Introduction

A revolution is happening in biology.  A recent time when obtaining the sequence of an individual gene constituted a dissertation project has been supplanted by an era in which surveys of whole-genome sequences across a large number of individuals, populations, and species are common.  Because an individual’s DNA sequence embodies the ultimate historical record of inheritance, this revolution provides unprecedented opportunities to understand the causes of genetic variation among individuals and species.  Our research harnesses the power of genomic data using concepts and tools from population genetics to draw fundamental insights on deep, long-standing questions about the evolutionary process and the nature of genetic variation.

 

Genetics of Speciation

Levels and patterns of biodiversity depend crucially on the process of speciation.  A powerful approach to understanding the origin of species is to study the genetic basis of reproductive barriers between recently evolved species.  This strategy has recently led to the identification of specific genes that cause between-species hybrids to be sterile or inviable.  We have also learned one of the basic mechanisms that underlies the evolution of reproductive isolation.  Mutations accumulate in separate populations that disrupt normal interactions between genes in hybrids. 

We use the house mouse, Mus musculus, to find genes that underlie the origin of new species.  The mouse is an especially powerful system for the genetics of speciation because three recently evolved species exist, these species show partial reproductive barriers, gene flow has been intensively studied in nature, and a plethora of genetic and genomic tools are available.  We apply an integrative approach to understand the genetics of speciation.  First, we associate genotypes with reproductive traits in mapping populations generated by species crosses between wild-derived inbred lines.  In particular, we map genomic regions and genes that cause hybrid male sterility (hybrid females are fertile).  In a novel scheme, we are mapping hybrid male sterility phenotypes in two species pairs, which will allow mutations underlying speciation to be ordered along the phylogenetic tree.  Second, we are using genome-wide sequence data for these species to measure variation in phylogenetic history among genomic regions.  Such variation is predicted by population genetic theory, and our results will provide one of the first genomic tests of the hypothesis that genes that form reproductive barriers have different phylogenetic histories than those that do not. Finally, we are analyzing genomic data from classical inbred mouse strains, which are hybrids of wild mouse species to identify combinations of genes that contributed to reproductive isolation during the breeding and evolution of the strains.

In addition to unraveling the genetics of speciation, our research is directly relevant to human health.  The mouse is the premier model organism for identifying and testing genes that cause male infertility in humans.  Candidate genes have been identified through studies of mouse mutants, but the connection of these mutants to natural variation is unclear.  Because our approach focuses on natural variation, the genes we identify may be strong candidates for sterility in human males.

Reconstructing Human Evolution from Genomic Patterns of DNA Variation

DNA variation among humans reflects the culmination of evolutionary processes – mutation, recombination, migration, natural selection, and genetic drift – acting over many generations.  As a result, the ability to survey variation at loci from throughout the genome provides unprecedented opportunities to understand human evolution.  Our laboratory integrates population genetic analyses of genome-wide polymorphism patterns with computer simulations to reconstruct evolutionary processes in humans.  Special emphasis is placed on combining variation across the two most commonly surveyed types of loci:  single nucleotide polymorphisms (SNPs) and microsatellites.  Because these loci mutate at different rates, they reveal evolutionary events on contrasting timescales.  The rapid mutation rate at microsatellites allows detection of recent events, while the slower mutation rate at SNPs facilitates reconstruction of older events.  Using this logic, we are developing new statistical tests that combine variation at SNPs and microsatellites to (i) find loci responsible for human adaptation, (ii) reconstruct human migration history, and (iii) identify genes that contribute to complex human diseases.  Our first step toward the latter effort has been to describe linkage disequilibrium – the association between different loci, which determines the power of association studies – between SNPs and microsatellites across the human genome.  In addition to providing insights into this research has important implications for human biomedical research, including the finding that microsatellites can detect associations with higher power than SNPs in some cases. 

 

Evolution of Recombination

The rate of genetic recombination varies across genomes, among individuals from the same species, and between species.  Despite the central significance of recombination to the field of genetics, the causes of this variation are poorly understood.  Our laboratory compares high-density genetic maps and genome sequences to characterize the evolution of recombination rate across mammalian species.  We are also using molecular genetics to characterize the evolution of recombination hotspots across closely related house mouse species.  In addition to providing some of the first detailed empirical genomic information on the evolution of recombination between species, this research has profound implications for linkage and association studies of human disease, both of which crucially depend on the rate of recombination.