Monday, December 5, 2011

Balancing selection as the natural outcome of adaptation

imageBalancing 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.

Monday, August 1, 2011

Faster than neutral evolution of constrained sequences


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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).

Monday, July 18, 2011

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


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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).

Saturday, April 23, 2011

Population Genomics of Transposable Elements in Drosophila


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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.

Saturday, April 9, 2011

Ruth Hershberg accepts a tenure track faculty position offer from Technion


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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.

Saturday, March 26, 2011

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

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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!

Friday, February 25, 2011

Alan Bergland wins prestigious NIH postdoctoral fellowship

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.