The interacting forces of natural selection, genetic drift, mutation and recombination shape the heritable differences among individuals and species. We are interested in understanding these dynamics and conversely, in leveraging the information carried by extant variation to learn about evolutionary and genetic forces. To this end, work in the group combines modeling, the development of statistical tools and data analysis, often in close collaboration with experimentalists. Currently, our main foci are (i) to model the effects of natural selection on genetic variation and (ii) to understand the recombination process in humans. The research in the group is not limited to these questions, however, and benefits from the diverse interests and expertise of individual members.
Modeling the effects of natural selection on genetic variation
What is the genetic basis of adaptation in natural populations: how many loci contribute, what are their effect sizes and interactions? Do adaptations tend to involve particular functions or genes? How frequent are they, and how strong? Answers to these questions can be garnered by identifying regions that underlie adaptations throughout the genome. Mapping selected regions also serves as one complementary approach to annotating functionally important regions of the genome.
With the forthcoming availability of genome-wide polymorphism data from many species, applications of this approach promise to yield unprecedented insight into adaptation and its effects on the genome. Interpreting the footprint of adaptation, however, will require an accurate characterization of the effects of natural selection in a range of settings. To this end, we embarked on a program to relax unrealistic assumptions and to develop more general models of natural selection.
Examples of recent publications on this topic include: Przeworski et al. 2005 Evolution; Teshima et al. 2006 Genome Research; Hernandez 2008 Bioinformatics.
Understanding the recombination process in humans
Recombination is a fundamental meiotic process that helps to align chromosomes, ensure proper disjunction and maintain genome integrity. These roles impose a number of constraints on the number and placement of crossover events on each chromosome. In humans, errors in the recombination process can lead to aneuploidy and chromosomal rearrangements, highly deleterious outcomes.
Yet selection experiments on model organisms reveal that, in spite of its essential role, recombination is a highly variable phenotype, with modifiers of the broad-scale recombination rate segregating in natural populations. As we, and others, have shown in humans, this variation has consequences for fertility: mothers with a higher mean recombination rate have slightly more children. At a finer-scale, extensive modeling work in evolutionary biology suggests that local modifiers of recombination can be selected for because of their effects on population dynamics, independent of the role of recombination in meiosis. Finally, cross-species comparisons indicate that local recombination rates are labile. In particular, we found that human and chimpanzee genomes differ markedly in the locations of recombination hotspots, indicating that a dramatic reshuffling of the recombination landscape has occurred over a short evolutionary time scale.
These considerations raise a number of questions, including: How much variation in recombination rates exists in natural populations, and over what genetic scales does it exert its effects? How is the recombination process so tightly regulated in the face of extensive variability? What precise constraints on the recombination process are imposed by its roles in meiosis and possibly by other roles? How can a process as essential as recombination evolve so rapidly? To understand the dynamics of this complex phenotype, we are interested in elucidating the genetic basis for rate variation as well as the selective pressures imposed by the roles of recombination in meiosis and in evolution.
Examples of recent publications on this topic include: Ptak et al. 2005 Nature Genetics; Bullaughey et al. 2008 Genome Research; Coop et al. 2008 Science.
For information about other ongoing projects, see the descriptions by individual lab members.