A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees

Abstract

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

Evolutionary biology of cancer

“…Recently, a suite of genes involved in carcinogenesis have been shown to exhibit signatures of positive selection [44][45][46] and, in each case, this selection appears to involve evolutionary antagonisms, such as those seen in parent-offspring conflict, sexual conflict, sexually selected conflict or intragenomic conflict [46][47][48].…”

“…Indeed, a whole suite of 'cancer-testis-associated (CTA) genes' is expressed only in the testes and malignant cells [47], and some of these genes have been subject to strong positive selection among species. Thus, genetic pathways involving CTA genes, which evolved in the context of sexual conflict and sexual selection, are apparently coopted by cancer cell lineages during somatic evolution, as developing cancer cells avoid apoptosis, dedifferentiate and take on properties of immortal male germ cells (5,46,47).…”

“…The hunt for genes related to cancer could be accelerated by evaluating for cancer-risk genes that have been subject to rapid evolution along the human lineage, with special emphasis on those that are expressed during gamete, embryonic and placental development [46,47,51]. Such genes, and known oncogenes and tumor suppressors, should also be sequenced in a much wider range of primates and other mammals, to identify positively selected amino acid sites and link adaptive molecular evolution to aspects of life history and mating systems.…”

New Methods for Detecting Lineage-Specific Selection

“…In the comparative genomics community, much attention has focused on two problems in particular: (1) identifying (especially noncoding) sequences that are unusually conserved across species, and thus are likely to be subject to negative selection (e.g., [3][4][5][6]); and (2) identifying protein-coding genes that show unusually high d N /d S ratios, and thus might be subject to positive selection (e.g., [7][8][9][10][11][12]). Methods focused on problem (1) generally have made the assumption (explicitly or implicitly) that selectional pressures are the same across all branches of a phylogeny-i.e., that each candidate sequence is under selection in all species or not under selection in any species.…”

The CD300a (IRp60) inhibitory receptor is rapidly up-regulated on human neutrophils in response to inflammatory stimuli and modulates CD32a (FcγRIIa) mediated signaling

“…The ligand for CD300a, as well as for the other members of the CD300 family, is unknown. It has been shown that the CD300a gene receptor ranks near the top of the human genes that show evidence of positive selection Nielsen et al, 2005), suggesting an important role for this receptor. Genetic studies have found that a nonsynonymous polymorphism within the immunoglobulin domain (R111Q) of the CD300a receptor is linked to psoriasis susceptibility (Speckman et al, 2003).…”