Balancing 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.

Faster 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 (http://f1000.com/13188956 and here is pdf).

High 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: http://f1000.com/11045956 and here is pdf).

Population 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.

Ruth 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 rutihersh@gmail.com.

T-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 http://petrov.stanford.edu/cgi-bin/Tlex_manual.html. Note that you can run T-lex (or other scripts) on a cloud using the Scalegenomics.com 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 here!

Alan Bergland wins prestigious NIH postdoctoral fellowship

Alan 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.

3rd Semiannual Bay Area Population Genomics Conference

The schedule for BAPG III at Stanford is all set. 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 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
Nothobranchius 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 presentation after the conference please go to
http://www.stanford.edu/group/petrov/BAPG.html

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.

Universal patterns of 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 they 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 inthe 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?

Physics 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.

James 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!

Every 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 articles on Faculty of 1000 and in PLoS Genetics.

Nadia 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!

Adaptation 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.

Philip 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.

Fabian 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: http://www.evolbio.mpg.de/english/people/staff/wissPersonal/wissM19/index.html

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

The PI's should also join: http://groups.google.com/group/bay-area-population-genetics/

Alan 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 (http://www.brown.edu/Departments/EEB) 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.

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.