NEW VARIABLE POLYMORPHISMS

这个子项目将致力于对大量新的多态进行基因分型，部分是由我们发现的，部分是由外部倡议发现的。我们计划与我们合作，对CEPH正在开发的世界范围内的细胞系提供的DNA进行基因分型，目的是了解人类进化史和经典进化因素(突变、自然选择、漂移和迁移)在决定人类遗传变异中的作用。基因分型方法将是在该项目中开发的，用于发现和测试新的遗传多态，DHPLC(变性高效液相色谱)。如果一种新的方法被证明在同等精度的情况下在成本方面更有价值，它将得到完善或被其他方法取代。特别是，我们将分析整个线粒体DNA的变异(不包括已经被广泛探索的D-loop)。在新的计划项目开始时，我们预计已经产生了大约450个mtDNA SNPs，其中大部分是新的。我们还想以同样的方式对大量Y染色体突变进行分型，我们计划在另一项拨款NIH GM55273的支持下，从染色体上越来越多的Y染色体位置中继续提供这些突变。选定的一些已知X染色体基因将在男性身上进行类似的研究。我们已经证明，Y突变体在种群之间的变异几乎是mtDNA突变体的三倍。我们给出了一些理由，让我们相信这一发现主要是由于男性和女性在婚姻迁移方面的差异，因为妻子在结婚时比丈夫更频繁地搬迁。我们希望用新的数据和独立的方法进一步检验这一假说。这也应该使我们能够测试我们对常染色体、Y染色体和mtDNA群体之间和群体内的相对变异的发现。X染色体应该表现出另一种可预测的模式。在所有这些情况下，我们计划使用各种统计分析方法，包括我们开发的新方法，基于突变数量的分布和突变的地理位置。我们的目标是重建并确定过去10万年现代人扩张期间的迁徙时间，并更多地了解进化因素的作用，包括突变和选择。

This subproject will be devoted to genotyping a large number of new polymorphisms in part found by us, and in part found by external initiatives. We plan to genotype DNAs supplied by the world wide collection of cell lines being developed at CEPH in collaboration with us, with the aim of understanding the history of human evolution and the role of the classical evolutionary factors (mutation, natural selection, drift and migration) in determining human genetic variation. The genotyping method will be that developed in the course of this Program Project for finding and testing new genetic polymorphisms, DHPLC (Denaturing High Performance Liquid Chromatography). It will be perfected or replaced by other methods should a new one prove more valuable in terms of cost, given equal accuracy. In particular, we will analyze the variation of the whole mitochondrial DNA (excluding the D-loop, which has already been widely explored). At the time the new Program Project begins, we expect to have generated about 450 mostly new mtDNA SNPs. We also want to type, in the same way, a large number of Y chromosome mutants, which we plan to continue to provide, with the support of another grant, NIH GM55273, from an increasing variety of Y chromosome locations on the chromosome. A selected number of known X chromosome genes will be similarly studied in males. We have shown that Y mutants have a variation between populations almost three times larger than mtDNA mutants. We have given reasons that lead us to believe this finding is mostly due to the difference in matrimonial migration of males and females, as wives relocate at marriage more frequently than husbands do. We want to test this hypothesis further with the new data and independent methods. This should also allows us to test our findings on the relative variation between and within populations of autosomes, Y chromosome and mtDNA. X chromosomes should show another, predictable pattern. In all these situations we plan to use a variety of methods of statistical analysis, including new ones we have developed, based on the distribution of the number of mutants, and on their geography of mutants. We aim to reconstruct and date migrations during the expansion of modern humans in the last 100,000 years, and to understand more about the role of evolutionary factors, including mutation and selection.