title: Functional and Structural Consequence of Rare Exonic Single Nucleotide Polymorphisms: One Story, Two Tales.
abstract: Genetic variation arising from single nucleotide polymorphisms (SNPs) is ubiquitously found among human populations. While disease-causing variants are known in some cases, identifying functional or causative variants for most human diseases remains a challenging task. Rare SNPs, rather than common ones, are thought to be more important in the pathology of most human diseases. We propose that rare SNPs should be divided into two categories dependent on whether the minor alleles are derived or ancestral. Derived alleles are less likely to have been purified by evolutionary processes and may be more likely to induce deleterious effects. We therefore hypothesized that the rare SNPs with derived minor alleles would be more important for human diseases and predicted that these variants would have larger functional or structural consequences relative to the rare variants for which the minor alleles are ancestral. We systematically investigated the consequences of the exonic SNPs on protein function, mRNA structure, and translation. We found that the functional and structural consequences are more significant for the rare exonic variants for which the minor alleles are derived. However, this pattern is reversed when the minor alleles are ancestral. Thus, the rare exonic SNPs with derived minor alleles are more likely to be deleterious. Age estimation of rare SNPs confirms that these potentially deleterious SNPs are recently evolved in the human population. These results have important implications for understanding the function of genetic variations in human exonic regions and for prioritizing functional SNPs in genome-wide association studies of human diseases.
authors.affiliation: Research Center for Learning Sciences, Southeast University, Nanjing, Jiangsu, China.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Medicine, The University of Arizona.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Gurguis
authors.affiliation: Department of Epidemiology and Biostatistics, The University of Arizona.
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Zhou
authors.affiliation: School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China College of Information Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, The University of Nevada School of Medicine, Reno.
authors.forename: Eun-A
authors.initials: EA
authors.lastname: Ko
authors.affiliation: Department of Physiology, College of Medicine, Chung-Ang University, Seoul, South Korea akdongyi01@cau.ac.kr twang@email.arizona.edu tongzhou@email.arizona.edu.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Department of Medicine, The University of Arizona akdongyi01@cau.ac.kr twang@email.arizona.edu tongzhou@email.arizona.edu.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Arizona akdongyi01@cau.ac.kr twang@email.arizona.edu tongzhou@email.arizona.edu.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
mesh_terms: D000483:Alleles; D005075:Biological Evolution; D003062:Codon; D004194:Disease / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger
chemical_list: D003062:Codon; D012333:RNA, Messenger
keywords: RNA structure; ancestral allele; positive selection; purifying selection; single nucleotide polymorphisms; translational selection