Mutation Rate Variation Among Human Genomic Regions

我们的目标是了解人类基因组区域间突变速率和模式的可变性，以及这种变异的原因。具体而言，我们将解决以下问题：不同类型染色体（常染色体、X染色体和Y染色体）上的同源序列的突变率有何不同？目的是估计男性和女性突变率之间的差异程度。2. 一条染色体或同一类型的染色体区域之间的突变率有多大变化？3. 不同基因组区域的突变模式不同吗？问题2和问题3是区域突变压力假说的实质，该假说假定在哺乳动物基因组的不同区域中突变率和模式是不同的。我们将检验这一假设，并研究富gc等杂项的起源和演化。4. 是人类基因组区域间单核苷酸多态性（SNO）水平的差异在很大程度上是由突变率的差异引起的。为研究这些问题，我们建议开展以下工作。1. 寻找X染色体和Y染色体之间、Y染色体和常染色体之间、X染色体和常染色体之间同源（非常相似）的非编码区对，选择几对（5 ~ 7对）适合估计突变率性别差异的区域。每对区域将在几种高等灵长类动物中进行测序。黑猩猩、大猩猩、红毛猩猩、暹罗猴、长臂猿，可能还有旧大陆猴子。2. 选择大约15个长度为2-5 kb的独特的y链DNA片段，这些片段应该是非编码的，应该在任何常染色体或X染色体上没有同源物，并且应该有广泛的GC内容。在几种高等灵长类动物中对每个片段进行排序。3. 同样，选择大约50个独特的常染色体DNA片段，每个片段的长度约为5kb。我们将尝试选择具有SNP数据的片段，并具有合适的GC内容和重组率。在黑猩猩、大猩猩、红毛猩猩、暹罗猴、狒狒和疣猴中对它们进行排序。4. 对新数据和现有数据进行统计分析，以解决上述问题。

Our goal is to understand variability in the rates and patterns of mutation among regions of the human genome and the causes of this variation. Specifically, we shall address the following issues: 1. How different are the mutation rates among homologous sequences on different types of chromosome (autosomes, X chromosome, and Y chromosome)? The aim is to estimate the magnitude of difference between male and female mutation rates. 2. How variable are the mutation rates among regions of a chromosome or chromosomes of the same type? 3. Does the pattern of mutation different among genomic regions? Issues 2 and 3 are the essence of the regional mutation pressure hypothesis, which postulates that the rate and pattern of mutation varies among regions of the mammalian genome. We shall test this hypothesis and study the origin and evolution of GC-rich isochores. 4. Is the variation in the level of single nucleotide polymorphism (SNO) among human genomic regions due in a large extent to variations in mutation rate. To study these issues, we propose to pursue the following work. 1. To search for pairs of non-coding regions that are homologous (very similar) between X and Y chromosomes, or between Y and an autosome, or between X and an autosome, and choose several (5 to 7) pairs of regions that are suitable for estimating sex differences in mutation rate. Each pair of regions will be sequenced in several higher primates (e.g.. chimpanzee, gorilla, orangutan, siamang, gibbon, and possibly Old World monkeys. 2. Select approximately 15 unique Y-linked DNA segments each of 2-5 kb in length, These segments should be non-coding, should have no homologue on any autosome or X chromosome, and should have a wide coverage of GC contents. Sequence each segment in several higher primates. 3. Similarly, select approximately 50 unique autosomal DNA segments each of approximately 5 kb in length. We will try to select segments that have SNP data and have suitable GC contents and recombination rates. Sequence each of them in chimpanzee, gorilla, orangutan, siamang, baboon and colobus. 4. To conduct statistical analyses of the new and existing data to address the above issues.