generate the genotype-to-fitness map for adaptation-driving mutations from a Saccharomyces cerevisiae population experimentally evolved by serial transfer under limiting glucose. We isolated and measured the fitness of thousands of independent adaptive clones, and sequenced the genomes of hundreds of clones. We found only two major classes of adaptive mutations: self-diploidization, and mutations in the nutrient-responsive Ras/PKA and TOR/Sch9 pathways. Our large sample size and precision of measurement allowed us to determine that there are significant differences in fitness between mutations in different genes, between different paralogs, and even between different classes of mutations within the same gene.

Wednesday, July 20, 2016

imageFirst empirical evidence that directional selection does commonly lead to heterozygote advantage

In a previous study using population genetic theory and simulations we predicted that adaptation in diploids follows different dynamics than adaptation in haploids. Adaptive mutations in diploids are expected to exhibit heterozygous advantage allowing directional selection to generate and maintain abundant genetic variation rather than to remove it. However, despite the broad implications for our understanding of adaptation, empirical evidence for heterozygote advantage in adapting populations has been lacking. In a paper just published in Genetics former graduate student Diamantis Sellis and collaborators evolved diploid yeast populations in a glucose limited environment in a chemostat and studied the arising adaptive mutations. Adaptation was highly repeatable with the same three adaptive mutations appearing multiple independent times. Heterozygotes for these adaptive mutations were more fit than both ancestral and derived homozygotes. The fact that fitness overdominant mutations were always the first step in independent adaptive walks supports the prediction that heterozygote advantage can arise as a common outcome of directional selection in diploids and demonstrates that overdominance of de novo adaptive mutations in diploids is not rare. We are continuing to explore this topic but the initial results are extremely promising.

Check out the F1000 review of this paper by Norman Johnson here.

Tuesday, June 21, 2016

imageSharon Greenblum receives the CEHG fellowship!

Sharon has been awarded the Stanford CEHG (Center for Computational Evolutionary and Human Genomics) postdoctoral fellowship.  CEHG is an umbrella program promoting enhanced interaction between the many labs at Stanford with diverse approaches to genomics research, and supporting training and outreach activities to enrich the scientific community.  The CEHG fellowship provides one year of funding to new postdocs as they transition from graduate school to postdoctoral work.  Sharon will be using the CEHG fellowship to study the dynamics of rapid adaptation in Drosophila populations. Congratulations Sharon!!


Thursday, June 16, 2016

imageLong-range LD and soft sweeps are common in D. melanogaster

The availability of multiple fully sequenced genomes from a single species is giving population geneticists a completely new way to study evolutionary process. Whereas before we were limited to having a few short (on the order of 1000 bp) regions sequenced from a few individuals, now we have the luxury of having hundreds and even thousands of fully sequenced genomes. Nandita Garud from out lab has taken advantage of this new type of data to discover that strong recent adaptation was extremely common in D. melanogaster. Specifically, sheand her collaborators (Philipp Messer, Erkan Buzbas, and Dmitri) found a large number of soft partial selective sweeps and very long-range linkage disequilibrium (LD) across the genome that are most easily explained by rampant adaptation taking place in extremely large populations of these flies.

The original paper used the genomic data from flies collected in North Carolina and left open the possibilty that this pattern might be unique to just this one population or only to the North America populations because of the severe bottleneck that the flies experienced on their way from Africa. Even more concerning was the possibility that the patterns were artifactual and generated by the way the flies were handled in the lab and in particular by the very strong inbreeding that the flies were subjected to before being sequenced.

Now, in a paper just published in Genetics, Nandita repeated the analysis in a large population genomic dataset from an acenstral population of D. melanogaster (Zambia, East Africa) generated with much less inbreeding. Nadita showed that the patterns she saw in Northa Carolina are still largely there. Specifically, there is abundant evidence of long-range LD and a large number of strong sweeps. The pattern is muted compared to what we saw in North Carolina and we see evidence of more hard sweeps. The paper establishes that long-range LD and soft sweeps are a generic feature of D. melanogaster evolution and we as field now need to figure out what kind of a evolutionary process can generate these patterns. We believe that local adaptation and very large population sizes are involved. Maybe also complex demography? In any case, nobody has so far demonstrated how this could in fact work in every detail and across the whole genome. What's your guess?


Tuesday, June 14, 2016

imageMore buzz about David Enard's paper on the role that viruses have played in adaptation

Nicolas Galtier just left a very generous review of David Enard's paper on Faculty of 1000. Check it out:

Saturday, June 11, 2016

imageCongratulations to Talia!

Here is a short but exciting update about Talia Karasov, our undergraduate lab alumnus who left the lab in 2010 after publishing a seminal paper in PLos Genetics. (This paper was certainly seminal for our lab's research direction but we believe it was also for the field at large.) Talia recently completed her Ph.D. in the laboratory of Joy Bergelson at the University of Chicago, and the wonderful news is that her thesis research was just awarded the best dissertation award from the Committee on Genetics Genomics and Systems Biology at UChicago. Congratulations!

After finishing her PhD, she joined the laboratory of Detlef Weigel at the Max Planck Institute for Developmental Biology in Tuebingen Germany. Her research in the Weigel lab focuses on microbial population genomics and is funded by two, count them two, very prestigious fellowships: the EMBO long-term research fellowship as well as a Human Frontiers in Science Program Post-doctoral fellowship. Way to go Talia! Proud of you.

Friday, May 20, 2016

imageAlison receives Lieberman Fellowship!

Graduate student Alison Feder has been awarded the Stanford Gerald J. Lieberman fellowship. Named in honor of Gerald J. Lieberman, a former Stanford provost, dean of graduate studies and professor of operations research and statistics, the fellowship honors twelve graduate students across the university who embody Dr. Lieberman’s commitment to scholarship, teaching and university service. Congratulations, Alison!

Thursday, May 19, 2016

imageVirus-driven evolution of mammalian genes

Multiple studies over the past 20 years revealed that adaptation is pervasive in genomes of many organisms including flies and humans. One deeply puzzling finding that emerged from all this work is that adaptation appears to affect proteins across all functional categories and types: young and old genes, housekeeping and genes responding to particular stimuli, enzymes and transcription factors. What can possibly drive adaptation across all these functional categories in all these genomes?

In a paper just published in Elife, postdoctoral fellow in the lab David Enard and colleagues argue that viruses might just be the long-sought culprit driving much of adaptation across the large swaths of mammalian and likely other genomes. Viruses are an ideal suspect - they interact with much of the cellular machinery and thus with many different proteins and as they constantly change they represent constantly shifting selective pressure for all their interacting partners. David argues that ~30% of all adaptive change in human proteins were driven by viruses and this is likely an underestimate. We will continue to investiagte the role that viruses and other pathogens have had on the evolution of genomes. Some exciting new findings are forthcoming. Stay tuned!

Check out the paper here and also a nice editorial by Sara Sawyer and Claus Wilke.


Thursday, April 28, 2016

imageWelcome Anisa!

Great news for the lab. Anisa Noorassa, a first-year graduate student from CMOB part of the Biology Department, has decided to join the lab after her Winter rotation. Anisa completed her B.S. in Cellular, Molecular, and Developmental Biology at the University of Washington in Seattle. She worked in Jennifer Nemhauser’s lab studying auxin signal transduction in Arabidopsis using a synthetic yeast system. After graduating from UW, she worked as a lab technician in Nicholas Ingolia’s lab at UC Berkeley for a year before coming to Stanford. She is interested in working on experimental evolution in yeast with a specific focus on antagonistic pleiotropy and evolvability.

Wednesday, April 6, 2016

imageCongratulations Yuping!

We are delighted to announce that a graduate student in our and Gavin Sherlock's lab, Yuping Li, has just been awarded a 6-month fellowship from Genetech Foundation. Yuping is using the yeast barcode technology to study the underlying mechanisms of how adaptive mutations gain their relative fitness in glucose-limited batch culture condition and what are the trade-offs in alternative conditions. Congratulations Yuping!

Wednesday, March 9, 2016

imageCongratulations Dr. Wilson!

Huge congratulations to a graduate student in the lab, Ben Wilson, who defended his dissertation today. In a packed room Ben told us about his investigations into the dynamics of rapid adaptation in large populations that (i) sharply vary in size and (2) decline in size exponentially due to changes in selective pressures unless rescued by adaptation (evolutionary rescue). Specifically he focused on the question of whether single (hard sweep) versus multiple (soft sweep) adaptive variants ends up responsible for adaptation should adaptation take place. Ben demonstrated that in the case of sharply variable populations soft sweeps are still possible but can be "hardened" when all but one adaptive variant gets lost during the period of population collapse. The hardening effect is much stronger in rapidly fluctuating populations and when selection is weak. The paper describing these results was published in Genetics in 2014.

In the case of evolutionary rescue similar patterns can be seen and interestingly Ben showed that there is a strong condition between how probable rescue is whether it will happen by soft sweeps. This pattern is exactly what another student in the lab, Alison Feder, just discovered in HIV. Ben's second key paper from his thesis is in preparation.

Beautiful work and beautiful defense. Congratulations!!!


Tuesday, March 8, 2016

imageDiapause and climatic adaptation in D. melanogaster

A recent Molecular Biology and Evolution paper by collaborator Xiaqing Zhao from Paul Schmidt's lab at UPenn, former postdoc Alan Bergland, and collaborators Emily Behrman, Brian Gregory, Paul Schmidt and Dmitri has shown that genes differentially regulated as a function of diapause, which is a primary adaptation to seasonality, show signatures of climatic adaptation. The propensities of expressing diapause in the North American D. melanogaster populations vary with season and latitude, with the spring and high latitude populations showing high diapause rate, and the fall and low latitude populations showing low diapause rate. By transcriptionally profiling flies that are able to enter diapause and those that are not, the authors find that these differentially regulated genes are enriched for seasonally oscillating and clinally varying genetic variants. This work draws a connection between mechanistic and quantitative genetic studies of naturally varying phenotypes that are known to be associated with adaptation to heterogeneous environments, and population genetic studies of populations that are known to have adapted to distinct environments. 

Check out our video abstract here.


Saturday, March 5, 2016

imageBad drugs = soft sweeps in HIV

A recent paper in eLife by graduate student Alison Feder in collaboration with Pleuni Pennings, Bob Shafer, Soo-Yon Rhee, Susan Holmes and Dmitri tests the prediction that fast evolution should be associated with soft sweeps of multiple beneficial (resistance) mutations rising in frequency simultaneously and slow evolution should be associated with hard sweeps of single drug resistance mutations rising to high frequencies by themselves. The authors analyze nearly 7000 HIV-infected individuals sampled between 1989 and 2013, and demonstrate that HIV populations that acquire drug resistance while being treated with poor drug therapies tend to retain genetic diversity, a signature of soft sweeps. However, when populations treated with efficacious treatments acquire drug resistance, the population genetic diversity decreases significantly, a signature of hard sweeps. This suggests that as treatments have improved, the dynamics through which drug resistance spreads have also changed. This study provides a concrete example of a more general principle: when adaptation happens quickly, the associated sweeps should be soft.

Check out our video abstract here.


Tuesday, February 23, 2016

imageParallel clines in D. melanogaster and D. simulans

A recent Molecular Ecology paper by graduate student Heather Machado in collaboration with Alan Bergland, Paul Schmidt, Katherine O'Brien, Emily Behrman, and Dmitri, presents the first comprehensive genomics analysis of clinal variation in D. simulans. Consistently with previous results Heather shows that D. simulans is much less clinal than D. melanogaster and argues that much of the reduced clinality is due to demographic difference between the two species. It appears that D. melanogaster populations are locally stable even at high latitudes, while D. simulans is likely to eb extirpated annually in the nothern locales and remigrates from more tropical locations or other refugia. As a result whatever clinality we see in D. simulans is likely to be due either to annual allele surfing or the action of strong natural selection, while clinality in D. melanogaster might have been established by the original patterns of migration (likely multiple waves of migration) and/or longer-term natural selection. Intriguingly, even though Heather does not detect any parallelism at the level of SNPs she does find that there is enrichment of genes that show parallel clinality arguing for the action of natural selection over and above the demographic noise. The paper is here!

Also, check out this very nice News and Views piece by Thomas Flatt that describes this study along with two other papers in the same issue of Molecaulr Ecology, one by Alan Bergland et al. on dual invasion of D. melanogaster in the US and Australia (see the next blog entry here) and one by Bozicevic et al on cold adaptation in the European populations of D. melanogaster.

Tuesday, February 23, 2016

imageDouble Invasion of D. melanogaster into North America and Australia?

A recent paper by former postdoc Alan Bergland (currently an Assistant Professor at the University of Virginia), former visiting student Ray Tobler, a former postdoc Josefa Gonzalez (currently Ramon y Cajal Researcher at the Institute of Evolutionary Biology (IBE) in Barcelona), our wonderful collaborator Paul Schmidt and Dmitri, strongly suggests that D. melanogaster invaded North America multiple times, with the high latitude (northern) populations along the East Coast primarily derived from European migrants and the tropical (southern) populations from the African colonizers. Even more surprisingly, a similar pattern of migration might have given rise to the Australian East Coast populations as well except with the high latitude (southern) populations coming from Europe and low latitude (northern) ones coming from Africa. We argue that the demographic history of North American and Australian populations of D. melanogaster are likely the primary cause of the latitudinal clines in genotype in these continents. Despite the role of secondary contact in generating clinal variation genome-wide in North American and Australia, we detect some signatures of spatially varying natural selection acting among populations. Nonetheless, our paper suggests that it is insufficient to show that a genetic polymorphism is clinal in North America or Australia or even on both continents in order to argue that it is/was subject to selection. Unfortunately for us all, much more data are necessary to make such claims! Check out our paper here.

