Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes.

摘要: The spectrum of single-base-pair substitutions logged in Human Gene Mutation Database (HGMD), comprising 7,271 different lesions the coding regions 547 human genes, was analyzed for nearest-neighbor effects on relative mutation rates. Owing to its retrospective nature, HGMD allows rates be estimated only terms. Therefore, a novel methodology devised order obtain these estimates iterative fashion, correcting, at same time, confounding differential codon usage and fact that types amino acid replacement come clinical attention with probabilities. Over above hypermutability CpG dinucleotides, reflected transition five times base rate, subtle locally confined influence surrounding DNA sequence substitution observed, which extended no farther than 2 bp from site. A disparity between two strands evidenced by that, when were conditional 5' 3' flanking nucleotides, significant rate difference emerged 10 96 possible pairs complementary substitutional events. Mutational bias, favoring toward bases, phenomenon reminiscent misalignment mutagenesis, apparent exhibited both directionality reading-frame sensitivity. No specific preponderance repeat-sequence motifs observed vicinity nucleotide substitutions, but moderate correlation mutability thermodynamic stability triplets emerged, suggesting either inefficient replication high or transient stabilization misaligned intermediates.