Abstract
BackgroundAny two unrelated people differ by about 20,000 missense mutations (also referred to as SAVs: Single Amino acid Variants or missense SNV). Many SAVs have been predicted to strongly affect molecular protein function. Common SAVs (> 5% of population) were predicted to have, on average, more effect on molecular protein function than rare SAVs (< 1% of population). We hypothesized that the prevalence of effect in common over rare SAVs might partially be caused by common SAVs more often occurring at interfaces of proteins with other proteins, DNA, or RNA, thereby creating subgroup-specific phenotypes. We analyzed SAVs from 60,706 people through the lens of two prediction methods, one (SNAP2) predicting the effects of SAVs on molecular protein function, the other (ProNA2020) predicting residues in DNA-, RNA- and protein-binding interfaces.ResultsThree results stood out. Firstly, SAVs predicted to occur at binding interfaces were predicted to more likely affect molecular function than those predicted as not binding (p value < 2.2 × 10–16). Secondly, for SAVs predicted to occur at binding interfaces, common SAVs were predicted more strongly with effect on protein function than rare SAVs (p value < 2.2 × 10–16). Restriction to SAVs with experimental annotations confirmed all results, although the resulting subsets were too small to establish statistical significance for any result. Thirdly, the fraction of SAVs predicted at binding interfaces differed significantly between tissues, e.g. urinary bladder tissue was found abundant in SAVs predicted at protein-binding interfaces, and reproductive tissues (ovary, testis, vagina, seminal vesicle and endometrium) in SAVs predicted at DNA-binding interfaces.ConclusionsOverall, the results suggested that residues at protein-, DNA-, and RNA-binding interfaces contributed toward predicting that common SAVs more likely affect molecular function than rare SAVs.
Highlights
Any two unrelated people differ by about 20,000 missense mutations
For these residues without observed Single amino acid variants (SAVs), the fraction predicted as ProNA-binding was similar, namely 22.6 ± 0.1%
SAVs at binding interfaces differ substantially between tissue types Suspecting that the type of binding might differ between tissues, we investigated all proteins expressed differentially according to the Human Protein Atlas (HPA [24])
Summary
Any two unrelated people differ by about 20,000 missense mutations ( referred to as SAVs: Single Amino acid Variants or missense SNV). Common SAVs (> 5% of population) were predicted to have, on average, more effect on molecular protein function than rare SAVs (< 1% of population). We analyzed SAVs from 60,706 people through the lens of two prediction methods, one (SNAP2) predicting the effects of SAVs on molecular protein function, the other (ProNA2020) predicting residues in DNA-, RNAand protein-binding interfaces. Focus on SAVs, binding proteins/DNA/RNA, and predictions Single nucleotide variants (SNVs; prior to modern sequencing referred to as SNPs) constitute the most frequent form of human genetic variation [1]. Non-synonymous or missense SNVs ( referred to as missense SNVs, nsSNVs, nsSNPs, or SAAVs) are one of the best-studied groups of variants in human diseases These are SNVs altering the amino acid sequence of the encoded protein, often termed Single Amino acid Variant (SAV) or missense variant [2]. This number has increased substantially since our original analysis [1], 1% was still too small for a representative analysis, in particular given that only 18 residue positions were observed at ProNA-binding
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