Functional and structural consequence of rare exonic single nucleotide polymorphisms: One story, two tales

Wanjun Gu, Christopher I. Gurguis, Jin J. Zhou, Yihua Zhu, Eun A. Ko, Jae Hong Ko, Ting Wang, Tong Zhou

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2929-2940
Number of pages12
JournalGenome biology and evolution
Issue number10
StatePublished - Oct 2015


  • Ancestral allele
  • Positive selection
  • Purifying selection
  • RNA structure
  • Single nucleotide polymorphisms
  • Translational selection

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics


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