Closely spaced multiple mutations as potential signatures of transient hypermutability in human genes

Abstract

Data from diverse organisms suggests that transient hypermutability is a general mutational mechanism with the potential to generate multiple synchronous mutations, a phenomenon probably best exemplified by closely spaced multiple mutations (CSMMs). Here we have attempted to extend the concept of transient hypermutability from somatic cells to the germline, using human inherited disease-causing multiple mutations as a model system. Employing stringent criteria for data inclusion, we have retrospectively identified numerous potential examples of pathogenic CSMMs that exhibit marked similarities to the CSMMs reported in other systems. These examples include (1) eight multiple mutations, each comprising three or more components within a sequence tract of <100 bp; (2) three possible instances of "mutation showers"; and (3) numerous highly informative "homocoordinate" mutations. Using the proportion of CpG substitution as a crude indicator of the relative likelihood of transient hypermutability, we present evidence to suggest that CSMMs comprising at least one pair of mutations separated by < or =100 bp may constitute signatures of transient hypermutability in human genes. Although this analysis extends the generality of the concept of transient hypermutability and provides new insights into what may be considered a novel mechanism of mutagenesis underlying human inherited disease, it has raised serious concerns regarding current practices in mutation screening.

Error-prone polymerase activity causes multinucleotide mutations in humans

“…Third, as already noted, the MNMs we infer are enriched for the same types as MNMs that were observed de novo in yeast. The patterns we observe are consistent with MNM patterns that have been previously found using Sanger sequencing and other high-fidelity variant detection methods (Drake et al 2005;Levy et al 2007;Lynch et al 2008;Chen et al 2009). …”

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

“…Recently, it has been demonstrated that multiple mutations may not be an infrequent cause of human genetic disease [Chen et al, 2009b]. Such multiple mutations may constitute the signatures of transient hypermutability in human genes.…”

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

“…Indeed the Lac1 Big Blue mouse transgenic model of spontaneous mutation shows that nonrandom sprays of mutations are the rule not the exception [31,32]. And there are recent other reports of mutational sprays in the human genome involving copy number variations (CNVs) [33,34]. We posit that such clustering of mutations is at least consistent with a processive polynucleotide synthetic process.…”

“…Can a plausible molecular mechanism based on supporting evidence from a number of fields of molecular and cell biology be advanced to explain the emergence of PFBs and thus AHs both within and beyond the MHC? (*Note on terminology : Terms such as "mutational/SNP cluster", "mutational/SNP burst" , "big bang burst model" , " quantal burst model", and "mutational/SNP shower" have all been used in the recent literature to describe these clustered mutation phenomena [5,24,25,[30][31][32][33][34]. To simplify the terminology we use the terms "mutational spray " or "SNP spray" to describe the same apparent phenomena.…”