We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.

Population genetics theory supplies powerful predictions about how natural selection interacts with genetic linkage to sculpt the genomic landscape of nucleotide polymorphism. Both the spread of beneficial mutations and removal of deleterious mutations act to depress polymorphism levels, especially in low-recombination regions. However, empiricists have documented extreme disparities among species. Here we characterize the dominant features that could drive variation in linked selection among species, including roles for selective sweeps being ‘hard’ or ‘soft’, and concealing by demography and genomic confounds. We advocate targeted studies of close relatives to unify our understanding of how selection and linkage interact to shape genome evolution.

Recently diverged taxa may continue to exchange genes. A number of models of speciation with gene flow propose that the frequency of gene exchange will be lower in genomic regions of low recombination and that these regions will therefore be more differentiated. However, several population-genetic models that focus on selection at linked sites also predict greater differentiation in regions of low recombination simply as a result of faster sorting of ancestral alleles even in the absence of gene flow. Moreover, identifying the actual amount of gene flow from patterns of genetic variation is tricky, because both ancestral polymorphism and migration lead to shared variation between recently diverged taxa. New analytic methods have been developed to help distinguish ancestral polymorphism from migration. Along with a growing number of datasets of multi-locus DNA sequence variation, these methods have spawned a renewed interest in speciation models with gene flow. Here, we review both speciation and population-genetic models that make explicit predictions about how the rate of recombination influences patterns of genetic variation within and between species. We then compare those predictions with empirical data of DNA sequence variation in rabbits and mice. We find strong support for the prediction that genomic regions experiencing low levels of recombination are more differentiated. In most cases, reduced gene flow appears to contribute to the pattern, although disentangling the relative contribution of reduced gene flow and selection at linked sites remains a challenge. We suggest fruitful areas of research that might help distinguish between different models.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Levels of recombination vary among species, among chromosomes within species, and among regions within chromosomes in mammals. This heterogeneity may affect levels of diversity, efficiency of selection, and genome composition, as well as have practical consequences for the genetic mapping of traits. We compared the genetic maps to the genome sequence assemblies of rat, mouse, and human to estimate local recombination rates across these genomes. Humans have greater overall levels of recombination, as well as greater variance. In rat and mouse, the size of the chromosome and proximity to telomere have less effect on local recombination rate than in human. At the chromosome level, rat and mouse X chromosomes have the lowest recombination rates, whereas human chromosome X does not show the same pattern. In all species, local recombination rate is significantly correlated with several sequence variables, including GC%, CpG density, repetitive elements, and the neutral mutation rate, with some pronounced differences between species. Recombination rate in one species is not strongly correlated with the rate in another, when comparing homologous syntenic blocks of the genome. This comparative approach provides additional insight into the causes and consequences of genomic heterogeneity in recombination.

Hybridization among diverging lineages is common in nature. Genomic data provide a special opportunity to characterize the history of hybridization and the genetic basis of speciation. We review existing methods and empirical studies to identify recent advances in the genomics of hybridization, as well as issues that need to be addressed. Notable progress has been made in the development of methods for detecting hybridization and inferring individual ancestries. However, few approaches reconstruct the magnitude and timing of gene flow, estimate the fitness of hybrids or incorporate knowledge of recombination rate. Empirical studies indicate that the genomic consequences of hybridization are complex, including a highly heterogeneous landscape of differentiation. Inferred characteristics of hybridization differ substantially among species groups. Loci showing unusual patterns – which may contribute to reproductive barriers – are usually scattered throughout the genome, with potential enrichment in sex chromosomes and regions of reduced recombination. We caution against the growing trend of interpreting genomic variation in summary statistics across genomes as evidence of differential gene flow. We argue that converting genomic patterns into useful inferences about hybridization will ultimately require models and methods that directly incorporate key ingredients of speciation, including the dynamic nature of gene flow, selection acting in hybrid populations and recombination rate variation.

Identifying genomic locations that have experienced selective sweeps is an important first step toward understanding the molecular basis of adaptive evolution. Using statistical methods that account for the confounding effects of population demography, recombination rate variation, and single-nucleotide polymorphism ascertainment, while also providing fine-scale estimates of the position of the selected site, we analyzed a genomic dataset of 1.2 million human single-nucleotide polymorphisms genotyped in African-American, European-American, and Chinese samples. We identify 101 regions of the human genome with very strong evidence (p < 10−5) of a recent selective sweep and where our estimate of the position of the selective sweep falls within 100 kb of a known gene. Within these regions, genes of biological interest include genes in pigmentation pathways, components of the dystrophin protein complex, clusters of olfactory receptors, genes involved in nervous system development and function, immune system genes, and heat shock genes. We also observe consistent evidence of selective sweeps in centromeric regions. In general, we find that recent adaptation is strikingly pervasive in the human genome, with as much as 10% of the genome affected by linkage to a selective sweep.

Hybrid zones between closely related species or subspecies provide useful settings for studying the genetic architecture of speciation. Using markers distributed throughout the mouse genome, we use a hybrid zone between two recently diverged species of house mice (Mus musculus and Mus domesticus) as a natural mapping experiment to identify genomic regions that may be involved in reproductive isolation. Using cline analysis we document a nearly 50-fold variation in level of introgression among markers. Some markers have extremely narrow cline widths; these genomic regions may contribute to reproductive isolation. Biological processes associated with these narrow clines include physiological and immune responses to the environment as well as physiological and behavioral aspects of reproduction. Other autosomal markers exhibit asymmetrically broad clines, usually with high frequencies of M. domesticus alleles on the M. musculus side of the hybrid zone. These markers identify genome regions likely housing genes with alleles that are spreading from one species to the other. Biological processes associated with these wide clines include cell signaling, olfaction, and pheromone response. These processes play important roles in survival and reproduction, and associated genes are likely targets of selection. Patterns of linkage disequilibrium in the center of the hybrid zone suggest that isolation may be caused by multiple epistatic interactions between sets of genes. These data highlight the complex genetic architecture underlying speciation even at early stages of divergence and point to some of the biological processes that may govern this architecture.