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A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness

机译:在整个关联度范围内进行单倍型定相的一般方法

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摘要

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally ‘unrelated’ individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
机译:许多现有的队列通过设计或偶然在基因型个体之间包含一系列相关性。在这类人群中,单倍型估计是许多下游分析的中心步骤。我们使用来自孤立人群的六个队列和来自非孤立人群的两个队列的基因型,研究了为名义上“无关”个体设计的不同定相方法的性能。我们发现,与其他方法(包括专为孤立人群设计的方法)相比,SHAPEIT2在所有队列中产生的开关错误率要低得多。特别是,当存在大量IBD共享时,SHAPEIT2推断接近完美的单倍型。基于这些结果,我们已经开发出一种总体策略,用于对具有不同水平的个体之间隐性或显性关联的人群进行分阶段。首先运行SHAPEIT2,忽略所有显式族信息。然后,我们应用新颖的HMM方法(duoHMM)将SHAPEIT2单倍型与任何家族信息相结合,以推断每个染色体上所有位点的每个减数分裂的遗传模式。这允许校正开关错误,检测重组事件和基因分型错误。我们表明,该方法检测到的重组事件数量与基于遗传图谱的预期非常吻合,并且与Merlin相比,它推断出的虚假重组事件要少得多。该方法还可以检测基因分型错误,并推断在其他方面没有信息的家族(例如三重奏和二重奏)中的重组事件。检测到的重组事件可用于重组表型的关联扫描。该方法提供了一种简单而统一的单倍型估计方法,这将是人类,动植物遗传学领域的研究人员感兴趣的。

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