Commercially available outbred mice for genome-wide association studies.
Commercially available outbred mice for genome-wide association studies.
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DOI：
10.1371/journal.pgen.1001085
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发表时间：
2010-09-02
期刊：
影响因子：
4.5
通讯作者：
Flint J
中科院分区：
文献类型：
--
作者：
Yalcin B;Nicod J;Bhomra A;Davidson S;Cleak J;Farinelli L;Østerås M;Whitley A;Yuan W;Gan X;Goodson M;Klenerman P;Satpathy A;Mathis D;Benoist C;Adams DJ;Mott R;Flint J
使用商业上可用的近交系小鼠进行的全基因组关联研究可以检测到与生物医学感兴趣的表型有关的基因。有用群体需要高频等位基因以确保检测数量性状基因座(QTL)的能力高，标记之间的低连锁不平衡以获得准确的定位分辨率，以及缺乏群体结构以防止假阳性关联。我们调查了66个群体的近亲繁殖、遗传多样性和连锁不平衡，我们证明其中一些群体的单倍型块小于100kb，从而实现了基因水平的定位分辨率。相同的等位基因会导致不同群体的差异，因此当在一个群体中绘制进展停滞时，另一个群体可以用来代替它。群体在遗传上是多样化的：45%的总遗传变异可归因于群体之间的差异。然而，造成这些群体差异的是等位基因频率的数量差异，而不是私人等位基因的存在。这些群体来自有限的祖先单倍型池，与近交系中发现的单倍型相似：在近交系中分离的序列变体中，超过95%是在近交系中发现的。因此，有可能从密集的SNP图谱中结合近交系的序列数据来推测任何小鼠的序列，这就打开了对所有变异进行分类和测试以进行关联的可能性，这一情况到目前为止还没有在完全杂交的种群中进行研究。我们通过确定H2-EA启动子中的一个缺失来展示菌落的潜力，这是一个强烈有助于设定CD4+和CD8+淋巴细胞比例的分子变化。我们表明，商业上可用的小鼠是通过全基因组关联来检测单基因的资源。我们调查了66个种群，并确定了那些具有有利于高分辨率地图绘制的特性。重要的是，我们证明了相同的等位基因会导致不同群体的差异，因此当绘制一个群体中的进度停滞时，可以使用另一个群体。作为原理的证明，我们在影响CD4+/CD8+比率的不同菌落中检测到相同的QTL，并将这种定位细化到基因水平。我们证明，H2-EA启动子的缺失是强烈有助于设定CD4+和CD8+淋巴细胞比例的分子变化。我们的结果使遗传学家有可能在利用群体进行小鼠复杂特征的全基因组关联研究方面做出明智的选择。
Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes. We show that commercially available mice are a resource for detecting single genes by genome-wide association. We surveyed 66 populations and identified those with properties conducive to high-resolution mapping. Importantly, we show that the same alleles contribute to variation in different colonies, so that when mapping progress stalls in one colony, another can be used in its stead. As a proof of principle, we detect the same QTL in different colonies influencing CD4+/CD8+ ratios and refine this mapping to the gene level. We show that a deletion in the promoter of H2-Ea is the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes. Our results make it possible for geneticists to make informed choices on the use of colonies for genome-wide association studies of complex traits in mice.
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DOI：
10.1073/pnas.80.1.273
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
MATHIS, DJ;BENOIST, C;MCDEVITT, HO
通讯作者：
MCDEVITT, HO
DOI：
10.1073/pnas.230304397
发表时间：
2000-11-07
影响因子：
11.1
作者：
Mott, R;Talbot, CJ;Flint, J
通讯作者：
Flint, J
影响因子：
11.4
作者：
DEMBIC, Z;AYANE, M;MATHIS, DJ
通讯作者：
MATHIS, DJ
稀有变体会产生整个基因组的关联。
影响因子：
9.8
作者：
Dickson SP;Wang K;Krantz I;Hakonarson H;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D