Saturday, January 23, 2016

imageA Bird with Four Sexes

A recent paper in Current Biology by Elaina Tuttle ( Indiana State Univeristy), the Petrov Lab postdoctoral fellow Alan Bergland (who just moved to the University of Virginia as an Assistant Professor to start his own lab), and colleagues describes what essentially is a system with four sexes in the white throated sparrow (

For several decades, it has been known that this inconspicuous species harbors a large (>100 Mbp) inversion based supergene that affects aspects of morphology, behavior, and reproductive effort. Alternate alleles at this locus can be tracked in the field by morphology because the inversion is perfectly associated with color morph. Half of the population bears a white stripe on its head whereas the other half bears a tan stripe. White birds tend to invest more time and resources into securing additional matings and defending territory whereas tan birds tend to invest more in parental care. Remarkably, white and tan birds almost exclusively perform disassortative mating - i.e., tan (almost) always mates with white, white with tan. This morphological polymorphism is present in both sexes.

Tuttle, Bergland, et al assessed the fitness consequences of this supergene from twenty years of field data and complemented it with in-depth genomic analysis to examine the evolutionary history of this remarkable system. They find that alternate supergene alleles are extremely old, predating some speciation events in the genus. Based on patterns of polymorphism and divergence, they conclude that these alleles recently came into contact via introgression following inter-specific hybridization. They also show that these supergene alleles are evolving like neo sex-chromosomes, owing to the particular genetics of this system. White birds are heterozygous (2/2m) whereas tan birds are homozygous (2/2) for the 100Mb locus. 2m/2m homozogotes are extremely rare, preventing recombination on 2m, as in W and Y sex chromosomes.

This mating system in the white-throated sparrow gives rise to a situation where there are effectively four sexes. Such systems are exceptionally rare in animals and some aspects of theory suggest that their rarity is expected. Thus, the four sex system in the white-throated sparrow may be a transient consequence of hybridization (and possibly ‘reverse speciation’). Results presented by Tuttle, Bergland, et al raise the intriguing idea that supergene alleles such as this one on the white-throated sparrow may arise in homotypic species, become polymorphic via hybridization, and may ultimately disappear due to intrinsic instability over long-time scales.


Thursday, January 7, 2016

imagePopulation Genetics of Drug Resistance

Several graduate students in the lab -- Ben Wilson, Nandita Garud, Zoe Assaf, and Alison Feder -- teamed up with a former postdoc and current collaborator extraordinaire Pleuni Pennings to write a wonderful review of population genetics of drug resistance in several systems. The review was just published in Molecular Ecology. Here is a blogpost by Pleuni that also has videos prepared by all the authors. Check it out!

Thursday, October 22, 2015

imageEarly Embryonic Mitosis in Humans is a Mess

Deviation from the typical 46-chromosome set---a phenomenon termed aneuploidy---is a common feature of human embryonic development and is the leading cause of pregnancy loss. It has long been recognized that many aneuploidies arise during female meiosis and that these meiotic errors increase with maternal age. With the advent of preimplantation genetic screening (PGS) of in vitro fertilized embryos, it became apparent that mitotic errors are also extremely common during the initial embryonic cell divisions, which occur prior to embryonic genome activation. These mitotic errors lead to mosaicism, with different cells in the embryo having different chromosome sets.

In collaboration with the prenatal testing company Natera, we analyzed PGS data from nearly 50,000 embryo biopsies, characterizing rates and patterns of aneuploidy with unprecedented precision. We distinguished aneuploidies of meiotic and mitotic origin based on specific chromosomal signatures. While meiotic errors were elevated on particular chromosomes (16, 15, 22, 21), mitotic errors were not strongly biased in their impacts. While meiotic errors were associated with maternal (but not paternal) age, mitotic errors were frequent in embryos from patients of all ages. We contrasted results from embryo biopsies taken at day 3 (cleavage stage) and day 5 (blastocyst), finding evidence of selection against cells and embryos with drastic forms of mitotic-origin aneuploidy involving multiple chromosomes. This finding is consistent with previous studies showing that mitotic spindle abnormalities are common in cleavage stage embryos, but comparatively rare at the blastocyst stage.

Together, these results highlight the diversity of mechanisms contributing to frequent embryonic aneuploidy and the strong impact on human fertility.


Tuesday, October 6, 2015

imageWelcome Sharon!

Happy to announce that Sharon Greenblum has joined the Petrov Lab.  Sharon recently completed her PhD at the University of Washington, studying systems level properties of the human gut microbiome.  In her work, Sharon demonstrated that interactions between the microbiome and the dynamic gut environment may play a large role in shaping both global features of microbial community organization, as well as genomic adaptation within individual species. She published several high-profile papers including the 2015 paper on the extensive microbial strain-level copy number variation that was featured on the cover of Cell. The full list of papers can be found here or here. In the Petrov lab, Sharon will continue to investigate genomic responses to rapid environmental variation in a new realm, examining how fruitfly populations adapt to seasonal changes.


Monday, May 18, 2015

imageImperfect drug penetration and resistance

In viral infections with large populations of rapidly mutating pathogens—including HIV, tuberculosis, and hepatitis viruses—multidrug resistance can cause even combination drug treatment to fail. In a paper that just came out in PNAS, Stefany Moreno-Gomes, fomer postdoctoral fellow Pleuni Pennings, and coauthors present a mathematical model suggesting that part of the propblem can be a mismatch of the drug penetration profiles in the body. We show that imperfect penetration can dramatically increase the chance of treatment failure by creating regions where only one drug from a combination reaches a therapeutic concentration. The resulting single-drug compartments allow the pathogen to evolve resistance to each drug sequentially, rapidly causing multidrug resistance. More broadly, our model provides a quantitative framework for reasoning about trade-offs between aggressive and moderate drug therapies.

Pleuni put together a wonderful video abstract. Check it out!

Tuesday, May 5, 2015

imageStaggered selective sweeps

Recessive deleterious mutations have fitness effects which are hidden in individuals containing only one copy (i.e. heterozygotes); however individuals containing two copies (i.e. homozygotes) suffer negative effects. This class of mutation is responsible for a number of human genetic disorders, including cystic fibrosis, Tay-Sachs, and albinism, in addition to causing the widespread phenomenon of inbreeding depression. Furthermore, data suggest that recessive deleterious mutations, often of moderate to strong effects, are abundant in natural populations of sexually reproducing diploids, likely due to their ability to persist for long timescales at moderate frequencies. Given these data, it is thus possible that when an adaptive mutation occurs it may land on a chromosome containing a recessive deleterious mutation.

In the paper that just came out in PNAS, graduate student Zoe Assaf and a postdoctoral fellow Jamie Blundell develop a model for the dynamics of adaptive mutations which land on a chromosome containing a more strongly deleterious, yet recessive, allele. In this case the dynamics of adaptation are qualitatively changed, and the beneficial mutation can be trapped in a temporary balanced state, which we term a ‘staggered sweep’. We find that recessive deleterious alleles cause a substantial reduction in the fixation probability of linked beneficial mutations, an effect which can extend for vast genomic distances around the deleterious mutation. This suppression of adaptation becomes particularly dramatic in small populations, at short recombination distances, and when the adaptive mutation is much weaker in homozygotes than the deleterious mutation. Our model predicts patterns of evolution commonly seen in data: apparent heterozygote advantage, in which beneficial alleles reach intermediate frequencies but never go to fixation. This is a behavior which has been seen repeatedly in experimental evolutions of sexually-reproducing diploid populations. Staggered sweeps may also be contributing to the commonly observed genomic signatures of partial and soft selective sweeps, due to the necessary generation of alternative haplotypes in order for the adaptive mutation to reach fixation. Given current estimates for the prevalence of recessive deleterious variation in natural populations, we argue that these effects can be significant for organisms like humans and Drosophila melanogaster, potentially affecting anywhere between 3 and 30% of new adaptive events in the human genome.


Friday, May 1, 2015

imageCongratulations to Chris McFarland!

We are delighted to announce that a postdoctoral fellow in the lab, Chris McFarland, has just been awarded a 2-year Cancer Systems Biology Scholars Fellowship at Stanford. He will be co-mentored by Monte Winslow to study the dynamics of lung tumor progression and to investigate how newly-implicated cancer-causing genes, identified by recent genomic screens, impact tumor growth. The project is an exciting confluence of modern genetic engineering, genomics, and evolutionary modeling. Congratulations!!

Monday, April 20, 2015

imageCongratulations Professor Bergland!

We are delighted to announce that Postdoctoral Fellow in the lab, Alan Bergland, just accepted an Assistant Professor position at the Department of Biology at UVA. This is a really stellar department with a great strength in evolutionary ecology and the study of phenotypic evolution in the wild. Alan should fit in beautifully. Thank you for amazing 5 years and we all wish Alan the best of luck in this new adventure!

Friday, April 10, 2015

imageWhat drives such a high rate of aneuploidy in humans?

Errors occurring during egg formation and embryonic cell division often result in aneuploidy—extra or missing chromosomes compared to the typical 46-chromosome complement. It is estimated that 75% of human embryos are at least partially aneuploid by day 3 of development. The vast majority of aneuploid embryos do not survive to term, and most are lost before pregnancy is even detected. Rare exceptions include trisomy 21 (Down syndrome) and Trisomy 18 (Edwards syndrome). The propensity to produce aneuploid embryos increases with maternal age, but also varies substantially among mothers of the same age. We hypothesized that variation in maternal gene products, which control the initial embryonic cell divisions, may help explain variation in aneuploidy rates.

In collaboration with the prenatal genetic testing company, Natera, Rajiv Mccoy and collaborators performed a genome-wide association study of human aneuploidy risk. The paper describing this work was just published in Science. We identified a maternal genetic variant strongly associated with putative mitotic-origin aneuploidy in day-3 blastomere biopsies of in vitro fertilized embryos. The variant is extremely common, present at frequencies of 20-45% in diverse human populations. The associated region contains the gene Polo-like kinase 4 (PLK4), a strong causal candidate given its well-characterized role in the centriole duplication cycle. The region also displays an intriguing signature of a potential selective sweep in ancient humans. You can find the paper online at the Science website.

A Perspective article by Samuel Vohr and Ed Green was published in the same issue of Science. This article provides a nice summary of our study and interesting commentary on the implications of the findings. Rajiv and Dmitri also wrote a summary of the work for The Conversation.

(The image above showing anaphase lag, the key process undergirding the high rate of mitotic error in the first human embryonic divisions, is courtesy of Angelika Amon's lab at MIT).

Wednesday, March 18, 2015

imageBarcoding Evolution.

Evolution is at the centre of many diseases which are hard to treat such as bacterial infections and cancer. These diseases are often characterized by large numbers of cells which divide rapidly, enabling many cells to accumulate mutations. Some of these mutations are “beneficial” enabling cells to evade drug treatment. These rogue cells are what makes the diseases hard to treat. Understanding how these cells arise and spread would profoundly affect our understanding of these diseases but observing this process in a real experiment has been near impossible as the tools and technologies have been lacking.

In a paper published in Nature in March 2015, Sasha Levy and Jamie Blundell (co-first authors on the paper) together with Sandeep Venkataram, Dmitri, Daniel Fisher and Gavin Sherlock describe the application of a novel technology that uses DNA “barcodes” to watch the evolution of large cell populations as it happens. The DNA “barcode” acts like a family name: daughter cells inherit the name from their mothers and by sequencing just the DNA barcode a “census” of the family names can be taken at various times over the evolution. By leveraging next generation sequencing technology and by using randomly generated barcodes the system can simultaneously track the abundance of ~500,000 families each of which started out with ~100 member cells.

Over time most of the families of cells crashed out of the population to extinction, but a small fraction of families — about 25,000 of them — acquired beneficial mutations that enabled them expand and to persist in the population for hundreds of generations. The expansion of these families could be tracked with exquisite precision. The re-measurement of the expansion rate, or fitness, of some of the adaptive mutations found that the measurements inferred using this novel technology agreed well with more traditional techniques: a crucial proof of principle opening up the technology to other interesting problems.

What was surprising in this first experiment was the sheer number of families that expanded. Beneficial mutations occurred far quicker and on a larger scale than anyone had anticipated. One consequence of this was that the evolution across difference “runs” of the experiment were almost exactly the same for the first ~100 generations meaning that evolution in these systems is, for a period of time at least, far more predictable than one would expect. The technology to track hundreds of thousands of competing lineages promises to have wide applications to the study of disease. One possible avenue being explored is to insert barcodes into tumors, which would enable researchers to better understand cancer progression.

Check out the Nature News and Views article by David Gresham and the Science Friday appearance by Gavin Sherlock.

Monday, March 16, 2015

imageSelection on noise. Beautiful paper from Dave Yuan's thesis in the Witkopp lab.

We typically think of the components for evolution as genetic variation generated by the mutational process, the resultant phenotypic variation, and selection in the environment acting on that phenotypic variation. And, of course, drift. When we observe genetic polymorphisms then, we can infer whether they resulted from selection by comparing them to a neutral expectation independent of selection. But what if the path between the mutational process and phenotypic variation is skewed? If the mutational process leads to a particular distribution of phenotypes, this could provide an unexpected mechanism underlying sequence evolution.

Indeed, this is what a current postdoctoral fellow in the lab Dave Yuan and his colleagues in the Patricia Witkopp lab (Dave and Brian Metzger are the co-first authors) describe in a paper that just came out in Nature. The authors investigated the origin of certain sequence polymorphisms in wild yeast. The sequence is the regulatory region of a gene involved in glycolysis: TDH3. Detecting selection in regulatory sequences can be difficult, as there is not yet a “neutral model of regulatory evolution.” They thus created an empirical neutral expectation using systematic de novo mutations in the TDH3 promoter. When they compared the phenotypic variation—expression measured using a fluorescent reporter—of the polymorphisms against that of the neutral expectation, they found signal of selection acting not on expression level but on expression noise, or variation in expression level among genetically identical individuals.

This may seem puzzling, but the distributions of mutational effects for expression level and noise shed some light. While most de novo mutations tested had similar likelihood of increasing or decreasing expression level, most of them increased expression noise and with much larger effect sizes relative to those for expression level. Thus, it is not that expression level is less important than noise for fitness, but that the mutational process creates bigger phenotypic targets with expression noise for selection to act on. This study shows how the mutational process may be biased in the phenotypic variation it generates and, in turn, influence evolution of regulatory sequences.

Dave also wrote a really nice blog entry about it. Check it out!

