BackgroundA major goal in the study of human evolution is to identify key genetic changes which occurred over the course of primate evolution. According to one school of thought, many such changes are likely to be found in noncoding sequence. An approach to identifying these involves comparing multiple genomes to identify conserved regions with an accelerated substitution rate in a particular lineage. Such acceleration could be the result of positive selection.ResultsHere we develop a likelihood ratio test method to identify such regions. We apply it not only to the human terminal lineage, as has been done in previous studies, but also to a number of other branches in the primate tree. We present the top scoring elements, and compare our results with previous studies. We also present resequencing data from one particular element accelerated on the human lineage. These data indicate that the element lies in a region of low polymorphism in humans, consistent with the possibility of a recent selective sweep. They also show that the AT to GC bias for polymorphism in this region differs dramatically from that for substitutions.ConclusionOur results suggest that screens of this type will be helpful in unraveling the complex set of changes which occurred during primate evolution.
Size has a profound effect on the structure of the brain. Many brain structures scale allometrically, that is, their relative size changes systematically as a function of brain size. Here we use independent contrasts analysis to examine the scaling of frontal cortex in 43 species of mammals including 25 primates and 15 carnivores. We find evidence for significant differences in scaling between primates and carnivores. Primate frontal cortex hyperscales relative to the rest of neocortex and the rest of the brain. The slope of frontal cortex contrasts on rest of cortex contrasts is 1.18 (95% confidence interval, 1.06 -1.30) for primates, which is significantly greater than isometric. It is also significantly greater than the carnivore value of 0.94 (95% confidence interval, 0.82-1.07). This finding supports the idea that there are substantial differences in frontal cortex structure and development between the two groups. C omparative neuroanatomists have long been interested in the relationship between size and brain structure. Early work focused on how the brain scales with the body, and how gross morphological characteristics such as cortical folding change with size (1, 2). More recently, emphasis has been put on the scaling of various brain structures with each other and with overall brain size (3-6).The scaling of frontal cortex presents an interesting case. From the beginning, workers have been drawn to this region because of the supposition that volume increases occurred in the line leading to humans. Brodmann's regio frontalis consisted of frontal cortex minus areas 4 and 6 and parts of the cingulate. He described a ''progressive'' expansion of this region in the primate line going from prosimians to humans, and argued that primates more closely related to humans have a disproportionally larger regio frontalis (7). However, primates more closely related to humans also have larger brains. The disproportionate expansion of the frontal region could be due to allometric scaling only.Von Bonin (8) explicitly argued that frontal cortex hyperscales with brain size, and man has ''precisely the frontal lobe which he deserves by virtue of the overall size of his brain''. A number of subsequent workers used allometric lines as a kind of standard for comparing whether human frontal cortex is bigger or smaller than one would expect for a similarly sized primate (9-11). However, neither Von Bonin nor later workers had adequate data or methods to establish whether frontal cortex hyperscaling is a regular and systematic relationship with size, or simply an artifact of grade differences. As was originally pointed out by Felsenstein (12), the phylogenetic structure of a sample of species can make it appear that there is a systematic relationship between two variables where none exists.To make the distinction between a series of grade shifts and systematic allometry, one must apply a method such as independent contrasts, which can factor out the effects of phylogeny (12). In addition, one must have data from a phylogenetical...
The alternative sigma factor RpoS is a central regulator of many stress responses in Escherichia coli. The level of functional RpoS differs depending on the stress. The effect of these differing concentrations of RpoS on global transcriptional responses remains unclear. We investigated the effect of RpoS concentration on the transcriptome during stationary phase in rich media. We found that 23% of genes in the E. coli genome are regulated by RpoS, and we identified many RpoS-transcribed genes and promoters. We observed three distinct classes of response to RpoS by genes in the regulon: genes whose expression changes linearly with increasing RpoS level, genes whose expression changes dramatically with the production of only a little RpoS ("sensitive" genes), and genes whose expression changes very little with the production of a little RpoS ("insensitive"). We show that sequences outside the core promoter region determine whether an RpoS-regulated gene is sensitive or insensitive. Moreover, we show that sensitive and insensitive genes are enriched for specific functional classes and that the sensitivity of a gene to RpoS corresponds to the timing of induction as cells enter stationary phase. Thus, promoter sensitivity to RpoS is a mechanism to coordinate specific cellular processes with growth phase and may also contribute to the diversity of stress responses directed by RpoS. IMPORTANCEThe sigma factor RpoS is a global regulator that controls the response to many stresses in Escherichia coli. Different stresses result in different levels of RpoS production, but the consequences of this variation are unknown. We describe how changing the level of RpoS does not influence all RpoS-regulated genes equally. The cause of this variation is likely the action of transcription factors that bind the promoters of the genes. We show that the sensitivity of a gene to RpoS levels explains the timing of expression as cells enter stationary phase and that genes with different RpoS sensitivities are enriched for specific functional groups. Thus, promoter sensitivity to RpoS is a mechanism that coordinates specific cellular processes in response to stresses. KEYWORDS RpoS, promoters, S , stress response, transcriptional regulation, transcriptome G enome-wide measurements of RNA levels have revolutionized our understanding of how cells organize their patterns of transcription. These studies have given us snapshots of how patterns of gene expression change in response to changes in the external environment. They have also allowed us to define the regulons controlled by specific transcription factors (TFs). A major weakness of the vast majority of these
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