First 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 http://groups.google.com/group/bayareapopulationgenomics

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
albomicans"

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

"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.

Graduate 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 (dpetrov@stanford.edu) - 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.

Papers 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.

Estimating 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.

Yuan 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!

Global 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.

The 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.

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.