Monday, March 9, 2015

imageCongratulations Dr. Garud!

We are very happy to report that Dr. Nandita Garud just defended her really beautiful Ph.D. dissertation with flying colors! Much of her work focused on the identification of hard and soft sweeps in genomic data. The main paper was just published in PLOS Genetics and at least two more are on the way. Predictably a celebration ensued: see photos here and here! Congratulations!!! Nandita is planning on a postdoc with Katherine Pollard at the UCSF. We will miss you.


Monday, December 22, 2014

imageCongratulations Meike!

Postdoc Meike Wittmann in the lab has just been granted a post-doctoral fellowship from the German Research Foundation. Together with Joachim Hermisson at the University of Vienna and with Dmitri, she will be studying and comparing the genetic footprints of various ecological mechanisms giving rise to long-term balancing selection. Congratulations!!


Thursday, November 20, 2014

imageAdaptation by natural selection from Spring to Fall

Organisms living in temperate environments are exposed to highly variable selection pressures between seasons. Some species are able to exploit the favorable season (summer) and avoid the unfavorable season (winter) by migrating or entering a facultative hibernation/diapause state. In many cases - such as for temperate endemic species - every individual in a population is capable of exploiting the favorable season and avoiding the unfavorable season to roughly the same degree. In other species, such as Drosophila melanogaster, there is genetic variation in the ability to exploit and avoid alternate seasons. If there is a negative genetic correlation between performance in summer and winter, genetic variation in traits that contribute to fitness in these alternate seasons will be maintained. In such a scenario populations will likely adaptively evolve in a cyclic fashion over the course of the year in response to seasonal fluctuations in selection pressures. A recent study published in PLoS Genetics by a post-doc in the lab, Alan Bergland, in collaboration with Emily Behrman, Katherine O’Brien, and Paul Schmidt at U Penn provides genome-wide support for the model that adaptive oscillations occur in response to seasonal fluctuations in selection pressure.

Using pooled resequencing, we estimated allele frequencies genome-wide from populations of flies sampled in the spring and fall over the course of three years from a temperate orchard in Pennsylvania. We identified hundreds of polymorphisms with dramatic and repeatable oscillations in allele frequencies between seasons. On average, these alleles shift between 40- and 60%, corresponding to a selection coefficient of >10%/locus/generation (assuming 10 generations per season). We demonstrate that these alleles are old, balanced polymorphisms that are associated with stress tolerance traits and vary in predictable ways in response to accute and persistent differences in climate within and among populations.

This work highlights the role of environmental heterogeneity in the maintenance of fitness related genetic variation and demonstrates that it is possible to watch adaptive evolution proceed in the wild. We are extending this work by resolving the functional effects of adaptively oscillating polymorphisms and by examining adaptation to seasonal fluctuations in selection pressure in other temperate populations.


Wednesday, November 19, 2014

imageEvolution of a simple pathway is not so simple

An increasing body of literature indicates that "system-level" properties emerging from the interactions of gene products may influence the ability of component genes to evolve. Metabolic pathways display such system-level properties since their output is a function of all of the kinetics of component enzymes. In the paper that is coming out in Evolution, recently matriculated graduate student in the lab Diamantis Sellis and a collaborator Mark Longo from Ward Watt's lab combine two complementary models from population genetics and enzyme kinetics to explore genetic variation as a function of an enzyme's position in a simple linear pathway. They specifically focused on testing seemingly straightforward prediction that the genes encoding upstream versus downstream enzymes should display stronger evolutionary constraint and exhibit less variation. Intriguingly, empirical tests of these prediuctions have produced varied results. Using their model, Diamantis and Mark were able to qualitatively reproduce empirically observed patterns of polymorphism and divergence and suggest that expectations should vary depending on the evolutionary trajectory of a population. During initial stages of adaptation after an environmental change, upstream genes should be initially more polymorphic and diverge faster, while they expect to see the opposite trend as the population approaches its fitness optimum. In many ways these results harken back to Orr results using Fisher's geometric model in which he predicted the early steps in adaptation are expected to be large; in Sellis&Longo the early genes in the pathway represent places where large step adaptive mutations are more likely and thus expected to happen more often. However, eventualy the fine-tuning takes place in the downstream genes because it requires smaller effect adaptive events. Finally, we end up at mutation-selection balance with more variation in the downstream genes.

Tuesday, October 14, 2014

imageHardening of soft sweeps by bottlenecks

When beneficial mutations at a certain gene occur in more than one individual in the population, it is possible that more than one independent copy of the beneficial mutation will eventually rise in frequency and sweep through the population. Such soft selective sweeps are becoming an increasingly important model of adaptation as they have been observed in many case studies of rapid adaptation (Messer and Petrov, 2013). Theory predicts that soft sweeps should be observable when one or more beneficial mutations enter the population per generation, such as should be the case in large populations or when the rate of adaptive mutation at a locus is very high. Interestingly this prediction should hold independently of the magnitude of the selective benefit of adaptive mutations.

One important caveat to these theoretical predictions is that they were made in models that assumed that populations were constant in size. In natural populations, population size can fluctuate many orders of magnitude over often very short timescales e.g. during pathogen transmission bottlenecks or during natural population cycles over a season. Until now it was not clear how such rapid and sharp fluctuations in population size interact with the simultaneous increase in frequency of multiple adaptive mutations. In a paper just published in Genetics, graduate student Ben Wilson, Dmitri, and former postdoctoral fellow Philipp Messer, derive how the probability of observing soft sweeps changes in populations of varying size.

We show that populations busts can harden soft sweeps, by eliminating all but one sweeping allele. The key consequence of this hardening phenomenon is that stronger adaptations which sweep through the population faster are more likely to give rise to soft sweeps because they can sweep before the population size crashes. We also provided a mathematical framework for predicting the likelihood of soft sweeps in populations of varying size.

Our results show the importance of understanding recent demographic histories because they will impact the process of adaptation and the signatures left behind in the genome. Our results also highlight the importance of using methods that are able to detect both hard and soft sweeps in genome scans of population samples, as some of the strongest recent adaptations may be missed if the methods used are only able to detect hard sweeps.


Monday, September 29, 2014

imageWelcome Kerry!

The Petrov lab is delighted to announce that Dr. Kerry Geiler-Samerotte from Mark Siegal's group in NYU will be visiting our lab for the 2014/2015 year. One of Kerry's latest projects in NY investigated whether HSP90, a protein-folding chaperone, buffers the phenotypic effects of new mutations. Kerry will continue this research in collaboration with the Petrov lab by using experimental evolution in yeast to study how the interaction between protein-folding chaperones and new mutations influences evolutionary trajectories. Prior to her postdoc at NYU, Kerry received her PhD at Harvard University where she studied the cost of protein misfolding and the proteomic response to mild protein-folding perturbations. Welcome Kerry!


Monday, September 29, 2014

imageWelcome Yiwen!

Happy to announce that Yiwen Chen, 1st year graduate student in the Department of Chemical and Systems Biology, decided to be a Rotation Student in our Lab in the Fall of 14/15. She did her undergraduate work in Chemical Engineering at Purdue University and then came to Stanford to get her master’s degree. Fascinated about the beauty of biology and how elegantly the Mother Nature has engineered the complex systems of life, Yiwen subsequently joined the Department of Chemical and Systems Biology. She is interested in understanding how epigenetic changes may contribute to rapid adaptations under fluctuating environments.

Thursday, September 25, 2014

imageWelcome Emily!

We are delighted that Emily Ebel, 1st year graduate student in EcoEvo, decide to do a rotation in our lab. She is interested in applying genomic and computational approaches to broad evolutionary questions. She has previously worked on the evolution of sexual conflict, sex-specific genetic loads, and sex ratio in the Phillips lab at the University of Oregon, first as an undergraduate and later as a research technician. Emily completed an M.A. in 2014 with Sean Mullen at Boston University, where she used genomic markers in tropical butterflies to evaluate species relationships, diversification rates, and their connections to phenotypic evolution. In the Petrov lab, she will be working on quantifying migration patterns in Drosophila using alleles involved in rapid adaptation. Welcome Emily!

Thursday, September 25, 2014

imageWelcome Chris!

Happy to announce that Christopher McFarland has joined the Petrov Lab. Chris recently completed his PhD at Harvard University on "The role of deleterious passengers in cancer" under the guidance of Professor Leonid Mirny. Check out his 2013 PNAS paper on the subject. Chris was awarded a postdoctoral fellowship by the Center for Computational, Evolutionary and Human Genomics to investigate "Why evolutionary models of cancer predict fewer driver genes than observed". Welcome Chris!

Thursday, September 14, 2014

imageGenetic diversity in introduced populations with an Allee effect

For species with a so-called strong demographic Allee effect, the per-capita population growth rate is negative in small populations and then increases with population size. This can happen for example if individuals have trouble finding mating partners in sparse populations. There has been a lot of empirical and theoretical work in ecology looking at the consequences of the Allee effect for the extinction risk of endangered species and the establishment success of introduced species. Less appreciated is the fact that by influencing the population dynamics of small populations, the Allee effect should also influence the amount of genetic drift they experience, and hence levels of genetic diversity, for example in recently introduced populations.

Together with her PhD advisers Dirk Metzler and Wilfried Gabriel at the University of Munich (LMU), current Petrov lab postdoctoral CEHG fellow Meike Wittmann took a stochastic modeling approach to explore various aspects of the population genetic consequences of the Allee effect. The results just appeared in the form of two companion papers (part 1 and part 2) in the September 2014 issue of Genetics. These papers focus on populations that do not go extinct directly after their introduction but successfully reach some high population size, i.e. those populations that we would be able to see and sample in the field. One important and counter-intuitive result is that for small initial population sizes (see red dot in the plot) populations with a strong demographic Allee effect, given that they are successful in the end, often escape more rapidly from the region of small population sizes where genetic drift is strongest and maintain on average more genetic diversity than successful populations without Allee effect.


Thursday, September 4, 2014

imageAssembing genomes with synthetic long reads

Repetitive DNA sequences are ubiquitous features of genomes of species across the tree of life and can dramatically affect genome structure and function. While high-throughput sequencing approaches have revolutionized our understanding of genome evolution, sequencing technologies based on short reads (~100 bp) generally fail at reconstructing long, abundant, and/or nearly identical families of repeats. In a paper recently published in PLoS ONE, members of the Petrov lab collaborated with the developers of a novel library preparation method called Illumina TruSeq synthetic long-reads (previously Moleculo) to evaluate the utility of this technology for de novo genome assembly. This approach uses highly-parallel library preparation on barcoded 384-well plates to generate extremely accurate, long synthetic reads spanning up to 10Kbp through local sub-assemblies of standard Illumina short reads.

By applying this method to sequence and assemble the genome of the reference strain of Drosophila melanogaster, we were able to compare the assembly and the underlying synthetic long-read data by mapping back to the existing high-quality reference. This work highlighted key advantages of synthetic long-reads over traditional short read sequencing approaches, especially for the accurate reconstruction of repeats such as transposable elements. We also identified important limitations of the technology, including systematic gaps in synthetic long-read coverage in regions harboring tandem arrays of highly-identical repeats from a single family. Our work demonstrates that along with PacBio and other third generation sequencing platforms, synthetic long-read technology can improve representation of repeats in newly-sequenced genomes thereby enhancing our understanding of the strong influence of repeats on genome evolution.

Tuesday, August 14, 2014

imageThe toughest insect sports a tiny and tidy genome

In collaboration with the Kelley lab at Washington State University, Bustamante lab at Stanford, and the Denlinger lab at Ohio State University, postdoctoral fellow in the lab Anna-Sophie Fiston-Lavier (now an Assistant Professor at the University of Montpellier 2/ISEM) helped to sequence and assemble the genome of the Antarctic midge Belgica Antarctica. This midge is adapted to some of the world's harshest environment and is known to have the tiniest known insect genomes (99 Mbp). The sequencing and analysis showed that while most of the Dipteran genes are conserved in this midge, its genome lacks practically all known repetitive and transposable elements. This work was just published in Nature Communication and used the TE-detection and annotation tool T-lex2 developed in the lab.

Monday, June 16, 2014

imageCongratulations Philipp!

We are delighted to report that the Research Associate Philipp Messer has accepted an offer to be an Assistant Professor in the Department of Biological Statistics and Computational Biology at Cornell University. Philipp will continue his exceptionally productive study of rapid adaptation, combining theory, computational and empirical adat analysis. Best of luck and congratulations Prof. Messer!

Monday, June 16, 2014

imageCongratulations Pleuni!

Very happy to announce that the Research Associate Pleuni Peninngs has accepted an offer to be an Assistant Professor in the Department of Biology at SF State. Pleuni will her prolific and thorughly original work on adaptation in large populations in general and drug resistance in HIV in particular, hoping to learn what determines how easily resistance evolves in HIV in order to better stop HIV and other viral infections. Best of luck and congratulations Prof. Pennings!

Tuesday, December 3, 2013

imagePredicting evolution forward and backward

One of the ideals of science is to develop theories that can predict future events, not just explain past ones. This is particularly challenging for evolutionary biology due to the inherently random nature of the processes involved. However, instead of trying to predict a single event, one can try to predict the probability at which an event will occur given a large number of trials. This statistical approach attempts to circumvent the random nature of single events to understand the underlying processes involved.

In a paper just submitted to brand new bioRxiv, Sandeep Venkataram, Diamantis Sellis, and Dmitri formalize the terminology for two very different approaches for predicting evolutionary trajectories of adapting populations. The first, which is inspired by Gould's famous thought-experiment on "replaying the tape of life", asks whether we can forecast evolution, and determine the path or the final destination of the evolutionary process from a given starting population. It is also possible, however, to ask whether we can retrocast evolution, and reconstruct the true evolutionary trajectory given the final state and possibly the ancestral state. Forward predictability analysis tries to predict the future evolutionary trajectory or future adapted state of an evolving population, while backwards predictability analysis tries to determine the likelihood of the possible alternative adaptive trajectories that lead to the observed adapted state.

