Using the plurality of codon positions to identify deleterious variants in human exomes

Abstract

Motivation: A codon position could perform different or multiple roles in alternative transcripts of a gene. For instance a nonsynonymous position in one transcript could be a synonymous site in another. Alternatively, a position could remain as nonsynonymous in multiple transcripts. Here we examined the impact of codon position plurality on the frequency of deleterious single nucleotide variations (SNVs) using data from 6500 human exomes. Results: Our results showed that the proportion of deleterious SNVs was more than twofold higher in positions that remain nonsynonymous in multiple transcripts compared to that observed in positions that are nonsynonymous in one or some transcript(s) and synonymous or intronic in other(s). Furthermore we observed a positive relationship between the fraction of deleterious nonsynonymous SNVs and the number of proteins (alternative splice variants) affected. These results demonstrate that the plurality of codon positions is an important attribute, which could be useful in identifying mutations associated with diseases.