Quantifying the Intragenic Distribution of Human Disease Mutations

Abstract

SummaryA wide variety of functional domains exist within human genes. Since different domains vary in their roles regarding overall gene function, the ability for a mutation in a gene region to produce disease varies among domains. We tested two hypotheses regarding distributions of mutations among functional domains by using (1) sets of single nucleotide disease mutations for six genes (CFTR, TSC2, G6PD, PAX6, RS1, and PAH) and (2) sets of polymorphic replacement and silent mutations found in two genes (CFTR and TSC2). First, we tested the null hypothesis that sets of mutations are uniformly distributed among functional domains within genes. Second, we tested the null hypothesis that disease mutations are distributed among gene regions according to expectations derived from the distribution of evolutionary conserved and variable amino acid sites throughout each gene. In contrast to the mainly uniform distribution of sets of silent and polymorphic mutations, sets of disease mutations generally rejected the null hypotheses of both uniform and evolutionary-influenced distributions. Although the disease mutation data showed a better agreement with the evolutionary-derived expectations, disease mutations were found to be statistically overabundant in conserved domains, and under-represented in variable regions, even after accounting for amino acid site variability of domains over long-term evolutionary history. This finding suggests that there is a nonadditive influence of amino acid site conservation on the observed intragenic distribution of disease mutations, and underscores the importance of understanding the patterns of neutral amino acid substitutions permitted in a gene over long-term evolutionary history.

The vertebrate connexin family

“…Analyzing the identities, similarities and differences in functions and sequences may help to define the parts of the proteins that are likely to be of decisive importance in their function in humans. Changes in amino acids in such important parts of the proteins may have more serious consequences, and knowledge about their molecular evolution may therefore promote the understanding of patterns of human diseasecausing mutations [55,56].…”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…Certain DNA sequences have been found to be hypermutable, thereby providing important clues as to the nature of the endogenous mechanisms underlying different types of human gene lesion, but also emphasizing the nonuniform nature of mutagenesis [Antonarakis and Cooper, 2007]. Of course, human gene mutations also lack a uniform distribution within genes for functional reasons that are bound up with the nature of the gene product in question [Miller et al, 2003;Subramanian and Kumar, 2006].…”

Fold Designability, Distribution and Disease

“…Preliminary work also suggests that the majority of disease-causing mutations tend to be located in structural domains [15]. Protein designability was subsequently estimated by counting the number of families in each domain fold and taking the minimum count.…”