There are a limited number of experiments studying both kinds of predictability, but their extremely laborious nature makes it difficult to get enough observations to make statistical generalizations. Therefore, we simulate and analyze thousands of adaptive walks using Fisher's geometric model (FGM) to study predictability. Previous work in this model from our lab (Sellis et al 2011) has shown that diploid FGM simulations often result in overdominant mutations, while haploid simulations do not. Overdominant mutations lead to stably maintained polymorphisms in the population, which are never observed in the haploid simulations. Therefore, we study the impact of ploidy on predictability.

We observe that the presence of balanced polymorphisms in diploids leads to a number of novel dynamics when studying predictability. It greatly increases the phenotypic diversity in diploid adaptive walks, leading to low forward predictability relative to haploids. We also detect mutations which are stably maintained but subsequently lost in diploid adaptive walks, and are thus hidden from sampling at the end of the simulation. We show that these hidden mutations, which also go unobserved in almost all empirical studies, strongly limit the inferences that can be made when analyzing backward predictability. Finally, we observe that when the same set of mutations is introduced into a diploid population in different orders, the final adapted allele is often balanced against different intermediate alleles, resulting in different adapted population states. Our results show the importance of considering stable polymorphisms when analyzing adaptive trajectories, and detail, for the first time, some of the limitations in conducting such analysis using empirical data. In natural population, stable polymorphisms can be generated in both haploids and diploids by a wide range of mechanisms, including niche construction, frequency dependent selection, balancing selection and spatially and temporally fluctuating selection pressures. Therefore, our results should be relevant for all natural populations, regardless of ploidy.

Sunday, November 24, 2013

imageGenomic inference of recent bottleneck works surprisingly well

Demographic events including migrations, expansions, and bottlenecks shape patterns of genomic variation within and between populations. Several methods have therefore been devised to infer demography from large-scale genomic data. However, real-life tests of these methods have been sorely lacking. The checkerspot butterfly Euphdyryas gillettii provides an opportunity to carry out such a test, given that a population of E. gillettii was intentionally introduced to Rocky Mountain Biological Laboratory in Gothic, Colorado in 1977, from a donor population in Wyoming. Our collaborator, Prof. Carol Boggs and other researchers performed nearly annual field surveys since that time, documenting wild demographic fluctuations including extreme bottlenecks of fewer than 25 adults. In a just published paper in Molecular Ecology, a graduate student in the lab Rajiv McCoy and colleagues Nandita Garud, Joanna Kelley, Carol Boggs, and Dmitri Petrov performed de novo transcriptome assembly and generated the first genomic resources for E. gillettii. We used the software package δaδi to perform demographic inference, finding that the approach accurately estimates the bottleneck timing and duration. This study also demonstrates that multiplex RNA-seq provides a reasonably cheap way to generate sufficient data to reconstruct a recent bottleneck, which is especially relevant for species of conservation concern and to obtain key genomic resources at the same time.

Friday, September 27, 2013

imagePopulation Genomics of Rapid Adaptation by Soft Selective Sweeps

Organisms can often adapt surprisingly quickly to evolutionary challenges, such as the application of pesticides or antibiotics, suggesting an abundant supply of adaptive genetic variation. In these situations, adaptation should commonly produce ‘soft’ selective sweeps, where multiple adaptive alleles sweep through the population at the same time, either because the alleles were already present as standing genetic variation or arose independently by recurrent de novo mutations. Most well-known examples of rapid molecular adaptation indeed show signatures of such soft selective sweeps. In a Trends in Ecology and Evolution article that came out today, Philipp Messer and Dmitri review the current understanding of the mechanisms that produce soft sweeps and the approaches used for their identification in population genomic data that just came out. We argue that soft sweeps might be the dominant mode of adaptation in many species and suggest that most cases of adaptation remain to be discovered.

Tuesday, September 10, 2013

imageCongratulations to Alan and Ryan!

Alan Bergland and Ryan Taylor just won prestigious research grants from the new Center of Computational, Evolutionary, and Human Genomics. Alan's grant entitled "Physiological mechanisms underlying rapid adaptive evolution" will support his efforts to characterize the physiological and hormonal state of adaptively differentiated populations of D. melanogaster collected in the spring and fall in a temperate orchard. This work will complement Alan's current research examining adaptive evolution in response to seasonal fluctuations in selection pressures. Ryan Taylor's grant "Red squirrel de novo genome assembly" will fund the generation of sequence data for a draft assembly of the red squirrel genome. Building a reference genome is a fundamental first step towards bringing the Kluane Red Squirrel Project (a model evolutionary ecology system) into the genomics era; and in doing so generate a dataset with high quality genotypic, phenotypic (including fitness), relatedness, and environmental data for thousands of individuals spanning nearly a decade.

Saturday, September 7, 2013

imageHIV drug resistance

Many of you probably know that the majority of the world's HIV patients live in poor countries, especially in southern Africa. You may not know that many of these people are now receiving very good treatment. HIV treatment almost always consists of a combination of three drugs, often in a single pill. However, treatment only works well when the virus is not resistant against the drugs used. Fortunately, there is good news about drug resistance too: HIV treatments have become better and better at slowing down the evolution of drug resistance. Thanks to the powerful drugs and close monitoring, many patients are now treated for many years without having any resistance problems. In a review paper just published in Infectious Disease Reports Pleuni Pennings describes that drug resistance is virtually solved in rich countries, but still remains a problem in poor countries. One reason for this is that poor countries often lack the possibilities to monitor the viral load of patients and to sequence the patient's virus. The review paper also describes what is known about the relevance of pre-existing mutations for the evolution of drug resistance in a patient (also known as standing genetic variation or minority variants, depending on which field you're from). Finally, Pleuni writes about pre-exposure prophylaxis (taking HIV drugs to prevent infection) and how this is related to drug resistance. Read more about this review paper at Pleuni's blog.


Tuesday, August 13, 2013

imageBacteria on flies

Although fruit flies are one of the most important model organisms in Genetics, Evolution, and Immunology, surprisingly little is known about their associated microorganisms. This is the more surprising as it is known that the microbiota can strongly affect quantitative traits in flies, for example their growth rate and cold tolerance. Furthermore, the natural environment of fruit flies - rotting fruit - is very rich in microorganisms. Because interactions with microbes are expected to be plentiful and influence phenotypes, they are most likely also subject to natural selection. Therefore, it appears mandatory for understanding the evolution of fruit flies to also better understand how they interact and coevolve with their associated microorganisms. In our paper “Host species and environmental effects on bacterial communities associated with Drosophila in the laboratory and in the natural environment" Fabian Staubach and others shed light on some of the major questions regarding Drosophila associated microbes: Beyond finding out which bacteria are present in flies, we assessed the relative roles of host species and environmental effects, detect candidate natural pathogens, and find interesting results regarding lab-of-origin-effects on the fly microbial community. These results are not only highly relevant for everyone working with Drosophila, but are also a strong reminder that we cannot understand any model organism without taking its associated microbiota into account. The paper is a fun and easy read and can be found at

Thursday, August 1, 2013

imageSLiM - fast, efficient, and flexible forward evolution simulator by Philipp Messer

Most of the current machinery of population genetics is still deeply rooted in the mindset of neutral theory, which assumes that adaptation is rare and that linkage effects from recurrent selective sweeps can thus be neglected. However, this assumption may be violated in many species. It is hence essential to verify with forward simulations under realistic scenarios of selection and linkage whether population genetics methods, and our estimates of key evolutionary parameters obtained from them, are robust to linkage effects. In a paper that just came out Genetics, Philipp Messer describe his new software tool SLiM, which can simulate hitchhiking, for the first time, on the scale of entire chromosomes and in reasonably large populations. The paper has been chosen as an issue highlight and even made it onto the journal cover!

Sunday, July 7, 2013

imagePetrov Lab is going to SMBE

This week many of us are going to SMBE in Chicago. There are 12 posters and talks from the lab - by far the most ever. So many, in fact, that we had to put together a schedule so that we do not miss each other's presentations. Check it out! Also, follow the conference on twitter using twitter handle #smbe13

Tuesday, May 21, 2013

imageSurprisingly strong selection at synonymous sites

Synonymous mutations do not alter the sequence of amino acids encoded by the gene in which they occur. Even though it is known that natural selection does act on synonymous mutations, they are generally neglected as a possible source of important functional changes because selection is believed to be either absent or at most very weak. In a paper just published in PLoS Genetics, David Lawrie, Philipp Messer, Ruth Hershberg, and Dmitri overturn this ingrained intuition and find that a substantial proportion (~22%) of synonymous mutations in D. melanogaster are very strongly deleterious. Mutations at these synonymous sites are thus disrupting some function crucial to the fitness of the fly. We were able quantify the intensity of the strong constraint and distinguish it from potential confounding factors such as mutation and linked selection. Genes enriched for synonymous sites under strong constraint are often highly expressed, operating in key developmental pathways. Interestingly, the function underlying this inferred strong constraint appears to be separate from splicing, nucleosome positioning, and even the translational optimization generating canonical codon bias. These results demonstrate that there is widespread, intense purifying selection at synonymous sites – comparable in strength with selection on non-synonymous variation with many synonymous mutations being effectively lethal over evolutionary time. This dramatically changes our understanding of the functional and evolutionary importance of synonymous sites. Given that the observed functional importance of synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated. This paper was amongst the most viewed on PLoS Genetics during June 2013.


Tuesday, May 21, 2013

imageCongratulations Anna!

Anna-Sophie Fiston-Lavier, a former Research Associate in the lab, has just accepted an offer for a tenured Assistant Professor position at the Institute of Evolution in Montpellier (ISEM). Located on the south coast of France on the Mediterranean Sea, Montpellier is the third-largest French city on the Mediterranean coast after Marseille and Nice. The city of Montpellier includes many internationally recognized research centers especially in the fields of medicine, agriculture, and environment. Anna will join the Genomic Adaptation team led by Mylene Weill in the Genome Department led by Nicolas Galtier. She will continue to study fundamental evolutionary forces and assess the impact of repetitive DNA elements on genome structure, function, and adaptation by using and developing computational tools for the analysis of next-generation sequencing (NGS) data. Congratulations Anna!!!


Wednesday, March 20, 2013

imageCongratulations Fabian!

Fabian Staubach just accepted an offer for an Assistant Professorship at the University of Freiburg in Germany's beautiful black forest. The Biology department at the University of Freiburg is supported by the German “Excellence Initiative”, a program that supports only the best Universities in the country. Fabian will have the opportunity to build his own lab group and follow his interest to deepen our understanding of the role of microbes in adaptation. Congratulations all around!

Monday, January 28, 2013

imageVIIth Semiannual Bay Area Population Genomics Conference coming to Stanford on 02/02/13

The Bay Area Population Genomics (BAPG) Conference is entering its fourth year with BAPG VII at Stanford on 02/02/13. Over 100 students, postdocs, and faculty members from around the Bay Area are coming to Stanford for this meeting. If you are interested in participating, please sign up. Registration is FREE but REQUIRED. The meeting is starting at 9 AM with coffee and features 9 short talks, catered lunch, and a poster session. All details can be found at

To receive updates about future BAPG conferences or to register to give a talk/poster please sign up at the BAPG google group.


Kirk Lohmueller, Nielsen/Lohmueller Labs, Berkeley/UCLA
Exome sequencing and heterogeneity of complex trait
Ben Callahan, Fisher Lab, Stanford
Experimental evolution of niche construction
Joshua Schraiber, Slatkin Lab, Berkeley
Theory and application of Wright-Fisher diffusion bridges
Pleuni Pennings, Petrov Lab, Stanford
Soft and hard selective sweeps in HIV
Anand Bhaskar, Song Lab, Berkeley
Exact comparison between Kingman's coalescent and discrete Wright-Fisher model for large sample sizes
Qi Zhou, Bachtrog Lab, Berkeley
Atlas of avian sex chromosome evolution
Nandita Garud, Petrov Lab, Stanford
Evidence that recent adaptation in Drosophila is primarily driven by soft sweeps
Jeremy Roop, Brem Lab, Berkeley
Rare variants drive common traits in S. paradoxus
Hunter Fraser, Fraser Lab, Stanford
Gene expression drives local adaptation in humans

Thursday, November 22, 2012

imageBacterial diversity associated with Drosophila in the laboratory and in the natural environment

Host associated bacterial communities are ubiquitous, have a variety of effects on the host phenotype and participate in host adaptations to new environments. Some clear examples of such adaptations are known but generally these are ancient associations between host and symbiont, such as the association between aphids and the obligate symbiotic bacterium Buchnera that provides the aphid with essential amino acidsor the association between bee wolfs and Streptomycesthat protects bee wolf larvae from fungal infections. We are investigating the potential of bacterial communities to underlie short-term adaptation using adaptation of D. melanogasterand D. simulans to different fruit as a study system and just published our first study in arXiv. As the first step, the postdoctoral fellow in the lab Fabian Staubach and colleagues have profiled the diversity and composition of bacterial communities associated with Drosophila across multiple species, habitats, and substrates. We amplified and sequenced a region of the bacterial ribosomal DNA from whole body fly samples using 454 technology. We mostly focused on D. melanogaster and D. simulans collected by aspiration from the same fruit in nature. We show that natural bacterial communities associated with Drosophila contain a greater variety of bacterial taxa than previously thought. We find acetic acid bacteria of the genera Acetobacter and Gluconobacter to be the dominant taxa constituting two thirds of all sequences. Acetic acid bacteria oxidize sugars and ethanol to acetic acid and are known to be directly involved in the development of a specific process of decay called 'sour rot' on grapes that causes wine spoilage. There is previous evidence that Drosophila is essential for the dispersal of acetic acid bacteria among rotting fruit: grapes covered with nets in the field do acquire yeasts, but no acetic acid bacteria and acetic acid bacteria thrive on grapes only when flies are present. At the same time, Acetobacter has been shown to promote Drosophila larval growth and shorten development time under certain nutritional conditions. It is possible that the relationship between Acetobacteraceae and Drosophila is mutualistic. We hope that our data will serve as a solid foundation for future studies especially for the growing community of scientists that are interested in the microbial communities that are associated with Drosophila.

