PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population.
PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population.
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DOI：
10.1371/journal.pcbi.1004139
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发表时间：
2015-03
影响因子：
4.3
通讯作者：
Nicolae DL
中科院分区：
文献类型：
--
作者：
Livne OE;Han L;Alkorta-Aranburu G;Wentworth-Sheilds W;Abney M;Ober C;Nicolae DL
创始群体和大谱系为基因图谱研究提供了许多众所周知的优势，包括成本效益高的研究设计。在这里，我们描述了PRIMAL（系谱IMputation ALgorithm），一种快速准确的基于系谱的创始人群体的相位和IMputation算法。PRIMAL结合了现有的和原创的想法，例如基于派系图的IBD分段索引策略。我们能够从98个全基因组序列中推导出1317个南达科他州赫特人的基因组，这些赫特人具有约30万个常见单核苷酸变异（snv）的全基因组基因型。结合基于家系和基于ld的归算，我们能够在整个等位基因频率范围内分配87%的基因型，准确率为bb0 - 99%。利用IBD小组，我们还能够推断出83%的等位基因的亲本来源，以及没有基因型信息的已故近祖先的基因型。该数据集将使我们能够以最小的成本更好地研究罕见和常见变异对人类表型的相对贡献，以及疾病风险等位基因的亲本起源效应。最近全基因组和全外显子组测序的可用性使人类疾病和特征的遗传研究能够以前所未有的分辨率进行，尽管它们的成本限制了研究样本的大小。为了克服这一限制并设计具有成本效益的研究，我们开发了一种两步方法：对具有良好特征的创始群体中相对较少的成员进行测序，然后对许多具有全基因组基因型数据的其他个体进行基于系谱的全基因组插入。我们表明，通过对98个Hutterites进行测序，我们可以在另外1317个Hutterites中推算出700万个变体，准确率为99%，平均调用率为87%。此外，83%的等位基因为亲本起源。在Hutterites和其他创始人群中进行的此类研究应该会对常见疾病的遗传结构、基因表达特征和临床相关的疾病生物标志物产生新的见解，并最终为在这些特征良好的人群中进行个性化医疗提供出色的机会。
Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost. The recent availability of whole genome and whole exome sequencing allows genetic studies of human diseases and traits at an unprecedented resolution, although their cost limits the size of the studied sample. To overcome this limitation and design cost-efficient studies, we developed a two step method: sequencing of relatively few members of a well-characterized founder population followed by pedigree-based whole genome imputation of many other individuals with genome-wide genotype data. We show that by sequencing only 98 Hutterites, we can impute 7 million variants in an additional 1,317 Hutterites with >99% accuracy and an average call rate of 87%. Furthermore, parental origin was assigned to 83% of the alleles. Such studies in the Hutterites and other founder populations should yield new insights into the genetic architecture of common diseases, gene expression traits, and clinically relevant biomarkers of disease, and ultimately provide outstanding opportunities for personalized medicine in these well-characterized populations.
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影响因子：
3.7
作者：
Li L;Li Y;Browning SR;Browning BL;Slater AJ;Kong X;Aponte JL;Mooser VE;Chissoe SL;Whittaker JC;Nelson MR;Ehm MG
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
30.8
作者：
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通讯作者：
Cardon, LR