Doctoral Dissertation Improvement: Haplotype Variation and Linkage Disequilibrium in SORT1 and SORL1: Implications for Human Demographic History and Late-Onset Disease

博士论文改进:SORT1 和 SORL1 中的单倍型变异和连锁不平衡:对人类人口统计史和迟发性疾病的影响

基本信息

  • 批准号:
    0550998
  • 负责人:
  • 金额:
    $ 1.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-03-15 至 2007-02-28
  • 项目状态:
    已结题

项目摘要

Many genetic studies have assumed that modern human populations were panmictic and genetically unstructured for much of their prehistory, especially in Africa. However, some recent evidence has suggested that prehistoric populations within continental regions were more subdivided with distinct genetic lineages and patterns of linkage disequilibrium (LD). Thus, human demographic history may arguably have been more complex than previously depicted by more simple models. However, more research is necessary in order to characterize the extent of this structure across a broader range of geographically and ethnically diverse populations. The demographic history of human populations also has implications for the evolution of genetic variation underlying complex diseases. Particularly, variants for late-onset disease (not under strong selection) are subject to the same demographic forces as neutral variation. Thus, under a model of population subdivision, alleles which predispose individuals to disease-related traits are predicted to occur at different frequencies in diverse populations, affecting the risk for acquiring disease. This project will examine SNP haplotype variation in the SORT1 and SORL1 genes, two newly identified risk factors for late-onset Alzheimer's Disease (LOAD): (a) to characterize the genetic structure and patterns of LD within major continental regions (~1500 individuals from 56 populations) (b) to infer demographic models that explain observed patterns of diversity, and (c) to determine if genetic structure contributes to differential risk for LOAD in African-Americans, Caribbean-Hispanics and European-Americans (~900 cases and ethnically-matched controls). In particular, this study will test for geographic variation in haplotype frequencies among diverse populations within continents, as well as correlations between population subdivision and variance in LD. This project will also test whether or not genetic risk for LOAD is different in populations with distinct population histories. The researchers in this project will select SNPs located in coding and non-coding regions of SORT1 and SORL1 from the International HapMap Project for High Throughput Genotyping. Haplotypes will be reconstructed using two algorithms with different underlying assumptions and other analytical methods, such as Wright's Fst and Lewontin's D' parameter, will be used to calculate population divergence and variance in LD. Disease-marker association analyses between LOAD and the above genes will also be performed using cases and ethnically-matched controls. Intellectual Merit: This project represents the first study of SNP variation in both genes in a large sample of healthy individuals from diverse human groups, including 10 distinct African populations which are mostly underrepresented in genetic studies. By conducting this research, it will lead to more detailed knowledge of the demographic history of human populations, and ultimately modern human origins. Broader Impacts: On a broader scale, the effective design of therapeutic strategies for LOAD will be enhanced by more detailed information on genetic factors involved in disease susceptibility in different human groups. In the end, treatments can be developed that will effectively decrease the incidence of LOAD across the human species. This project will also directly support the training of a minority graduate student, from an underrepresented group, in molecular biology and population genetics. In addition, the data collected from this research, including SNPs, will be made available publicly to online databases.
许多遗传学研究认为,现代人类在史前的大部分时间里都是全系繁殖的,遗传上是非结构化的,特别是在非洲。然而,最近的一些证据表明,大陆地区内的史前人口更细分与不同的遗传谱系和模式的连锁不平衡(LD)。因此,人类的人口统计历史可能比以前用更简单的模型描述的更复杂。然而,需要进行更多的研究,以确定这一结构在更广泛的地理和种族多样性人口中的程度。人类的人口统计学历史也对复杂疾病的遗传变异的演变有影响。特别是,迟发性疾病的变异(不受强选择的影响)受到与中性变异相同的人口统计学因素的影响。因此,在人口细分模型下,预测使个体易患疾病相关性状的等位基因在不同人群中以不同的频率出现,影响获得疾病的风险。该项目将研究SORT 1和SORL 1基因中的SNP单倍型变异,这两个新发现的迟发性阿尔茨海默病(LOAD)的风险因素:(a)确定主要大陆区域内LD的遗传结构和模式(来自56个种群的约1500个个体)(B)推断解释观察到的多样性模式的人口统计模型,以及(c)确定遗传结构是否有助于非洲裔美国人、加勒比裔西班牙人和欧洲裔美国人(约900例病例和种族匹配对照)的LOAD差异风险。特别是,这项研究将测试在大陆内不同人群之间的单倍型频率的地理变异,以及人口细分和LD方差之间的相关性。该项目还将测试具有不同群体历史的群体中负载的遗传风险是否不同。本项目的研究人员将从国际高重复基因分型单体型图计划中选择位于SORT 1和SORL 1编码区和非编码区的SNP。将使用具有不同基本假设的两种算法重建单倍型,并且将使用其他分析方法(例如Wright的Fst和Lewontin的D'参数)来计算LD中的群体分歧和方差。还将使用病例和种族匹配的对照进行LOAD与上述基因之间的疾病标记物关联分析。 智力优势:该项目代表了对来自不同人群的健康个体的大样本中两种基因的SNP变异的首次研究,其中包括10个不同的非洲人群,这些人群在遗传研究中大多数代表性不足。通过进行这项研究,它将导致对人类人口统计历史的更详细的了解,并最终导致现代人类的起源。更广泛的影响:在更广泛的范围内,LOAD治疗策略的有效设计将通过不同人群中疾病易感性相关遗传因素的更详细信息得到加强。最后,可以开发出有效降低人类LOAD发病率的治疗方法。该项目还将直接支助对一名来自代表性不足群体的少数民族研究生进行分子生物学和群体遗传学方面的培训。此外,从这项研究中收集的数据,包括SNPs,将公开提供给在线数据库。