Monday, November 12, 2012

imageLinkage estimates from pooled sequence data

Pooled sequencing of non-barcoded individuals offers researchers a quick and cheap way to gain genomic information across an entire population. Although allele frequencies can be recovered from pooled samples (see the PLoS ONE paper by Yuan Zhu et al), individual haplotype information is necessarily discarded, except on a read length scale. In a paper published in PLoS One, an incoming graduate student Alison Feder working in collabortation with Alan Bergland and Dmitri introduce the tool LDx, which combines allele frequency estimation and counts of neigboring SNPs present on the same read to produce an approximate maximum likelihood estimation for r2, thus reclaiming some of this lost linkage information. In the paper, we provide a validation of our method using the Drosophila Genome Reference Panel and investigate the program's performance using simulated pooled data at varying coverages. We go on to demonstrate that LDx's estimates of increased r2 correlate with areas of lower recombination rates, and that the tool can be used to distinguish demographic scenarios identical according to non-linkage based tests. LDx can be found here:

Thursday, November 1, 2012

imageMcDonald-Kreitman test for quantifying adaptation is generally biased under even moderate adaptation

 The McDonald-Kreitman (MK) test is the basis of most modern approaches to measure the rate of adaptation from population genomic data. This test was used to argue that in some organisms, such as Drosophila, the rate of adaptation is surprisingly high. However, the MK test, and in fact most of the current machinery of population genetics, relies on the assumption that adaptation is rare so that the effects of selective sweeps on linked variation can be neglected. In the paper posted on arXiv Philipp Messer and Dmitri test this assumption using a powerful forward simulation called SLiM that was developed by Philipp to model selection with linkage. We show that the MK test is severely biased even when the rate of adaptation is only moderate. The biases arise from the complex linkage effects between slightly deleterious and strongly advantageous mutations. In order to deal with these biases, we suggest a new robust approach (asymptotic MK test) based on a simple asymptotic extension of the MK test. We further show that already under very moderate amounts of adaptation, linkage effects from recurrent selective sweeps can profoundly affect key population genetic parameters, such as the fixation probabilities of deleterious mutations and the frequency distributions of polymorphisms. In synonymous polymorphism data, these linkage effects leave signatures that can easily be mistaken for the signatures of recent, severe population expansion. The bigger claim of our paper is that the effects of linked selection cannot be simply swept under the rug by introducing effective parameters, such as effective population size or effective strength of selection, and then using these effective parameters in formulae derived from the diffusion approximation under the assumption of free recombination. Given that most of our estimates of the key evolutionary parameters are still obtained from methods based on this paradigm, we argue that it is crucial to verify whether they are robust to linkage effects.

Monday, October 15, 2012

imagePleuni Pennings joins the Lab

We are very happy to announce that Pleuni Pennings will join our lab as a postdoc. Pleuni got her PhD from the University of Munich where she worked with Joachim Hermisson. In her Ph.D. she has written already classic papers on "soft sweeps" and in fact coined the term. She has also worked on sympatric speciation and slavemaking ants. After receing her Ph.D. Pleuni moved to Harvard where she worked with John Wakeley and also collaborated with Susanne Foitzik at the University of Munich (LMU). Pleuni now focuses on the evolution of drug resistance in HIV using genetic and epidemiological data and population genetic theory. She has analyzed the role of standing genetic variation for drug resistance in HIV (Pennings, 2012) and currently works on selective sweeps and mutation-selection balance in HIV. In the Petrov lab she will continue her work on drug resistance in HIV. Specifically, she will study selective sweeps and mutation-selection balance using time-series and deep-sequencing data from HIV in treated and untreated patients. We are very excited that she has chosen to join our lab and looking forward to collaborating!

Pleuni also makes cool videos about science. A video about her recent HIV paper can be found here, one about recent work on slavemaking ants is here and an old favorite about experimental evolution is here. The link to her website is here.

Wednesday, September 5, 2012

imageIntrogression from other subspecies contributes to adaptation in natural populations of house mice

 There is a long-standing debate about the source of adaptive genetic variation. Much of this debate focuses on whether adaptive mutations arise via de novo mutation or are recruited from standing variation. A potential role of introgression of adaptive alleles from other species or subspecies has been largely ignored. In a study published in PLoS Geneticsthis week Fabian Staubach, Anna Lorenc, Philipp W. Messer, Kun Tang, Dmitri A. Petrov, and Diethard Tautz conducted a systematic, genome wide survey for introgressed adaptive haplotypes in two subspecies of house mice. The authors indeed find large haplotype blocks that crossed the sub-species boundary between the eastern (Mus musculus musculus) and the western house mouse (Mus musculus domesticus). Many of the introgressed haplotypes are longer and at a higher frequency than expected from neutral evolutionary processes like migration or incomplete lineage sorting. Some of these long introgressed haplotypes contain intriguing genes, such as, for instance, the alpha-Amylase locus that is known to be involved in human adaptation to high starch diet. The authors find that introgression affected up to 25% of the mouse genome thereby contributing substantially to the genomic make up of natural (wild) populations of house mice.

Tuesday, July 31, 2012

imageValidation of pooled resequencing on the genome level in Drosophila

 The sequencing of pooled non-barcoded individuals is an inexpensive and efficient means of assessing genome-wide population allele frequencies, yet its accuracy has not been thoroughly tested. In a just published PLoS ONE paper by Yuan Zhu, Alan Bergland, Josefa González and Dmitri Petrov we assessed the accuracy of this approach by comparing allele frequency estimates from pooled sequencing to those of individually sequenced strains. As expected, pooled sequencing provides a faithful estimate of population allele frequency with the error well approximated by binomial sampling, and is a reliable means of novel SNP discovery with low false positive rates. However, a sufficient number of strains must be used in the pooling because variation in the amount of DNA derived from individual strains is a substantial source of noise when the number of pooled strains is low. We conclude that pooled sequencing is a very powerful and cost-effective technique for assessing of patterns of sequence variation in populations on genome-wide scales, and is applicable to any dataset where sequencing individuals or individual cells is impossible, difficult, time consuming, or expensive.


Friday, June 1, 2012

imageEstimating the strength of selection from deep sequencing data

 In a paper just published in Genetics, the postdoctoral fellow in the lab Philipp Messer and his collaborator Richard Neher develop a powerful new approach to measure the strength of positive selection using genomic data. In contrast to previous methods, which typically analyze the reduction in the levels of preexisting diversity caused by a selective sweep, this method utilizes patterns of new variation that arises from de novo mutations occurring on the sweeping haplotypes. This method requires much shorter sequences compared to the current methodology which is one of its advantages. However, because it utilizes low-frequency variants it requires much greater sequencing depth then the current methods. Provided such deep sequence data the Messer-Neher method consistently outperforms existing approaches. When applying this method to HIV populations, the authors observed several examples of strong adaptation involving both hard and soft sweeps. What's particularly nice is that this approach does not rely on recombination at all and can be used in clonal organisms. The flood of deep sequencing data forthcoming in near future will surely make this approach one of the most widely used in the field.

Saturday, December 10, 2011

imageVth Semiannual Bay Area Population Genomics Conference

The Bay Area Population Genomics (BAPG) Conference has entered its third year with BAPG V at Stanford on 12/10/11. Over 100 students, postdocs, and faculty members from around the Bay Area came to Stanford. The meeting started at 9:30AM with coffee and then featured 7 talks, catered lunch, and a poster session. You can find photos of the meeting at and Graham Coop write-up about it here. The consensus was that the conference was a resounding success with the only complaint being that the room was quite cold. On the other hand this might be why we had so few people falling asleep and so many asking such insightful and pointed questions.

To receive updates about future BAPG conferences or to register to give a talk/poster please sign up at the BAPG google group.

BAPGV Talks:

Erkan Buzbas, Rosenberg Lab, Stanford
Approximate Bayesian Computation when Simulating Data is Difficult
Michael Palmer, Feldman Lab, Stanford
Evolution Is Very Repeatable in Lattice Proteins
Jiankui He, Quake Lab, Stanford
Immune Repertoire Profiling by High-throughput Sequencing
Philipp Messer, Petrov Lab, Stanford
McDonald-Kreitman test under frequent adaptation: problems and solutions
Erik Corona, Butte Lab, Stanford
Analysis of the genetic basis of disease in the context of human migration
Matthias Steinrücken, Song Lab, Berkeley
A simple method for finding explicit analytic transition densities of diffusion processes with general diploid selection
Graham Coop, Coop Lab, UC Davis
The effect of partial sweeps on genetic diversity

BAPGV Posters:

David Enard, Petrov Lab, Stanford
Background selection hides selective sweeps in the human genome           
Melinda Yang, Slatkin Lab, Berkeley
Ancient structure or recent admixture? The doubly conditioned frequency spectrum decides           
Torsten Günther, Coop UC Davis
Finding the traces of selection in the genome of Arabidopsis thaliana
Sandra Beleza, Tang Lab, Stanford            
Genetic architecture and evolution of human pigmentation: Genome-wide association study in the admixed population of Cape Verde           
Ethan Jewett, Rosenberg Lab, Stanford
A coalescent model of genotype imputation           
Kelley Harris, Nielsen Lab, Berkeley           
Reconstructing admixture histories from long tracts of DNA sequence identity           
Benjamin Peter, Nielsen Lab, Berkeley           
Distinguishing selection from standing variation and de novo mutations.

Monday, December 5, 2011

imageBalancing selection as the natural outcome of adaptation

Balancing selection is often presented in opposition to directional selection. Indeed, balancing selection promotes maintenance of genetic variation while directional selection pushes one genetic variant at the expense of the other and removes natural selection from populations. Directional selection is expected to leave genomic signatures of allelic change that is too fast to be explained by the neutral theory while balancing selection is often detected as allelic changes that are too slow. It is thus to our great surprise that we discovered that this opposition might in fact be illusory. In a PNAS paper by Diamantis Sellis, Benjamin Callahan, Dmitri Petrov and Philipp Messer we showed that directional selection in diploids is in fact expected to generate balanced genetic variants. Both directional and balancing selection might be two sides of the same coin, both being the consequence of genetic adaptation. One way to see this is to consider that new adaptive mutations in diploids exist first as heterozygotes. Thus they need to be adaptive as heterozygotes or they would not be seen by natural selection (the so called Haldane sieve). On the other hand nothing ensures that the mutant homozygote needs to be better than the heterozygote. That is not a requirement for the invasion of the adaptive mutation. Using Fisher's phenotypic model of adaptation we showed that if one allows suficiently large mutations to occur then many adaptive mutations should show heterozygote advantage. These adaptive mutations invade the population, persist in the balanced state often for a very short period of time, and then removed due to the invasion of new adaptive mutations that are themselves often overdominant. We argue that balancing selection might be widespread, that balanced alleles do not need to be old as often presumed, and that adaptation might be a force that promotes rather than exhausts genetic variation.

To comment: go to Petrov Lab Blog

Monday, August 1, 2011

imageFaster than neutral evolution of constrained sequences

One of the key insights from the neutral theory of molecular evolution is that functional sequences should generally evolve slower than nonfunctional sequences. The reasoning is very simple - some mutations in functional sequences will damage the function, will be removed by natural selection and thus will not contribute to evolutionary change. It is true that adaptation should speed up evolution because adaptive mutations would contribute to evolution at a much higher probability than neutral ones. This insight is the basis of much of comparative genomics. Find regions that evolve slower than neutral and you find functional sequences even if you know nothing about their function. Find paterns of evolution of functional regions that are too rapid and you find adaptation. Easy. In a paper published in GBE by David Lawrie, Dmitri Petrov and Philipp Messer we show that this is not always so easy. Specifically, when mutation is strongly biased (say in favor of A and T nucleotides) and these nucleotides tend to be weakly deleterious, one can generate very fast flip-flopping between the mutationally preferred state (A and T) and selectively preferred state (G or C in this example). The rate of evolution might even exceed that expected under neutrality without any adaptation. We show that this effect might be important in comparative genomics and urge the development of comparative genomic methods that explicitly incorporate mutational biases, selective processes, and crucially their interactions. The paper has been evaluated by Faculty of 1000 ( and here is pdf).

To comment: go to Petrov Lab Blog

Monday, July 18, 2011

imageHigh rate of false positives in the estimates of positive selection due to faulty alignments

In a paper published in Genome Research, Penka Markova (who successfully graduated this year) and Dmitri, continue to shine light on the often underapprecaited step in studying natural selection in protein and DNA sequences. This step - alignment of homologous sequences - is key as it determines which positions in proteins are the "same" and thus can be meaningfully compared across species or individuals. Because it is often hard to assess the error at this step, the common practice is to accept the alignments as if they were in fact true and to investigate all other sources of possible error. Unfortunately, as this paper shows in particular, this assumption might be woefully wrong especially in the studies of positive selection. After all, we often define possible cases of positive selection by detecting patterns of evolution that are faster or different than predicted by the model of unchanging constraint. It is hard to generate a more unsual pattern than that produced by misalignments. Our paper suggests that 50-80% (!) of all cases of detected positive selection in the alighments of Drosophila proteins are due to misaligments. The problem is very severe and calls for computational and statistical solutions, manual curation of candidates, and above all caution in interpreting scans for positive selection based on massive, genome-level aligments of proteins. Our paper has been positively reviewed by Faculty of 1000 (two evaluations can be found here: and here is pdf).

To comment: go to Petrov Lab Blog

Saturday, May 21, 2011

imageIVth Semiannual Bay Area Population Genomics Conference

The schedule for BAPG IV at Berkeley is all set for Saturday, May 21, 2010. We have a great lineup of speakers from Berkeley, UCSF, UC Davis and Stanford. The meeting will start at 9AM with coffee, will feature 5 talks, a lunch (pulled pork sandwiches, burgers, vegetarian food), a poster session and a then we were all graciously invited by John Pool to come hang out in his house.

9:30 AM Peter Ralph, UC Davis, Coop Lab
Geographic patterns under models of adaptation
10:00 AM Ryan Hernandez, UCSF, Hernandez Lab
Interrogating signatures of selective sweeps
10:30 AM Paul Norman, Stanford, Parham Lab
Population-specific Evolution of Human Natural Killer Cell Diversity
11:30 AM Qi Zhou, Berkeley, Bachtrog Lab
Genomic evolution of Drosophila miranda's neo-sex chromosomes
12:00 PM Dmitri Petrov, Stanford, Petrov Lab
Heterozygote advantage as a natural consequence of adaptation in diploids

For additional information (schedule, registration, poster lineup) and the latest news go to BAPG IV. If you are planning to come PLEASE REGISTER.

