A genome-wide genealogical framework for statistical and population genetic analysis
用于统计和群体遗传分析的全基因组谱系框架
基本信息
- 批准号:10658562
- 负责人:
- 金额:$ 56.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdmixtureAfrican American populationAfrican ancestryAllelesAsian populationBenchmarkingCollectionComplexDNADataData SetDevelopmentDisciplineDiseaseDistantEast AsianEpidemiologistEtiologyEuropeanEventEvolutionGenealogical TreeGenealogyGenesGeneticGenetic RecombinationGenetic ResearchGenetic VariationGenetic studyGenomeGenomic SegmentGenomic medicineGenomicsGenotypeGeographyGoalsGraphHaplotypesHeritabilityHeterogeneityHispanic PopulationsHistorical DemographyHumanHuman GeneticsIndigenous AmericanIndividualInheritedLatinoMethodsMinority GroupsModelingMutationNative HawaiianNatural SelectionsPatient RecruitmentsPersonsPhenotypePolynesianPopulationPopulation GeneticsPopulation HeterogeneityPopulation SizesPositioning AttributeProcessRecording of previous eventsResearchSamplingStructureTestingTimeTreesUnited Statesanalytical methodcausal variantdesignethnic minority populationexperiencegenetic analysisgenetic architecturegenetic pedigreegenetic risk factorgenome wide association studygenome-widehuman diseaseimprovedinnovationinterestmethod developmentnovelnovel strategiesopen sourcepopulation basedpreventsimulationtrait
项目摘要
PROJECT SUMMARY
Genetic studies have improved our understanding of disease etiology and treatment. However, there are at
least two shortcomings preventing current studies from reaching their potential in elucidating the genetic
architecture of complex traits for all humans. First, current genetic studies largely ignore the genetic
relationships among individuals in a study. Many of these relationships may be distant, but nonetheless can be
connected on genealogical trees at every position of the genome through a coalescent process. The collection
of such (unobserved) trees is encoded by the ancestral recombination graph (ARG). Second, genetic studies
are generally biased towards relatively homogeneous, continental, populations such as European or East
Asian populations, in part due to a lack of methods tailored towards admixed populations. In this proposal we
aim to develop new methods to address both shortcomings. Our framework leverages recent breakthroughs
that allow, for the first time, accurate and scalable estimation of ARGs. In Aim 1 we will leverage a new
estimator of relatedness based on the ARG that can retain more information of relatedness from incomplete
genetic data (e.g. array genotype data) compared to the current standard estimator for relatedness. We will
use this estimator to estimate trait heritability and cross-population genetic correlation of complex traits and
diseases in humans, as well as to correct for confounding due to population structure in genome-wide
association studies. In Aim 2, we will develop an association-testing framework that uses the ARG to identify
trait-associated genomic regions and prioritize trait-associated haplotypes. This principled approach can
naturally account for allelic heterogeneity and has the potential to improve the power of association studies
through lowered multiple testing burden, which is particularly important for understudied populations where
recruitment of participants is more challenging. Finally, in Aim 3 we will develop a population genetic
framework that uses ARGs to model the admixture history of a population. Using this model, we will develop
new ways to detect genes that have responded to recent selection and identify complex traits that have
evolved under different kinds of phenotypic selection. Importantly, our framework will address these
evolutionary questions in each ancestral component of the admixed population. Throughout each Aim we will
benchmark our methods with extensive simulations. We will also evaluate our methods empirically using large-
scale real-world human genetic data. Finally, we will apply our methods to genotyping and sequencing data
from admixed populations to discover new loci associated with human diseases and/or experienced natural
selection in the past. In summary, we will mine the wealth of information from the ARG and address
fundamental population- and human-genetic questions, particularly in understudied and admixed populations.
项目摘要
遗传学研究提高了我们对疾病病因和治疗的理解。然而,在
至少有两个缺点阻止目前的研究发挥其潜力,阐明遗传
所有人类复杂特征的结构。首先,目前的遗传学研究在很大程度上忽视了遗传学的作用。
研究中的个体关系。这些关系中的许多可能是遥远的,但尽管如此,
在基因组的每一个位置上都通过一个结合过程连接在家谱树上。收集
这种(未观察到的)树的编码由祖先重组图(ARG)编码。第二,基因研究
通常偏向于相对同质的大陆人群,如欧洲或东方
亚洲人群,部分原因是缺乏针对混合人群的方法。在本提案中,我们
旨在开发新的方法来解决这两个缺点。我们的框架利用了最近的突破
这是第一次允许对ARG进行准确和可扩展的估计。在目标1中,我们将利用新的
基于ARG的相关度估计,可以从不完全相关度中保留更多的相关度信息,
遗传数据(例如,阵列基因型数据)与当前的标准估计相关性。我们将
用该估计量估计复杂性状的性状遗传力和群体间遗传相关,
人类疾病,以及纠正由于全基因组的人口结构造成的混淆
协会研究。在目标2中,我们将开发一个关联测试框架,该框架使用ARG来识别
性状相关的基因组区域,并优先考虑性状相关的单倍型。这种原则性的方法可以
自然地解释等位基因异质性,并有可能提高关联研究的能力
通过降低多重检测负担,这对于研究不足的人群尤其重要,
招募参与者更具挑战性。最后,在目标3中,我们将开发一种群体遗传学,
框架,使用ARG来模拟人口的混合历史。利用这个模型,我们将开发
新的方法来检测对最近的选择做出反应的基因,并识别出具有
在不同的表型选择下进化。重要的是,我们的框架将解决这些问题
混合种群中每个祖先组成部分的进化问题。每一个目标,我们将
用大量的模拟来衡量我们的方法。我们还将评估我们的方法经验使用大-
真实世界的人类基因数据。最后,我们将把我们的方法应用于基因分型和测序数据
从混合人群中发现与人类疾病相关的新基因座和/或经历自然
过去的选择。总之,我们将从ARG和地址中挖掘丰富的信息
基本的人口和人类遗传问题,特别是在研究不足和混合人口。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Charleston Chiang其他文献
Charleston Chiang的其他文献
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{{ truncateString('Charleston Chiang', 18)}}的其他基金
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10689017 - 财政年份:2022
- 资助金额:
$ 56.21万 - 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10365815 - 财政年份:2022
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations - diversity supplement
阐明和解释不同群体复杂性状遗传结构的进化框架 - 多样性补充
- 批准号:
10539156 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations
阐明和解释不同人群复杂性状遗传结构的进化框架
- 批准号:
10624515 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations
阐明和解释不同人群复杂性状遗传结构的进化框架
- 批准号:
10640193 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations
阐明和解释不同人群复杂性状遗传结构的进化框架
- 批准号:
10458746 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations
阐明和解释不同人群复杂性状遗传结构的进化框架
- 批准号:
10727037 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
An evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations
阐明和解释不同人群复杂性状遗传结构的进化框架
- 批准号:
10275367 - 财政年份:2021
- 资助金额:
$ 56.21万 - 项目类别:
Using whole genomes to study demography and mapping power of a population isolate
使用全基因组研究人口统计学和群体隔离的绘图能力
- 批准号:
8527468 - 财政年份:2013
- 资助金额:
$ 56.21万 - 项目类别:
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