The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions.

摘要: Reports of single base-pair substitutions that cause human genetic disease and have been located characterized in an unbiased fashion were collated; 32% point mutations CG → TG or CA transitions consistent with a chemical model mutation via methylation-mediated deamination. This represents 12-fold higher frequency than predicted from random expectation, confirming dinucleotides are indeed hotspots causing disease. However, since also appears hypermutable irrespective deamination, second mechanism may be involved generating mutations. The spectrum occurring outwith is non-random, at both the mono- dinucleotide levels. An intrinsic bias clinical detection was excluded frequencies specific amino acid did not correlate ‘chemical difference’ between acids exchanged. Instead, strong correlation observed mutational experimentally measured mispairing vertebrate DNA polymerases α β vitro. to independent any difference efficiency enzymatic proofreading/mismatch-repair mechanisms but physical through nucleotide misincorporation as result transient misalignment bases replication fork. further supported by mutability stability, possibly because must stabilized long enough for occur. Since genes neither arise error nor their local sequence environment, predictive models considered. We present computer (MUTPRED) based upon empirical data; it designed predict location within gene coding regions factor IX shown resemble closely haemophilia B. Further, able successfully rank order prevalence and/or rates associated various autosomal dominant sex-linked recessive conditions. Although still imperfect, this nevertheless initial attempt relate variable inherent sequences underlying genes.