Development of Multi-Null-Hypotheses Method for Detection of Selective Forces at Molecular Level in Evolution of Human Genes involved in DNA-Repair Mechanism Impaired in Cancer Progression

摘要

We developed a multi-null-hypotheses (MNH) method for testing signatures of natural selection in Kimura's neutral model of human evolution with population growth and limited migration between dems. To evaluate the influence of such time changes and demography in population size, we employed different variants of the null hypothesis, corresponding to constancy, growth, or substructure and growth, respectively. We apply the model for searching in SNP haplotypes from four genes implicated in impairing DNA-repair mechanism in human familial cancers: ataxia telangiectasia (ATM), human helicase RECQL, Bloom's syndrome (BLM) and Werner's syndrome (WRN). The sample is composed of about 600 chromosomes, derived from residents of Houston, TX (USA), representing major ethnic backgrounds: Caucasian, African, Asian and Hispanic. The method is illustrated with Bloom's neutrality tests B and Q. Our study suggests that detected deviations from neutrality may be obscured by presence of recombination, substructure and changes of population size in the case of RECQL haplotypes, while in the ATM haplotypes the signal is rather strong. The BLM and especially WRN haplotypes do not register deviations from neutrality.