Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human-Neandertal Divergence

• Type of Material: Article
• Authors: Omer Gokcumen, Brigham and Women's Hospital; Qihui Zhu, Brigham and Women's Hospital; Lubbertus C. F. Mulder, Mount Sinai School of Medicine; Rebecca C. Iskow, Brigham and Women's Hospital; Christian Austermann, Mount Sinai School of Medicine; Christopher Scharer, Emory University; Towfique Raj, Harvard University; Jeremy Boss, Emory University; Shamil Sunyaev, Harvard University; Alkes Price, Harvard University; Barbara Stranger, Harvard University; Viviana Simon, Mount Sinai School of Medicine; Charles Lee, Brigham and Women's Hospital
• Language: English
• Date: 2013-04-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Gokcumen et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1003404
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 9
• Issue: 4
• Start Page: e1003404
• End Page: e1003404
• Grant/Funding Information: This work is funded by NIH grants R01 AI089246, RO1 GM081533, and R03 HG006170.; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: COPY-NUMBER VARIATION; DNA POLYMORPHISM; Science & Technology; MOLECULAR EVOLUTION; HAPLOTYPE; GENETIC-VARIATION; HUMAN EXOMES; POSITIVE SELECTION; HUMAN-POPULATIONS; NATURAL-SELECTION; Genetics & Heredity; Life Sciences & Biomedicine; HUMAN GENOME
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health; Biology, Microbiology

Abstract

Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ~36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p < 10 -15 ). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant F ST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human-Neandertal divergence and is evolving under balancing selection, especially among European populations.