De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton-related protein coding regions.

Abstract

Human mutagenesis is largely random, thus large coding regions, simply on the basis of probability, represent relatively large mutagenesis targets. Thus, we considered the possibility that large cytoskeletal-protein related coding regions (CPCRs), including extra-cellular matrix (ECM) coding regions, would have systemic nucleotide variants that are not present in common SNP databases. Presumably, such variants arose recently in development or in recent, preceding generations. Using matched breast cancer and blood-derived normal datasets from the cancer genome atlas, CPCR single nucleotide variants (SNVs) not present in the All SNPs(142) or 1000 Genomes databases were identified. Using the Protein Variation Effect Analyzer internet-based tool, it was discovered that apparent, systemic mutations (not shared among others in the analysis group) in the CPCRs, represented numerous deleterious amino acid substitutions. However, no such deleterious variants were identified among the (cancer blood-matched) variants shared by other members of the analysis group. These data indicate that private SNVs, which potentially have a medical consequence, occur de novo with significant frequency in the larger, human coding regions that collectively impact the cytoskeleton and ECM.