A Genome-wide Comparison of the Functional Properties of Rare and Common Genetic Variants in Humans

• Published in: American journal of human genetics Vol. 88; no. 4; pp. 458 - 468
• Main Authors: Zhu, Qianqian, Ge, Dongliang, Maia, Jessica M., Zhu, Mingfu, Petrovski, Slave, Dickson, Samuel P., Heinzen, Erin L., Shianna, Kevin V., Goldstein, David B.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 08.04.2011; Cell Press; Elsevier
• Subjects: Alleles; Biological and medical sciences; Comparative analysis; Conserved Sequence; European Continental Ancestry Group - genetics; Evolution, Molecular; Evolutionary biology; Fundamental and applied biological sciences. Psychology; Gene Frequency; General aspects. Genetic counseling; Genes, Regulator; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genome-Wide Association Study; Genomes; Genotype & phenotype; Humans; Medical genetics; Medical sciences; Models, Genetic; Molecular and cellular biology; Mutation; Phenotype; Polymorphism, Single Nucleotide; Selection, Genetic; Studies; Human; Genetics; Genome; Genetic variant; Comparative study
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.03.008

One of the longest running debates in evolutionary biology concerns the kind of genetic variation that is primarily responsible for phenotypic variation in species. Here, we address this question for humans specifically from the perspective of population allele frequency of variants across the complete genome, including both coding and noncoding regions. We establish simple criteria to assess the likelihood that variants are functional based on their genomic locations and then use whole-genome sequence data from 29 subjects of European origin to assess the relationship between the functional properties of variants and their population allele frequencies. We find that for all criteria used to assess the likelihood that a variant is functional, the rarer variants are significantly more likely to be functional than the more common variants. Strikingly, these patterns disappear when we focus on only those variants in which the major alleles are derived. These analyses indicate that the majority of the genetic variation in terms of phenotypic consequence may result from a mutation-selection balance, as opposed to balancing selection, and have direct relevance to the study of human disease.