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Genes with monoallelic expression contribute disproportionately to genetic diversity in humans

2016; Nature Portfolio; Volume: 48; Issue: 3 Linguagem: Inglês

10.1038/ng.3493

1546-1718

Virginia Savova, Sung Chun, Mashaal Sohail, Ruth B. McCole, Robert M. Witwicki, Lisa Gai, Tobias L. Lenz, C-ting Wu, Shamil Sunyaev, Alexander A. Gimelbrant,

Genetic Associations and Epidemiology

Shamil Sunyaev, Alexander Gimelbrant and colleagues report an analysis of the genetic variability in human monoallelically expressed genes. They find that genes with monoallelic expression show greater genetic diversity than biallelically expressed genes and that this diversity is associated with greater allelic age. An unexpectedly large number of human autosomal genes are subject to monoallelic expression (MAE). Our analysis of 4,227 such genes uncovers surprisingly high genetic variation across human populations. This increased diversity is unlikely to reflect relaxed purifying selection. Remarkably, MAE genes exhibit an elevated recombination rate and an increased density of hypermutable sequence contexts. However, these factors do not fully account for the increased diversity. We find that the elevated nucleotide diversity of MAE genes is also associated with greater allelic age: variants in these genes tend to be older and are enriched in polymorphisms shared by Neanderthals and chimpanzees. Both synonymous and nonsynonymous alleles of MAE genes have elevated average population frequencies. We also observed strong enrichment of the MAE signature among genes reported to evolve under balancing selection. We propose that an important biological function of widespread MAE might be the generation of cell-to-cell heterogeneity; the increased genetic variation contributes to this heterogeneity.