New 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!

Drosophila 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).

Young human disease genes evolve slowly

Genes underlying human heritable diseases are not only important for medicine but are also of great interest for evolutionary biologists. This is because we know that such genes can be mutated to produce deleterious phenotypes and we can use them to study how function is acquired in evolution. In a paper just published in Genome Biology and Evolution and 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.

Unusual adaptation via TE-induced regulatory change in Juvenile hormone metabolism

We recently demonstrated that transposable elements underlie much recent adaptation in 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.

Philip 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.

Talia 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!

Fast 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.

Hitchhiking 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.

High 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.

New 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 http://petrov.stanford.edu/cgi-bin/recombination-rates_updateR5.pl. We are grateful to Peter Andolfatto for pointing this problem out.

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.

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?

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 lost from the D. melanogaster population but that they do contribute significantly to local adaptation in this species.

High 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.

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.

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.

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.

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.

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: http://www.f1000biology.com/article/id/1027308/evaluation and was rated as a Must Read.