Saturday, April 23, 2011

imagePopulation Genomics of Transposable Elements in Drosophila

Transposable elements (TEs) are the primary contributors to the genome bulk in many organisms and are major players in genome evolution. TEs in Drosophila melanogaster come in a large diversity of families with individual familes varying in size from a few to over a hundred copies per genome. In a paper that was just published in Molecular Biology and Evolution, we carried out the first global population genomic analysis of ~800 TEs from all of the major families (55 in total) in 75 D. melanogaster strains. We found strong evidence that TEs in Drosophila are deleterious because ectopic recombination among dispersed TE copies generates inviable gametes. We showed that strength of this selection varies predictably with recombination rate, length of individual TEs, and copy number and length of other TEs in the same family. These rules do not appear to vary across orders, suggesting that selection based on ectopic recombination is a universal force preventing the uncontrolled spread of TEs in the Drosophila genome. Consistently with this notion we were able to build a statistical model that considered only individual TE-level (such as the TE length) and family-level properties (such as the copy number) and explained more than 40% of the variation in TE frequencies.

To comment: go to Petrov Lab Blog

Saturday, April 9, 2011

imageRuth Hershberg accepts a tenure track faculty position offer from Technion

We are very happy to announce that Ruth Hershberg has just accepted a tenure track position at the Ruth & Bruce Rappaport Faculty of Medicine at the Technion (Israel Institute of Technology). Ruth will establish an interdisciplinary lab, combining evolutionary theory, bioinformatics, computational and experimental genomics, and microbiology. She will continue studying the most fundamental driving forces in evolution: mutation and natural selection, and elucidating how each of these process shapes microbial genomic variation. More specifically Ruth will pursue the following topics: (i) Elucidating variation in the efficacy with which natural selection acts on different bacteria, and understanding the consequences of such variation on the evolution of bacterial genomes, (ii) Studying variation in mutational patterns across bacteria, (iii) Quantifying changes in mutational rates and patterns in response to stress, (iv) Understanding the evolutionary processes that drive codon usage bias, (v) The bacterial species concept.

The Technion is one of Israel’s top Universities, and provides some of the best research resources available in Israel. Ruth has been a star in the lab, publishing several beautiful papers, showing: (i) how the identity of optimal codons is chosen in evolution, (ii) that mutation is universally biased towards AT in bacteria and that variable genomic GC content is likely driven by natural selection, (iii) that the reduced selection on M. tuberculosis leads to high functional diversity, and (iv) that the reduced selection on Shigella led to a loss of many genes. We will miss her very much and hope to collaborate with her in the future. Anyone interested in joining Ruth’s lab, as either a postdoc, graduate or undergraduate student, or in collaborating with Ruth in any other way should contact her at

Thursday, April 7, 2011

imageFelicia King wins the Woods Institute Fellowship

Felicia King, an undergraduate who joined the lab this Fall, was awarded a prestigious UIRP fellowship from the Woods Institute at Stanford to study adaptation of the tropical Drosophila to the cold of the temperate winter. To test for local adaptation Felicia, under the guidance of Alan Bergland, will assay genetic markers and traits known to vary across broad latitudinal clines in new collections of Drosophila she will make through the growing season and along altitudinal gradients in Northern California. Specifically she will be establishing collection sites along the elevational gradients in California this summer and will continue sampling all through the summer and fall. The focus of this work is on the adaptations that allow originally tropical Drosophila melanogaster and simulans to survive through the winter cold of temperate areas.

Saturday, March 26, 2011

imageT-lex: automatic assessment of the presence of individual transposable elements using next generation sequence data

Anna-Sophie Fiston-Lavier and Josefa González (with the participation of a summer student Matthew Carrigan and Dmitri) have just published a very powerful and easy to use tool for the assessment of presence/absence of known TEs in the new resequenced genomes. The paper was published in Nucleic Acids Research (with the open access option) and we hope that people will find it helpful. This tool, which we called T-lex (T for transposable element and -lex for Solexa), obviates the need to run thousands of PCR in order to study population genetics of TEs and, more specifically for us, to find TEs that are likely to be adaptive. Anna-Sophie is working now on a new module for this program that would also allow us to detect new TE insertions in the nextgen data. Together these two programs (in conjunction with several other similar programs that are becoming available now) will revolutionize the TE research for us. To read more about T-lex or to use it please go to Note that you can run T-lex (or other scripts) on a cloud using the next-generation cloud service. We are in the process of creating the T-lex ScaleGenomics app so that you can run T-lex without any installation hassles.

Please give us feedback about T-lex by leaving comments on our Lab Blog!

Wednesday, February 23, 2011

imageAlan Bergland wins prestigious NIH postdoctoral fellowship

Alan Bergland was just awarded an NIH NRSA postdoctoral fellowship to study the evolution of Drosophila melanogaster in temperate climates. The experiments outlined in his proposal will use whole genome resequencing of populations of flies collected along latitudinal clines and through the growing season. These data will allow him to test hypotheses about the demographic consequences of seasonal population booms and busts. He will also be able to use these data to identify alleles that show both latitudinal and seasonal variation; these spatially and temporally balanced polymorphisms are likely to directly underlie adaptation to temperate environments. 
This fellowship will give Alan the opportunity to learn population genomics and will complement his graduate studies on evolutionary quantitative genetics of life history traits. The project is going to be done in collaboration with Prof. Paul Schmidt (U. Penn) - the premier scholar in Drosophila evolutionary biology and genetics of adaptation to temperate climates.

To comment: go to Petrov Lab Blog

Tuesday, December 7, 2010

image3rd Semiannual Bay Area Population Genomics Conference

The schedule for BAPG III at Stanford is all set for Saturday, December 11, 2010. This time and hopefully in the future BAPG is sponsored by the Ecology and Evolution Group at the Stanford Biology Department. We have an exceptional lineup of speakers from Berkeley, UC Santa Cruz and Stanford. The meeting will start at 9AM with coffee and will end with a lunch and a poster session.

9:30 AM Rachel Brem, UC Berkeley
Pathway evolution in Saccharomyces
10:00 AM Dario Valenzano, Stanford
Genetic architecture of longevity in the short-lived fish Noth

obranchius furzeri
10:30 AM Paul Jenkins, UC Berkeley
A new approach to computing likelihoods in population genetics models with recombination
11:30 AM Jared Wenger, Stanford
Adaptive mutations effect minimal trade-offs across the yeast adaptive landscape
12:00 PM Ed Green, UC Santa Cruz
Recent human evolution as revealed by ancient hominin genome sequences

For additional information (schedule, parking, registration, poster lineup), the latest news and the videos of the presentations after the conference please go to

To comment: go to Petrov Lab Blog

Wednesday, December 1, 2010

Broker Genes in Human Disease

Genes that underlie human disease are important subjects of systems biology research. In a paper just published in GBE by James Cai, Elhanan Borenstein and Dmitri, we demonstrated that Mendelian and complex disease genes have distinct and consistent protein–protein interaction (PPI) properties. Disease genes have unusually high degree (number of connections to other proteins) and low clustering coefficients (their neighbor proteins tend not to be connected). We describe such genes as brokers in that they connect many proteins that would not be connected otherwise. In contrast, disease genes identified in genome-wide association study (GWAS) do not have these broker properties. We suggest that the mapping of the GWAS-identified SNPs onto the genes underlying disease is highly error prone. This research can be used to help improve this mapping and prioritize the identification of disease genes in GWAS studies.

To comment: go to Petrov Lab Blog

Monday, September 6, 2010

Universal AT bias in mutation

Natural selection sorts through the variability generated by mutation and biases evolution toward fitter outcomes. Mutation, while generally agnostic to fitness can also bias evolutionary outcomes because certain types of mutations occur more frequently than others. For instance, it was generally assumed that the extreme variation observed in nucleotide content among bacteria (from ~20% to ~80% GC) is predominantly driven by extreme differences in mutational biases between different bacterial lineages. Under such an assumption, mutation would have to be strongly AT-biased in some lineages and strongly GC-biased in others. In sexually reproducing organisms mutational biases can be investigated by examining low frequency polymorphisms. In bacteria, however, this has not been possible because the concepts of species and polymorphism are ill-defined. In a paper recently published in PLoS Genetics, Ruth Hershberg and Dmitri Petrov demonstrated that bacterial lineages that recently developed clonal, pathogenic lifestyles evolve under extremely relaxed selection, and are uniquely suitable for the study of bacterial mutational biases.  We analyzed large sequence datasets from five clonal pathogens in four diverse bacterial clades spanning most of the range of genomic nucleotide content. Contrary to expectations we found that mutation is AT-biased in every case to a very similar degree. Furthermore in each case mutation is dominated by transitions from C/G to T/A. These findings demonstrate that mutational biases are far les variable than previously assumed and that variation in bacterial nucleotide content is not due entirely to mutational biases. Rather natural selection or a selection like process such as biased gene conversion must strongly affect nucleotide content in bacteria. A paper by Hildebrand and colleagues published back-to-back to ours in the same issue of PLoS Genetics reached similar conclusions: Evidence of Selection upon Genomic GC-Content in Bacteria. PLoS Genetics also published a commentary on this work by Eduardo Rocha and Edward Feil: Mutational Patterns Cannot Explain Genome Composition: Are There Any Neutral Sites in the Genomes of Bacteria?

To comment: go to Petrov Lab Blog

Friday, August 20, 2010

imagePhysics of Evolution

Dmitri is going to present two lectures at the "Physics of Evolution" workshop at UC San Diego at the end of this month. The workshop is dedicated to the applications of statistical physics to quantification of evolutionary process. The organizers say that:"This summer school will introduce graduate students and postdoctoral researchers in the fields of biological physics, statistical mechanics and non-equilibrium processes to the opportunities and challenges present in the area of Darwinian evolutionary dynamics. These have been enabled by sequencing technology advances, a new generation of quantitative laboratory-scale experiments, and new concepts in theoretical approaches to complex systems. Topics to be covered include: modern genomics tools, microorganism experiments, mutation-selection theory, the role of recombination and horizontal gene transfer, and applications to both the immune system and to infectious disease". Dmitri will talk about two papers: (1) one about our recent finding that Drosophila appears to have such large effective population sizes that adaptation is not limited by mutation and (ii) one on the recent work of a postdoc in the lab, Ruth Hershberg, that mutation appears to be always biased towrads A's and T's across all bacteria potentially implying that GC-rich bacterial genomes are under selection to be GC rich. The paper about Ruth's work is about to come out in PloS Genetics.

To comment: go to Petrov Lab Blog

Tuesday, July 26, 2010

imageJames Cai is a new Assistant Professor at Texas A&M!

We are very happy to announce that James Cai, a postdoctoral fellow in the lab, has accepted an offer for a tenure-track Assistant Professor position at Texas A&M University, Department of Veterinary Integrative Biosciences. He will be moving in September and is already starting to build a computational genomics laboratory there. (See the ad for a postdoctoral position in James's new lab.) His group will focus on computational research in population genomics and molecular evolution, applying population genetic theory to modern biological data and developing statistical tests and computational tools to investigate evolutionary processes shaping genome variability patterns within and between species. James joined our lab in 2006 after the completion of his Ph.D. at the University of Hong Kong. Viola Luo, James's wife pictured above, moved from Hong Kong to the Bay Area and joined James at Stanford in 2007, where she started her career in regulatory affairs of clinical trials at Stanford Cancer Center. In our lab, James focused on understanding how positive selection shapes patterns of polymorphism in the human genome and published a key paper that showed for the first time that positive selection is indeed pervasive in the human genome and does leave the expected signatures in the patterns of polymorphism. See the description of this research in Stanford Daily. James was also interested how the timing of the gene's entry into the genome (gene age) interacts with the gene's importance to the functioning of the organism and the way natural selection shapes its evolution. He published a series of papers on this topic as well. Finally, James is famous for creating a set of Matlab based toolkits for population genetics and molecular evolution. We are all extremely proud of James and wish him the best of luck in his brilliant young career!

To comment: go to Petrov Lab Blog

Tuesday, July 13, 2010

imageEvery mutation, at every site, at any given time

Adaptation in eukaryotes is often assumed to be limited by the waiting time for adaptive mutations. This is because effective population sizes are believed to be relatively small, typically on the order of only a few million reproducing individuals or less. It should therefore take hundreds or even thousands of generations until a particular new mutation emerges. However, several striking examples of rapid adaptation appear inconsistent with this view. In a paper just published by PloS Genetics, we (co-first authors Talia Karasov and Philipp Messer, and Dmitri) investigate a showpiece case for rapid adaptation, the evolution of pesticide resistance in the classical genetic organism Drosophila melanogaster. Our analysis reveals distinct population genetic signatures of this adaptation that can only be explained if the number of reproducing flies is, in fact, more than 100-fold larger than commonly believed. We argue that the old estimates, based on standing levels of neutral genetic variation, are misleading in the case of rapid adaptation because levels of standing variation are strongly affected by infrequent population crashes or adaptations taking place in the vicinity of neutral sites. We suggest that much of the time adaptation in Drosophila takes place in populations that are much larger that a billion meaning that every single-step mutation at every site exists in the population at every given time. This means that soft sweeps should be very common and that complex, multi-step adaptations should fix all at once without intermediate fixations of single-step mutations. We also argue that adaptation should be not mutation-limited in all species with population sizes that exceed a billion (roughly the inverse of mutation rate per site), which is the case for many insects and most marine invertebrates. Nick Barton wrote a great perspective article and the work was also highlighted in Nature Review Genetics and Faculty of 1000. It is currently in the top 10 most viewed artciles on Faculty of 1000 and in PLoS Genetics.

