Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

Abstract

Channels and developmental genes belong to the molecular key players in the human central nervous system (CNS). Mutations in these genes often cause monogenic neurological disease and interspecies comparisons had shown reduced divergence. On the other hand, accelerated evolution of genes with roles in neurotransmission and development had indicated widespread positive selection in hominids. In the present study, we hypothesized that recombination hotspots could be enriched at genes with particularly important role in the CNS, because at those loci beneficial mutations may occur on a highly constrained background and consequently increased recombination could promote their fixation. To test this hypothesis, we retrieved CNS genes based on keyword search, expression data and expert knowledge. Consistent with our hypothesis, we find an enrichment of hotspot predictions around genes that are retrieved by all three strategies. Moreover, when comparing human genes based on their Gene Ontology annotations, we find hotspot predictions preferentially located around channels and neurodevelopmental genes. Taken together with the distinct sequence evolution that was reported by comparative genomic studies, this finding indicates continued positive selection at many CNS gene loci. In support of this interpretation, we also find an enrichment of recombination hotspot predictions around conserved noncoding regions that were reported to display a signature of accelerated evolution in the human lineage. Widespread positive selection acting on CNS gene loci could relate to the high prevalence of human nervous system disorders with genetically complex inheritance, potentially under an ancestral susceptibility allele model.