Department of Ecology and Evolutionary Biology, University of California, Irvine.
Genome Biol Evol. 2014 Jan;6(1):1-11. doi: 10.1093/gbe/evt180.
Human genome-wide association studies (GWAS) of longevity attempt to identify alleles at different frequencies in the extremely old, relative to a younger control sample. Here, we apply a GWAS approach to "synthetic" populations of Drosophila melanogaster derived from a small number of inbred founders. We used next-generation DNA sequencing to estimate allele and haplotype frequencies in the oldest surviving individuals of an age cohort and compared these frequencies with those of randomly sampled individuals from the same cohort. We used this case-control strategy in four independent cohorts and identified eight significantly differentiated regions of the genome potentially harboring genes with relevance for longevity. By modeling the effects of local haplotypes, we have more power to detect regions enriched for longevity genes than marker-based GWAS. Most significant regions occur near chromosome ends or centromeres where recombination is infrequent, consistent with these regions harboring unconditionally deleterious alleles impacting longevity. Genes in regions of normal recombination are enriched for those relevant to immune function and a gene family involved in oxidative stress response. Genetic differentiation between our experimental cohorts is comparable to that between human populations, suggesting in turn that our results may help explain heterogeneous signals in human association studies of extreme longevity when panels have diverse ancestry.
人类全基因组关联研究（GWAS）试图识别在极老年人中频率不同的等位基因，相对于年轻的对照样本。在这里，我们应用 GWAS 方法来研究源自少数近交系创始人的“合成”黑腹果蝇（Drosophila melanogaster）种群。我们使用下一代 DNA 测序来估计年龄队列中存活时间最长的个体的等位基因和单倍型频率，并将这些频率与来自同一队列的随机抽样个体进行比较。我们在四个独立的队列中使用了这种病例对照策略，并确定了八个基因组的显著分化区域，这些区域可能包含与长寿相关的基因。通过对局部单倍型的影响进行建模，我们比基于标记的 GWAS 有更大的能力来检测富含长寿基因的区域。最显著的区域发生在染色体末端或着丝粒附近，那里的重组频率较低，这与这些区域包含影响长寿的无条件有害等位基因一致。在正常重组区域中的基因富集了与免疫功能和参与氧化应激反应的基因家族相关的基因。我们的实验队列之间的遗传分化与人类群体之间的遗传分化相当，这反过来表明，当面板具有不同的祖先时，我们的结果可能有助于解释人类极端长寿关联研究中的异质信号。