To comment: go to Petrov Lab Blog

Sunday, April 25, 2010

imageNadia Singh is the newest Assistant Professor in the Genetics Department at NC State

Nadia Singh, a former PhD student in the lab, has accepted an Assistant Professor position in the Genetics Department at the North Carolina State University. Nadia received her PhD from Stanford in 2006, and went on to a postdoctoral position at Cornell University in the labs of Andy Clark and Chip Aquadro. Nadia will begin her new position at NCSU in the Fall of 2010. NCSU has a wonderfully rich community with a strong emphasis on molecular, quantitative, developmental, computational, and statistical genetics, and Nadia is looking forward to continuing her work on mutation and recombination rate variation in Drosophila in this new and interactive environment. Nadia is the first lab graduate student to start her own lab. We are all extremely proud and wish Nadia the best of luck!

Friday, April 9, 2010

imageAdaptation to temperate climates in Drosophila

The potential of geographic studies of genetic variation for the understanding of adaptation has been recognized for some time. In Drosophila, most of the available studies are based on a priori candidates giving a biased picture of the genes and traits under spatially varying selection. In a paper just published in PLoS Genetics and led by Josefa Gonzalez, we performed a genome-wide scan of adaptations to temperate climates associated with Transposable Element (TE) insertions. We integrated the available information of the identified TEs and their nearby genes to provide plausible hypotheses about the phenotypic consequences of these insertions. Considering the diversity of these TEs and the variety of genes into which they are inserted, it is surprising that their adaptive effects are consistently related to temperate climate-related factors. The TEs identified in this work add substantially to the markers available to monitor the impact of climate change on populations.

Monday, March 1, 2010

imagePhilip Bulterys is accepted to UCLA MD/PhD program!

Philip Bulterys, a fourth-year undergraduate in the lab, was just accepted into the extremely prestigious UCLA MD/PhD program (MSTP). Philip grew up in pre-genocide Rwanda and attended high school in Lusaka, Zambia. His parents are both medical epidemiologists and Philip became interested in public health at an early age. As a high school student he volunteered in the malnutrition ward of the University Teaching Hospital, initiated a street-kids project with friends, and conducted a microbial water quality study to look for fecal coliforms in a local community’s drinking water. He has also participated in the emergency response to the HIV epidemic - the response partly led by Philip's parents. He is firmly and passionately committed to public health and understanding, preventing, and curing infectious disease. Philip is currently working on an HIV evolution project and hopes to continue studying the evolution and transmission of infectious diseases throughout his training and career. We are all extremely proud and extend our congratulations for an honor and an opportunity that is so richly deserved.

Monday, February 17, 2010

imageFabian Staubach is joining our lab in May 2010!

Fabian Staubach from the Max Planck Institute for Evolutionary Biology is joining our lab in May 2010! During his Ph.D. research he worked on the evolution of gene expression in natural populations of house mice (Mus musculus) and found a de novo originated gene in the mouse lineage. Currently he is finishing his work on a 600k mouse genotyping array applied to natural populations and a metagenomics 454 sequencing project on the gut flora of mice. For his research he applied and developed a variety of molecular biology, statistical, and bioinformatics tools to shed light on transcriptional evolution, mouse population genetics and the evolution of new genes. Fabian will work on natural selection and adaptation in Drosophila.

For more information please go to:

Monday, February 1, 2010

imageSecond Bay Area Population Genomics Conference

On the heels of the success of the first Bay Area Population Genomics Conference at Stanford in the Fall 0f 2009 we are planning the second BAPG Conference at Berkeley on March the 13th. The labs of Doris Bachtrog, Michael Eisen, and Rasmus Nielsen are going to take the lead in organizing. Students and faculty from Stanford, Berkeley, UCSF, and UC Davis will be represented. If you want to receive updated news about the BAPG conference please join

The PI's should also join:

NB: There are rumors that Doris Bachtrog will cook homemade sausage for all!

Wednesday, January 13, 2010

imageAlan Bergland is joining the lab

We are excited that Alan Bergland from Brown University has decided to join our lab! Alan is currently finishing up his Ph.D. research ( which focused on understanding the interplay between environmental variation and both long- and short-term evolutionary processes. Specifically he studied the relationship between larval nutrition and adult fecundity in Drosophila melanogaster. This research used an impressive array of tools and concepts from evolutionary demography, ecology, molecular and quantitative genetics, and physiology to investigate how life history plasticity evolves in natural populations. Alan will arrive in September 2010 and will focus on the population and molecular genetics of local adaptation in Drosophila.

Monday, October 26, 2009

imageFirst Bay Area Population Genomics Conference

We just hosted the first Bay Area Population Genomics Conference at Stanford. Students and faculty from Stanford, Berkeley, UCSF, and UC Davis were represented. We met at 9AM for breakfast, heard 5 great talks from 10AM to 2PM, had lunch and talked about posters. The turnout, the talks, and the conversations were great. By all accounts it was a great success. We hope to have BAPG conferences take place every quarter. The next BAPG conference is likely to take place at Berkeley in the Winter Quarter with Michael Eisen and Rasmus Nielsen's groups taking the lead in organizing it. If you want to receive news about the BAPG conference please join

Talks: Graham Coop, UC Davis, Graham Coop Lab, "Meiotic
recombination hotspots in humans and mice

Dan Kvitek, Stanford, Gavin Sherlock Lab, "Molecular
characterization of the fitness landscape in asexually evolving
populations of Saccharomyces cerevisiae

David Goode, Stanford, Arend Sidow Lab, "Evolutionary
constraint facilitates interpretation of genetic variation in
resequenced human genomes

Qi Zhou, Berkeley, Doris Bachtrog Lab, "Deciphering neo-sex
and B chromosome evolution by the complete genome of Drosophila

Hunter Fraser, Stanford, Hunter Fraser Lab,
"Widespread adaptive evolution of gene expression in budding yeast"

Wednesday, October 7, 2009

imageGraduate School Applications are due December 1, 2009

If you are intetested in joining our lab as a graduate student, the deadline for applications is December 1. The Graduate Bioscience Admissions program coordinates all graduate admissions in the biological sciences at Stanford. Please consult their website for the current application procedures. Don't be scared off by the fact that the site is located in the medical school domain. It is this way for bureaucratic reasons only. It is essential that you list Dmitri as a potential advisor on your application form if you are interested in joining our lab and also to mark the Department of Biology and choose "evolution and ecology" as your interest within that. This will ensure that Dmitri will see your application. Also contact Dmitri ahead of time ( - and he will also help you with the admissions process. In general, it is a realy good idea to contact your potential advisors if you want to be successful in the admissions process. Departmental funding for graduate study at Stanford is limited. It is important to apply for an NSF Graduate Fellowship and any other sources of external funding at the same time as you are applying for graduate study.

Wednesday, October 7, 2009

image"Great fleas have little fleas upon their backs to bite 'em, and little fleas have lesser fleas, and so ad infinitum".

Transposable Elements (TEs) are fragments of DNA that can jump from one genome position to another producing extra copies of themselves in the process. In a recent issue of Science, Josefa Gonzalez and Dmitri Petrov write a perspective on a paper by Yang et al which showed how some TEs manage to dispense with almost all of their sequences and still remain extremely prolific. TEs generally encode among other genes proteins that promote their mobility, either a reverse transcriptase or a transposase and parasitize the key cellular functions. Interestingly, such TEs are themselves often parasitized. These parasites of parasites -- less judgmentally called non-autonomous TEs -- contain key recognition sequence required for mobility but dispense with making the protein products required for transposition. A spectacularly successful type of non-autonomous TEs, called MITEs, has been discovered fairly recently in plants. MITEs are present in many thousand copies in many plant genomes but because they are so small (~100- 500 bp) and encode no proteins it was hard to understand how they move. We now have a very good model but still have plenty of unresolved puzzles. For more details read our Perspective and the Yang et al. paper.

Friday, August 21, 2009

imageEstimating mutational rates and patterns from new genomic data

Mutations are the foundation of genetic diversity, yet we remain uncertain about their rates and patterns. This is because new mutations are difficult to assess experimentally as they occur at extremely low rates in individuals. Indirect estimates of mutation rates from levels of divergence or heterozygosity suffer from unknown selective and demographic biases and disregard deleterious mutations. In a paper just published by Genetics Philipp Messer demonstrates how unbiased mutation rate estimates can be obtained from polymorphism data gathered from deep sequencing projects. This promises to facilitate the assessment of several long-standing problems of evolutionary biology. The paper is also featured in the issue highlights and on the cover of Genetics' August issue.

Friday, August 21, 2009

imagePapers from the lab are getting noticed

First, Nature Review Genetics highlighted Ruth Hershberg's PLoS Genetics paper. And then Genetics published a paper by Philipp Messer and highlighted it on the cover and in the highlights. Yay for us! More details about Philipp's paper to follow.

Thursday, August 13, 2009

imageYuan Zhu joins the lab

Yuan Zhu, a second year graduate student from Genetics, is done with her rotations and has decided to join our lab. In her rotation project she studied evoltuion of prokaryotic genome size. It is not yet clear what she will focus on in her dissertation - she is broadly interested in the theoretical and experimental aspects of genome evolution, evolution of complex traits, and population genetics. She is hoping to combine experimental and theoretical/computation work in her thesis. We are all delighted with her choice!

Tuesday, July 14, 2009

imageGlobal rules for optimal codon choice
In many genomes, presence of some codons in the gene improves the rate and the accuracy of protein translation compared to other synonymous codons for the same amino acid. The identity of these so-called optimal codons varies greatly in evolution and at first glance quite idiosyncratically so. For example, the optimal codon for leucine in Escherichia coli and Drosophila melanogaster is CTG, in Bacillus subtilis TTA, in Saccharomyces cerevisiae TTG, and in Saccharomyces pombe CTT. The rules governing the identities of optimal codons in different organisms remained entirely obscure. In a recent study published in PLoS Genetics Ruth Hershberg and Dmitri Petrov provide as far as we know the first universal set of rules for the choice of optimal codons and also describe a simple model for how the identities of optimal codons can shift in evolution. First we systematically identified the optimal codons of 675 bacteria, 52 archea, and 10 fungi. Using these data, we showed that universally across all bacteria, archea, and fungi the identity of the favored codons tracks the nucleotide content of the genome as a whole. In AT-rich organisms primarily AT-rich codons are optimal. Conversely, GC-rich codons are optimal in the GC-rich organisms. This rule is dominant; however once this rule is taken into account, additional universal amino acid specific rules governing the identity of selectively favored codons became apparent. We used these findings to offer a scenario as to how the identity of optimal codons can shift between genomes by tracking the nucleotide patterns of the genome. Importantly our model does not require even a temporary reduction in the strength of natural selection and is thus prima facie much more plausible that the known alternatives.

Wednesday, July 1, 2009

imageThe role of transposable elements in evolution
Transposable elements (TEs) are short DNA sequences that can jump around the genome creating new copies of themselves. All this jumping creates many mutations, from subtle regulatory changes to gross genomic rearrangements. In a review just published by Gene, Josefa Gonzalez and Dmitri discuss the role that TE-generated mutations play in adaptation. The potential adaptive significance of TEs was recognized by those involved in their initial discovery, but subsequently TEs were largely considered to be intragenomic parasites leading to almost exclusively detrimental effects to the host genome. The sequencing of the Drosophila melanogaster genome provided an unprecedented opportunity to study TEs and led to the identification of the first TE-induced adaptations in this species. These studies were followed by our systematic genome-wide search that revealed that TEs do contribute substantially to adaptive evolution in D. melanogaster. This study also revealed that there are approximately twice as many TE-induced adaptations that remain to be discovered. To gain better understanding of the adaptive role of TEs in the genome we clearly need to (i) identify as many adaptive TEs as possible in a range of Drosophila species, and (ii) carry out in-depth investigations of the effects of adaptive TEs on as many phenotypes as possible. One such study by Josefa Gonzalez and others was just published by MBE from our lab.

Thursday, June 25, 2009

imageNew Lab Baby
Anna-sophie Fiston-Lavier and Cyril Lavier are happy and proud to announce the birth of their son, Eshan Lavier, born on Wednesday, May 13, 2009. Cyril and Anna call him "the eighth wonder of the world" and this wonder is the newest and by far the cutest member of our lab!

Monday, June 8, 2009

imageDrosophila genome under selection
Over the past four decades, the predominant view of molecular evolution saw little connection between natural selection and genome evolution, assumed that the functionally constrained fraction of the genome was relatively small, and that adaptation was sufficiently infrequent and played little role in shaping patterns of variation within and between species. In a paper that just came out in PLoS Genetics, Guy Sella, Dmitri Petrov, Molly Przeworski and Peter Andolfatto review recent evidence from Drosophila which strongly implies that this view is invalid. Analyses of genetic variation within and between species reveal that much of the Drosophila genome is under purifying selection, and thus of functional importance, and that a large fraction of coding and non-coding differences between species are adaptive. The findings further indicate that, in Drosophila, adaptations may be both common and strong enough that the fate of neutral mutations depends on their chance linkage to adaptive mutations as much as on the vagaries of genetic drift. The emerging evidence has implications for a wide variety of fields, from conservation genetics to bioinformatics, and presents challenges to modelers and experimentalists alike. The papers from our lab that are reviewed here include a paper on pesticide resistance in Drosophila (Aminetzach et al, 2005) and two papers providing evidence that adaptation is common and involves strong selection in Drosophila (Macpherson et al., 2007) and that it is common and significantly affects evolution of neutral sites in humans (Cai et al., 2009).

Thursday, May 28, 2009

imageYoung human disease genes evolve slowly
Genome Biology and Evolutionand spearheaded by James Cai we show that disease genes evolve under strong functional constraint independently of their genomic age. This is quite different from other genes which show a marked trend of weaker constraint for genes that entered human genome more recently in evolutionary terms. Disease genes also tend to be expressed only in some tissues and appear to lack close duplicate copies. We argue that disease genes possess these features because they need to be sufficiently important such that mutations in them can be of noticeable functional significance. However, their expression and impact need to be limited to particular tissues because mutations in important genes expressed ubiquitously would generate embryonic lethals instead of disease. Finally, we believe that young human genes that evolve under strong constraint in humans might in general be enriched for genes that encode important primate or even human-specific functions. The study of such genes might be profitable and we intend to pursue this line of research in the future.

