Genome-wide patterns of gene flow across a house mouse hybrid zone.

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.

More genes underwent positive selection in chimpanzee evolution than in human evolution.

Observations of numerous dramatic and presumably adaptive phenotypic modifications during human evolution prompt the common belief that more genes have undergone positive Darwinian selection in the human lineage than in the chimpanzee lineage since their evolutionary divergence 6-7 million years ago. Here, we test this hypothesis by analyzing nearly 14,000 genes of humans and chimps. To ensure an accurate and unbiased comparison, we select a proper outgroup, avoid sequencing errors, and verify statistical methods. Our results show that the number of positively selected genes is substantially smaller in humans than in chimps, despite a generally higher nonsynonymous substitution rate in humans. These observations are explainable by the reduced efficacy of natural selection in humans because of their smaller long-term effective population size but refute the anthropocentric view that a grand enhancement in Darwinian selection underlies human origins. Although human and chimp positively selected genes have different molecular functions and participate in different biological processes, the differences do not ostensibly correspond to the widely assumed adaptations of these species, suggesting how little is currently known about which traits have been under positive selection. Our analysis of the identified positively selected genes lends support to the association between human Mendelian diseases and past adaptations but provides no evidence for either the chromosomal speciation hypothesis or the widespread brain-gene acceleration hypothesis of human origins.

Did brain-specific genes evolve faster in humans than in chimpanzees?

One of the most distinctive characteristics of humans among primates is the size, organization and function of the brain. A recent study has proposed that there was widespread accelerated sequence evolution of genes functioning in the nervous system during human origins. Here we test this hypothesis by a genome-wide analysis of genes that are expressed predominantly or specifically in brain tissues and genes that have important roles in the brain, identified on the basis of five different definitions of brain specificity. Although there is little overlap among the five sets of brain-specific genes, none of them supports human acceleration. On the contrary, some datasets show significantly fewer nonsynonymous substitutions in humans than in chimpanzees for brain-specific genes relative to other genes in the genome. Our results suggest that the unique features of the human brain did not arise by a large number of adaptive amino acid changes in many proteins.

Genomic analysis of PIS1 gene expression.

The Saccharomyces cerevisiae PIS1 gene is essential and required for the final step in the de novo synthesis of phosphatidylinositol. Transcription of the PIS1 gene is uncoupled from the factors that regulate other yeast phospholipid biosynthetic genes. Most of the phospholipid biosynthetic genes are regulated in response to inositol and choline via a regulatory circuit that includes the Ino2p:Ino4p activator complex and the Opi1p repressor. PIS1 is regulated in response to carbon source and anaerobic growth conditions. Both of these regulatory responses are modest, which is not entirely surprising since PIS1 is essential. However, even modest regulation of PIS1 expression has been shown to affect phosphatidylinositol metabolism and to affect cell cycle progression. This prompted the present study, which employed a genomic screen, database mining, and more traditional promoter analysis to identify genes that affect PIS1 expression. A screen of the viable yeast deletion set identified 120 genes that affect expression of a PIS1-lacZ reporter. The gene set included several peroxisomal genes, silencing genes, and transcription factors. Factors suggested by database mining, such as Pho2 and Yfl044c, were also found to affect PIS1-lacZ expression. A PIS1 promoter deletion study identified an upstream regulatory sequence element that was required for carbon source regulation located downstream of three previously defined upstream activation sequence elements. Collectively, these studies demonstrate how a collection of genomic and traditional strategies can be implemented to identify a set of genes that affect the regulation of an essential gene.