Fish Alexandra E, Crawford Dana C, Capra John A, Bush William S
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA, ²Departments of Biological Sciences, Biomedical Informatics, and Computer Science, Vanderbilt University, Nashville, TN 37235, USA,
Pac Symp Biocomput. 2018;23:424-435.
Genomic maps of local ancestry identify ancestry transitions - points on a chromosome where recent recombination events in admixed individuals have joined two different ancestral haplotypes. These events bring together alleles that evolved within separate continential populations, providing a unique opportunity to evaluate the joint effect of these alleles on health outcomes. In this work, we evaluate the impact of genetic variants in the context of nearby local ancestry transitions within a sample of nearly 10,000 adults of African ancestry with traits derived from electronic health records. Genetic data was located using the Metabochip, and used to derive local ancestry. We develop a model that captures the effect of both single variants and local ancestry, and use it to identify examples where local ancestry transitions significantly interact with nearby variants to influence metabolic traits. In our most compelling example, we find that the minor allele of rs16890640 occuring on a European background with a downstream local ancestry transition to African ancestry results in significantly lower mean corpuscular hemoglobin and volume. This finding represents a new way of discovering genetic interactions, and is supported by molecular data that suggest changes to local ancestry may impact local chromatin looping.
本地祖先的基因组图谱可识别祖先转变——即混合个体中近期重组事件将两条不同祖先单倍型连接起来的染色体上的位点。这些事件将在不同大陆群体中进化的等位基因聚集在一起，为评估这些等位基因对健康结果的联合效应提供了独特的机会。在这项研究中，我们在近10000名有非洲血统的成年人样本中，评估了附近本地祖先转变背景下遗传变异对源自电子健康记录的性状的影响。使用代谢芯片定位遗传数据，并用于推导本地祖先。我们开发了一个模型，该模型可以捕捉单个变异和本地祖先的影响，并用它来识别本地祖先转变与附近变异显著相互作用以影响代谢性状的例子。在我们最引人注目的例子中，我们发现rs16890640的次要等位基因出现在欧洲背景上，且下游本地祖先转变为非洲血统，这会导致平均红细胞血红蛋白和体积显著降低。这一发现代表了一种发现基因相互作用的新方法，并得到了分子数据的支持，这些数据表明本地祖先的变化可能会影响本地染色质环化。