Monday, May 25, 2009

imageUnusual adaptation via TE-induced regulatory change in Juvenile hormone metabolism
Drosophila melanogaster(Gonzalez et al. 2008). In a paper just published by Molecular Biology and Evolution and led by Josefa Gonzalez we describe a follow-up detailed investigation of one such TE (called Bari-Jheh). Bari-Jheh is located inside a cluster of Juvenile hormone epoxyhydrolases (Jheh1, Jheh2, and Jheh3). We confirm that Bari-Jheh is the apparent cause of the adaptation and extend the study of its molecular effects to show that it leads to decreased expression of the neighboring Jheh genes (Jheh2 and Jheh3). Furthermore, we demonstrate that these molecular effects have predicted phenotypic effects on life history traits. The very curious part of this work is that Jheh genes appear very strongly conserved in evolution and do not show any signs of recurrent adaptation in Drosophila. The fact that in D. melanogaster we catch a recent adaptation in these genes might suggest that Bari-Jheh is either a very rare adaptive event and we were just lucky to catch it or that adaptation happens recurrently at the Jheh genes but leads to short-lived adaptive polymorphisms that are destined to be lost. This work further suggests that the focus on recurrent adaptation might obscure non-recurrent or ephemeral adaptation that might be important within species.

Sunday, May 3, 2009

imagePhilip is awarded BioX and VPUE grants to study HIV transmission in Africa
Philip Bulterys, an undergraduate in the lab, has received a UAR Major Grant and a Bio-X Undergraduate Research Award to pursue his study of the evolutionary dynamics of HIV-1 in the context of Mother-to-Child Transmission (MTCT). The project will involve comprehensive cloning and genotyping of HIV-1 found in plasma specimens (and other compartments) from infected mothers and their infants from prospective cohorts in Rwanda and Zambia. Together with collaborators at the Stanford School of Medicine, Philip will use molecular and epidemiological methods to characterize the relationship among viral diversity, strength of selection, and phylogenetics of HIV-1 and the risk of vertical HIV-1 transmission. Philip grew up in Rwanda and went to high school in Zambia (and has returned the last two summers to study malaria transmission dynamics in rural areas), so this project has personal meaning for him.

Wednesday, April 15, 2009

imageTalia decides to go to the University of Chicago for graduate school
After months of indecision Talia Karasov, a former undergraduate and currently a research assistant in the lab, has decided to go to the University of Chicago for graduate school. She will be a student there in the committee of genetics, genomics and systems biology and will likely be studying evolutionary and population genetics of Arabidopsis thaliana. Talia's graduate school application process resulted in what can only be described as an embarassment of riches. She was accepted and then heavliy recruited by every University she applied to. Cornell, Princeton, Berkeley, University of Chicago all wanted Talia to come. By all accounts the choice was extremely hard but had to be made. We are all extremely proud and planning to celebrate!

Tuesday, March 10, 2009

imageFast evolution of the basal transcription machinery in Drosophila testes
The basal transcription machinery is responsible for the initiation of transcription at core promoters. In Drosophila, basal transcription in testes requires several specialized basal transcription factors. Specifically, a number of TAFs (TATA-box binding protein Associated Factors) have been duplicated and function only in testis. In a paper just published in MBE we, in collaboration with the laboratory of Prof. Margaret Fuller at the Department of Developmental Biology, explored the evolutionary events and forces underlying evolution of Drosophila testis TAFs. We found that all five testis TAFs arose within a relatively short span of ~38 million years approximately 80-100 million years ago by independent duplication events. The evolution of testis TAFs has been consistently rapid with further coordinated accelerations in several Drosophila lineages. We found that testis TAFs evolve under sharply reduced purifying selection, pervasive positive selection, and in a tightly coordinated fashion. This study demonstrates that components of the basal transcriptional machinersy can evolve extremely fast and can participate in adaptation.

Friday, January 16, 2009

imageHitchhiking by natural selection in humans
There is much reported evidence for positive selection at specific loci in the human genome. Additional papers based on comparisons between the genomes of humans and chimpanzees have also suggested that adaptive evolution may be quite common. At the same time, it has been surprisingly hard to find unambiguous evidence that either positive or negative (background) selection is affecting genome-wide patterns of variation at neutral sites. In a paper just published in PloS Genetics, we evaluate the prevalence of hitchhiking by positive or negative selection by using two genome-wide datasets of human polymorphism. We document that levels of neutral polymorphism are substantially lower in the regions of (i) higher density of genes and/or regulatory regions, (ii) higher protein or regulatory divergence, and (iii) lower recombination. These patterns are robust to a number of possible confounding factors. We suggest that effects of hitchhiking cannot be ignored in the study of the human genome and that the patterns are most consistent with pervasive, genomewide positive selection. See how Stanford Report describes this work. A recent paper by Vicker et al presents very similar results that confirm and extend these findings to suggest that our estimates were very conservative and the effects of positive selection on linked variation are even stronger.

Tuesday, December 16, 2008

imageHigh functional diversity of Mycobacterium tuberculosis
Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. In a paper just published in PloS Biology Ruth Hershberg, Mikhail Lipatov, Dmitri A. Petrov, Peter M. Small, Marcus W. Feldman, Sebastien Gagneux and colleagues surveyed sequence diversity within a global collection of strains belonging to MTBC. They demonstrated that the members of MTBC affecting humans are more genetically diverse than was generally assumed, and that this diversity can be linked to human demographic and migratory events. Furthermore, they showed that MTBC bacteria are under extremely reduced purifying selection and that as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. These findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis, could contribute to the emergence and spread of drug-resistant tuberculosis. This article was featured as a Science Journal Editor’s Choice.

Tuesday, December 9, 2008

imageNew and improved D. melanogaster recombination rate calculator is available
Anna-sophie Fiston-Lavier further improved the Recombination Rate Calculator. The previously implemented procedure consistently overestimated recombination rate at telomeres. We now define regions of essentially no recombination near telomeres and set recombination rate there at zero. The exact procedure is described in We are grateful to Peter Andolfatto for pointing this problem out.

Tuesday, December 2, 2008

image Inferring selection strength under complex demographic scenarios
The strength of natural selection against transposable elements (TEs) can be inferred from the frequencies of a sample of TEs. However, complicated demographic histories could lead to a substantial distortion of the TE frequency distribution compared to that expected for a panmictic, constant-sized population. In a paper just published by MBE Josefa Gonzalez, Mike Macpherson, Philip Messer, and Dmitri develop a flexible maximum likelihood methodology that explicitly accounts both for demographic history and for the ascertainment biases of identifying TEs. We apply this method to the newly generated frequency data of the BS family of non-LTR retrotransposons in D. melanogaster in concert with two recent models of the demographic history of the species to infer the intensity of selection against this family. We find the estimate to differ substantially from our own prior estimates made under the assumptions of panmixis. These findings highlight the importance of accounting for demographic history and bear on study design for the inference of selection coefficients generally.

Friday, November 14, 2008

image Selection on codon bias
In a wide variety of organisms, synonymous codons are used with different frequencies, in a phenomenon known as codon bias. In an article just published in the Annual Review of Genetics, Ruth and Dmitri discuss the current understanding of the ways in which natural selection participates in the creation and maintenance of codon bias. We also raise several open questions: (i ) Is natural selection on codon bias always weak as suggested by a number of studies or is it weak only at equlibrium? (ii ) What determines the identity of the selectively optimal codons? (iii ) How do shifts in the identity of optimal codons take place? (iv) What is the exact nature of selection on codon bias?

Friday, November 7, 2008

image Hunter Fraser is coming to the Biology Department
Hunter Fraser is coming as a new Assistant Professor to the Biology Department. Here is what he says about his research program: "We study the regulation and evolution of gene expression using a combination of experimental and computational approaches. Our work brings together quantitative genetics, genomics, epigenetics, and evolutionary biology to achieve a deeper understanding of howgenetic variation within and between species affects genome-wide gene expression and ultimately shapes the phenotypic diversity of life."

Tuesday, October 21, 2008

image High rate of transposable element-induced adaptation in Drosophila
PLos Biology today published a paper by Gonzalez, J., Lenkov, K., Lipatov, M., Macpherson, J.M., and D.A. Petrov on the high rate of recent transposable element-induced adaptations in Drosophila melanogaster. In this work, we describe the first comprehensive genome-wide screen for recent adaptive TE insertions in D. melanogaster. Using several independent criteria, we identified a set of 13 adaptive TEs and estimate that 25–50 TEs have played adaptive roles since the migration of D. melanogaster out of Africa. We show that most of these adaptive TEs are likely to be involved in regulatory changes and appear to be involved in adaptation to the temperate climate. We argue that most identified adaptive TEs are destined to be

Monday, October 20, 2008

imageNew D. melanogaster recombination rate calculator is available
Anna-sophie Fiston-Lavier reimplemented and improved the Recombination Rate Calculator for the latest release of D. melanogastergenome (release 5).

Thursday, October 16, 2008

image New release of PGEToolbox is coming soon
The next release of PGEToolbox is coming soon. The major update is the support for HapMap phase 3 data manipulation. Genotypes and frequency data for HapMap phase 3 (NCBI build 36, dbSNP b126) are now available for browsing. New functions in PGEToolbox allow you to download genotype data of 11 populations from HapMap phase 3 website, calculate allele/genotype frequencies, and Fst between populations. The image at the left is the matrixcirle representation for values of Fst between 11 populations at the locus BMP5.

Monday, October 13, 2008

image Congratulations to Ruth Hershberg.
Ruth Hershberg has been awarded Stanford University Genome Training grant postdoctoral fellowship. Congratulations!


Friday, October 10, 2008

image Foraging for flies
Talia spent the month of September foraging for D. melanogaster and D. simulans along the West coast. She will use these flies to study adaptation along latitudinal clines. Let us know if you are interested in having these flies.

Friday, July 4, 2008

imageHigh redundancy and little new functionality among duplicated genes in yeast
PLoS Genetics published today a paper by Dean, J., Davis, J.C., Davis, R.W., and D.A. Petrov on the pervasive redundancy and apparent lack of new functionality among duplicated genes in yeast. We built a large number of yeast strains carrying single and double gene deletions of duplicated genes and measured their growth rates in rich medium. Using these data, we determined that many duplicated genes are functionally redundant to a substantial degree. We also demonstrated that the fitness effects of double deletions of duplicate genes are indistinguishable from our best estimate of the fitness effects of deletions of their ancestral singleton genes. We therefore argued that many duplicate genes do not gain substantial new functionality at least in the rich medium. Our results suggest that subfunctionalization does not generally proceed to completion, even after very long periods of time, and that neofunctionalization is either rare or of little consequence, at least under some growth conditions. This work was a collaboration between the Petrov and Davis labs.

Wednesday, January 16, 2008

image Fake partial selective sweeps
A beneficial mutation that has nearly but not yet fixed in a population produces a characteristic haplotype configuration, called a partial selective sweep. Whether nonadaptive processes might generate similar haplotype configurations has not been extensively explored. In a paper by Macpherson, J.M., Gonzalez, J., Witten, D., Davis, J.C., Rosenberg, N., Hirsh, A.E., and D. A. Petrov that was just published by Molecular Biology and Evolution, we demonstrate that a number of non-adaptive processes can indeed lead to haplotype configurations that resemble partial selective sweeps. We show that recent bottlenecks are particularly powerful in this regard. This work emphasizes the importance of knowing demographic history in interpreting population genetic data.

Wednesday, December 19, 2007

image High rate of strong adaptation in Drosophila
In a study just published in Genetics and authored by Macpherson, J.M., Sella, G., Davis, J.C., and D. A. Petrov, we study the correspondence between divergence at protein-coding sites and neutral polymorphism using genomewide data from Drosophila simulans. We find that neutral polymorphism is both lower and less homogeneous where nonsynonymous divergence is higher and that the spatial structure of this correlation is best explained by the action of strong positive selection. We introduce a method to infer the rate and selective strength of adaptation. Our results independently confirm a high rate of adaptive substitution (~1/3000 generations) and newly suggest that many adaptations are of surprisingly great selective effect (~1%), reducing the effective population size by ~15% even in highly recombining regions of the genome.

Wednesday, August 8, 2007

image Shigella loses genes at a very high rate
Shigella strains are ecotypes of E.coli and were only given a separate name because all Shigella strains cause a distinct disease (dysentery). Ruth Hershberg led a study (just published in Genome Biology) that demonstrated that Shigella strains lose genes at much higher rates than other E. coli strains and that this is largely due to a genome-wide reduction in the strength of purifying selection. This reduction in the strength of selection might be a result of the different lifestyle of Shigella strains compared to other E. coli strains.

Thursday, April 9, 2007

image Tempo and mode of genome size evolution
Eukaryotic genome size varies over five orders of magnitude. The genome size distribution is strongly skewed to small values. Genome size is highly correlated to a number of phenotypic traits, suggesting that the relative lack of large genomes in eukaryotes is due to selective removal. In a study by Oliver, M.J., Petrov, D.A., Ackerly, D., Falkowski, P.G., and O.M. Schofield that just came out in Genome Research we demonstrated that the rate of genome size evolution is proportional to genome size, with the fastest rates occurring in the largest genomes. Such a simple proportional model of genome size evolution appears to be virtually universal across eukaryotes. This model explains the skewed distribution of eukaryotic genome sizes without invoking strong selection against large genomes.

Friday, July 29, 2005

image Pesticide resistance by transposition
Using a genomic screen for adaptive transpositions in Drosophila, we have identified an adaptive insertion of a transposable element into a conserved gene involved in choline metabolism. We called this gene CHKov1. The transposition truncates CHKov1 and generates a new functional protein in the process. We hypothesize and then demonstrate that the truncated allele of CHKov1 confers increased resistance to organophosphate pesticides and has spread in D. melanogaster recently and under the pressure of positive natural selection. The paper describing this research and authored by Yael Aminetzach, Mike Macpherson, and D.A. Petrov was just published by Science. Here is how Science describes this work. This paper was also evlauated on Faculty 1000: and was rated as a Must Read.