项目成果

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Ralph Holloway其他文献

A paleoneurological survey of Homo erectus endocranial metrics.
直立人颅内指标的古神经学调查。
  • DOI:
    10.1016/j.quaint.2014.10.007
  • 发表时间:
    2015-05
  • 期刊:
  • 影响因子:
    2.2
  • 作者:
    Dominique Grimaud-Herve;Xiujie Wu;Jose Manuel de la Cuetara;Ralph Holloway
  • 通讯作者:
    Ralph Holloway
A reanalysis of the Taung endocranial surface: Comparison with large samples of living hominids
对汤恩颅骨内表面的重新分析:与现存人科动物大样本的比较
  • DOI:
    10.1016/j.jhevol.2024.103637
  • 发表时间:
    2025-03-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Shawn Hurst;Ralph Holloway;Heather Garvin;Grace Bocko;Kara Garcia;Zachary Cofran;John Hawks;Lee Berger
  • 通讯作者:
    Lee Berger

Ralph Holloway的其他文献

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{{ truncateString('Ralph Holloway', 18)}}的其他基金

Doctoral Dissertation Improvement: Neural Substrates of Primate Communication: A Comparative Study of Facial and Hypoglossal Nuclei
博士论文改进:灵长类动物交​​流的神经基质:面核和舌下核的比较研究
  • 批准号:
    0121286
  • 财政年份:
    2002
  • 资助金额:
    $ 1.18万
  • 项目类别:
    Standard Grant
Human Brain Evolution
人脑进化
  • 批准号:
    8418921
  • 财政年份:
    1985
  • 资助金额:
    $ 1.18万
  • 项目类别:
    Standard Grant
The Evolution of the Human Brain: a Morphometric Analysis
人脑的进化:形态计量分析
  • 批准号:
    7911235
  • 财政年份:
    1979
  • 资助金额:
    $ 1.18万
  • 项目类别:
    Continuing Grant
The Evolution of the Human Brain: a Morphometric Analysis
人脑的进化:形态计量分析
  • 批准号:
    7805651
  • 财政年份:
    1978
  • 资助金额:
    $ 1.18万
  • 项目类别:
    Standard Grant
Evolution of the Human Brain
人脑的进化
  • 批准号:
    7420149
  • 财政年份:
    1974
  • 资助金额:
    $ 1.18万
  • 项目类别:
    Standard Grant

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Doctoral Dissertation Improvement Award. The role of Hillforts in Integrating Settlement and Mobility
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    2321462
  • 财政年份:
    2023
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Doctoral Dissertation Improvement Award: Phytolith Analysis in Determination of Environmental Change
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