Abstract
Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee–human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.
Highlights
Discovering the genetic changes that accompanied the origins of modern humans and pinpointing the subset of changes driven by natural selection remain central problems in evolutionary anthropology
While divergence in gene complement [1,2,3,4] and amino acid sequence [5,6,7,8,9] are discernable from genome sequences, functional divergence in cis-regulatory regions is largely invisible in sequence data
The phylogenetic and population genetic data described above are difficult to reconcile with a simple selective scenario
Summary
Discovering the genetic changes that accompanied the origins of modern humans and pinpointing the subset of changes driven by natural selection remain central problems in evolutionary anthropology. These changes are likely to have included changes in the complement of genes, changes in the amino acid sequences of proteins, and changes in cisregulation. While statistical tests for discerning the signature of positive selection in protein-coding sequences are well developed, and genomic surveys have identified many human genes showing evidence of positive selection [12,13] or diminished negative selection [14], in only a single instance has positive selection been implicated in cis-regulatory divergence between humans and other apes [15]. Thirty years have passed since King and Wilson [21] argued that human evolution owes more to changes in gene regulation than to changes in gene structure, and their theoretical justifications remain strong, empirical study of human regulatory evolution has not kept pace [22]
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