Attempts to calibrate bacterial evolution have relied on the assumption that rates of molecular sequence divergence in bacteria are similar to those of higher eukaryotes, or to those of the few bacterial taxa for which ancestors can be reliably dated from ecological or geological evidence. Despite similarities in the substitution rates estimated for some lineages, comparisons of the relative rates of evolution at different classes of nucleotide sites indicate no basis for their universal application to all bacteria. However, there is evidence that bacteria have a constant genomewide mutation rate on an evolutionary time scale but that this rate differs dramatically from the rate estimated by experimental methods. Rates of molecular evolution in higher eukaryotes can be resolved through comparisons of homologous molecules in species for which divergence times have been inferred from fossil and geologic evidence. But without a robust fossil record, how is it possible to establish the age of bacterial species and to calibrate their rates of sequence divergence over an evolutionary time scale? In lieu of direct fossil evidence, divergence times for bacteria have been obtained by three approaches.Age Inferred by Association with Ecological Events. By linking the appearance of several bacterial lineages to large-scale events that occurred at known times in the geologic past, Ochman and Wilson (1, 2) constructed a time scale for bacterial evolution. Applying these dates, they calculated the absolute rates of 5S rRNA and 16S rRNA divergence; these were fairly uniform across bacterial species and similar to those observed for the homologous molecules in eukaryotes. Based on an estimated rate of 16S rRNA divergence of nearly 1% per 50 million years, they calculated that Escherichia coli and Salmonella enterica sv. Typhimurium (hereafter referred to as S. enterica)-the most closely related pair of bacterial species for which appreciable genetic information was available at the time-shared a common ancestor between 120 million and 160 million years ago. Comparisons of homologous protein-coding regions from E. coli and S. enterica indicated an average rate of sequence divergence at synonymous sites of 0.90% per million years. (Note that divergence between lineages is twice the substitution rate, and that this yields a substitution rate for E. coli and S. enterica of 0.45% per million years.) Ochman and Wilson (2) could not establish the synonymous substitution rates for bacterial taxa other than E. coli and S. enterica because of insufficient availability of protein-coding sequences for other pairs of closely related bacterial species.Age Inferred from Host Fossil Record. The unique association between bacterial endosymbionts and their insect hosts allowed Moran et al. (3) to estimate the dates of divergence for members of the genus Buchnera in the Proteobacteria. Buchnera live within specialized cells of aphids and are essential to the growth and reproduction of their hosts, which inherit the endosymbionts cytoplasmically....

Using genetic and molecular analyses, we identified over 1,000 polymorphic regulators that regulate expression levels of human genes.

Many studies of speciation rely critically on estimates of sexual isolation obtained in the laboratory. Here we examine the sensitivity of sexual isolation to alterations in experimental design and mating environment in two sister species of Drosophila, D. santomea and D. yakuba. We use a newly devised measure of mating frequencies that is able to disentangle sexual isolation from species differences in mating propensity. Variation in fly density, presence or absence of a quasi-natural environment, degree of starvation, and relative frequency of species had little or no effect on sexual isolation, but one factor did have a significant effect: the possibility of choice. Designs that allowed flies to choose between conspecific and heterospecific mates showed significantly more sexual isolation than other designs that did not allow choice. These experiments suggest that sexual isolation between these species (whose ranges overlap on the island of São Tomé) is due largely to discrimination against D. yakuba males by D. santomea females. This suggestion was confirmed by direct observations of mating behavior. Drosophila santomea males also court D. yakuba females less ardently than conspecific females, whereas neither males nor females of D. yakuba show strong mate discrimination. Thus, sexual isolation appears to be a result of evolutionary changes in the derived island endemic D. santomea. Surprisingly, as reported in a companion paper (Llopart et al. 2005), the genotypes of hybrids found in nature do not accord with expectations from these laboratory studies: all F1 hybrids in nature come from matings between D. santomea females and D. yakuba males, matings that occur only rarely in the laboratory.

Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWASs) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMCs) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMCs. We assessed the relevance of HCASMCs to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that may modulate CAD risk through HCASMCs, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMCs, while other annotated genes may have multiple cell and tissue targets. Together, these results provide tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.