Following the footprints of polymorphic inversions on SNP data: from detection to association tests
Following the footprints of polymorphic inversions on SNP data: from detection to association tests
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DOI：
10.1093/nar/gkv073
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发表时间：
2015-04-30
影响因子：
14.9
通讯作者：
Gonzalez, Juan R.
中科院分区：
文献类型：
--
作者：
Caceres, Alejandro;Gonzalez, Juan R.
倒位多态性对人类具有重要的表型和进化后果。两种不同的方法被用来从 SNP 密集数据中推断反演，使得他们的研究能够使用大型队列。一种方法依赖于断点间连锁不平衡的差异；另一种捕获标记染色体倒位状态的内部单倍型组。在本文中，我们评估了两种方法在检测文献中报道的 20 种人体倒立时的收敛性。这些方法收敛于四个反演，包括 inv-8p23，为此我们研究了它与美国儿童低体重指数的关系。使用一种控制倒置祖先的新型单倍型标记方法，我们计算了两个美国队列中 inv-8p23 的频率，并观察了倒置单倍型混合。考虑到单倍型血统，我们发现儿童中的欧洲反向等位基因具有体重不足的隐性风险，这一点在独立的西班牙队列中得到了验证（合并：OR = 2.00，P = 0.001）。虽然 SNP 数据上的倒转足迹很复杂，但我们表明，系统分析（例如不同方法的融合和对祖先的控制）可以揭示倒转对人群祖先组成和人类疾病遗传性的贡献。
Inversion polymorphisms have important phenotypic and evolutionary consequences in humans. Two different methodologies have been used to infer inversions from SNP dense data, enabling the use of large cohorts for their study. One approach relies on the differences in linkage disequilibrium across breakpoints; the other one captures the internal haplotype groups that tag the inversion status of chromosomes. In this article, we assessed the convergence of the two methods in the detection of 20 human inversions that have been reported in the literature. The methods converged in four inversions including inv-8p23, for which we studied its association with low-BMI in American children. Using a novel haplotype tagging method with control on inversion ancestry, we computed the frequency of inv-8p23 in two American cohorts and observed inversion haplotype admixture. Accounting for haplotype ancestry, we found that the European inverted allele in children carries a recessive risk of underweight, validated in an independent Spanish cohort (combined: OR=2.00, P = 0.001). While the footprints of inversions on SNP data are complex, we show that systematic analyses, such as convergence of different methods and controlling for ancestry, can reveal the contribution of inversions to the ancestral composition of populations and to the heritability of human disease.