Population genetic studies of human copy-number polymorphisms

人类拷贝数多态性的群体遗传学研究

• 批准号: 8175654
• 负责人: Catarina D. Campbell
• 金额: $ 5.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-16 至 2012-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8175654
• 关键词: African; Alleles; Biological Assay; CCL3L1 gene; Characteristics; Copy Number Polymorphism; Crohn' s disease; Custom; DNA Insertion Elements; DNA Sequence; Data; Disease; Disease susceptibility; Event; Frequencies; Future; Genetic; Genetic Population Study; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Human; Human Biology; Human Genome; Immune Response Genes; Inbreeding; Individual; Knowledge; Meiosis; Mutate; Mutation; Phenotype; Play; Population; Population Analysis; Population Genetics; Property; Psoriasis; Recording of previous events; Recurrence; Research; Research Design; Resolution; Role; Sampling; Systemic Lupus Erythematosus; Testing; Variant; cohort; design; genetic pedigree; human disease; hutterite; pressure; public health relevance; research study; response

DESCRIPTION (provided by applicant): Copy number variants (CNVs) are large insertions, duplications, or deletions of DNA sequence. CNVs can be common in human populations and are known as copy number polymorphisms (CNPs). Serval lines of evidence suggest that CNPs are important in human biology. First, CNPs have been associated with human diseases such as Crohn's disease and psoriasis. Second, CNPs with large population differences in frequency have been described suggesting that copy number changes may have occurred in response to population-specific selective pressures. However, several important questions remain to be answered. First, the full range of CNPs have not been thoroughly tested for population differences. Additionally, the recurrence and mutation rate of CNPs has not been well studied. Unstanding these issues will give a more complete picture of the dynamic forces acting on the human genome. The broad objectives of this proposal is to perform a more complete analysis of population differentiation by including CNPs in duplication-rich regions of the genome and insertions of sequence not in the reference genome assembly as these CNPs are understudied in previous analyses. A further objective of the proposed research is to estimate the mutation rate of CNPs. These goals are focused on testing the hypothesis that there will be differences between CNP loci in terms of both population differentiation and mutation rate. Because many CNPs are not well assayed by currently available platforms, I have developed and tested a custom microarray targeted to CNP loci defined at high resolution. I will hybridize over one thousand individuals from multiple populations to this microarray to discover population differentiated CNPs. To study CNP mutation rate, I will analyze individuals selected from a multigeneration pedigree of Hutterites. This cohort offers a unique oppurtunity to study individuals with a high degreee of allele sharing, due to inbreeding, but who are separated by an average of eight meioses. These characteristics should make these samples powerful for discovering mutated or recurrent CNPs and estimating the frequency of these events. Finally, to understand the role of paralogous variants in CNP loci, I will fully sequence population differentiated CNPs and CNPs with high mutation rates. These sequence data will allow for a better understanding of the interplay between copy number and sequence content. The experiments proposed here will provide a better understanding of this type of genetic variation and may influence the design of future studies involving CNPs. PUBLIC HEALTH RELEVANCE: This study of the population genetics of copy-number polymorphisms, differencs in the number of copies of certain regions of the genome between individuals, aims to gain a better understanding of genetic variation among humans. The knowledge gained here has the potential to influence studies of the genetics of human diseases.

描述（由申请人提供）：拷贝数变异（cnv）是DNA序列的大量插入、重复或缺失。CNVs在人类群体中很常见，被称为拷贝数多态性（CNPs）。一些证据表明CNPs在人类生物学中很重要。首先，CNPs与克罗恩病和牛皮癣等人类疾病有关。其次，在频率上存在较大种群差异的CNPs已经被描述，这表明拷贝数的变化可能是对种群特异性选择压力的响应。然而，仍有几个重要的问题有待回答。首先，所有的CNPs都没有经过彻底的种群差异测试。此外，CNPs的复发和突变率尚未得到很好的研究。理解这些问题将使我们更全面地了解作用于人类基因组的动态力量。本提案的主要目标是通过包括基因组中重复丰富区域的CNPs和不在参考基因组组装中的序列插入来执行更完整的种群分化分析，因为这些CNPs在之前的分析中未得到充分研究。提出的研究的另一个目标是估计CNPs的突变率。这些目标的重点是验证CNP基因座之间在群体分化和突变率方面存在差异的假设。由于目前可用的平台无法很好地分析许多CNP，因此我开发并测试了一种针对高分辨率CNP基因座的定制微阵列。我将把来自多个种群的一千多个个体杂交到这个微阵列上，以发现种群分化的CNPs。为了研究CNP突变率，我将分析从huterites多代谱系中选择的个体。这个队列提供了一个独特的机会来研究由于近亲繁殖而具有高度等位基因共享的个体，但这些个体平均相隔8个减数分裂。这些特征应该使这些样本强大的发现突变或复发的CNPs和估计这些事件的频率。最后，为了了解同源变异在CNP位点中的作用，我将对群体分化的CNPs和高突变率的CNPs进行全测序。这些序列数据将允许更好地理解拷贝数和序列内容之间的相互作用。这里提出的实验将更好地理解这种类型的遗传变异，并可能影响涉及CNPs的未来研究的设计。

项目成果

Human copy number variation and complex genetic disease.

• DOI: 10.1146/annurev-genet-102209-163544
• 发表时间: 2011
• 期刊: Annual review of genetics
• 影响因子: 11.1
• 作者: Girirajan S;Campbell CD;Eichler EE
• 通讯作者: Eichler EE

Properties and rates of germline mutations in humans.

• DOI: 10.1016/j.tig.2013.04.005
• 发表时间: 2013-10
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Campbell, Catarina D.;Eichler, Evan E.
• 通讯作者: Eichler, Evan E.