Finding Haplotypic Signatures in Proteins

Abstract

The non-random distribution of alleles of common genomic variants produces haplotypes, which are fundamental in medical and population genetic studies. Consequently, protein-coding genes with different co-occurring sets of alleles can encode different amino acid sequences: protein haplotypes. These protein haplotypes are present in biological samples, and detectable by mass spectrometry, but are not accounted for in proteomic searches. Consequently, the impact of haplotypic variation on the results of proteomic searches, and the discoverability of peptides specific to haplotypes remain unknown. Here, we study how common genetic haplotypes influence the proteomic search space and investigate the possibility to match peptides containing multiple amino acid substitutions to a publicly available data set of mass spectra. We found that for 9.96 % of the discoverable amino acid substitutions encoded by common haplotypes, two or more substitutions may co-occur in the same peptide after tryptic digestion of the protein haplotypes. We identified 342 spectra that matched to such multi-variant peptides, and out of the 4,251 amino acid substitutions identified, 6.63 % were covered by multi-variant peptides. However, the evaluation of the reliability of these matches remains challenging, suggesting that refined error rate estimation procedures are needed for such complex proteomic searches. As these become available and the ability to analyze protein haplotypes increases, we anticipate that proteomics will provide new information on the consequences of common variation, across tissues and time.