Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens
Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens
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DOI：
10.1371/journal.pgen.1007279
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发表时间：
2018-05-01
期刊：
影响因子：
4.5
通讯作者：
Bahlo, Melanie
中科院分区：
文献类型：
--
作者：
Henden, Lyndal;Lee, Stuart;Bahlo, Melanie
鉴定血统相同的基因组区域(IBD)已被证明对人类遗传学研究很有用，在人类遗传学研究中，分析导致发现家族亲缘关系并精细绘制疾病关键区域。然而，不幸的是，IBD分析在包括人类病原体在内的其他生物的分析中一直没有得到充分利用。这在一定程度上是因为除了多克隆感染的复杂性外，缺乏非二倍体基因组的统计方法。因此，我们开发了一种称为IsoRelate的IBD方法学，用于分析存在多克隆感染的单倍体重组微生物。利用在基因组位置推断的IBD状态，我们还开发了一种新的统计方法，用于在正选择下识别基因座，并建议将关联网络作为探索群体内共享单倍型的一种手段。我们评估了我们检测和选择IBD的方法的性能，包括与现有工具的比较，然后对全球恶性疟原虫超过2500个基因组的数据集进行了探索性分析。这项分析确定东南亚有许多高度相关的分离株，这可能是由于加强控制努力减少了传播，以及出现抗疟疾药物耐药性后的人口瓶颈。除了在多个国家观察到的两个尚未详细探索的新信号外，还发现了许多选择信号，其中大多数与已知与耐药性有关的基因重叠。此外，我们调查了选定基因座上的关联网络，并确定其中一个扫描已经在大陆之间传播，而另一个则独立地出现在不同的国家。利用IsoRelate对微生物进行IBD分析可用于探索种群结构、正选择和单倍型分布，并将成为监测疾病控制和消除许多疾病的有价值的工具。
Identification of genomic regions that are identical by descent (IBD) has proven useful for human genetic studies where analyses have led to the discovery of familial relatedness and fine-mapping of disease critical regions. Unfortunately however, IBD analyses have been underutilized in analysis of other organisms, including human pathogens. This is in part due to the lack of statistical methodologies for non-diploid genomes in addition to the added complexity of multiclonal infections. As such, we have developed an IBD methodology, called isoRelate, for analysis of haploid recombining microorganisms in the presence of multiclonal infections. Using the inferred IBD status at genomic locations, we have also developed a novel statistic for identifying loci under positive selection and propose relatedness networks as a means of exploring shared haplotypes within populations. We evaluate the performance of our methodologies for detecting IBD and selection, including comparisons with existing tools, then perform an exploratory analysis of whole genome sequencing data from a global Plasmodium falciparum dataset of more than 2500 genomes. This analysis identifies Southeast Asia as having many highly related isolates, possibly as a result of both reduced transmission from intensified control efforts and population bottlenecks following the emergence of antimalarial drug resistance. Many signals of selection are also identified, most of which overlap genes that are known to be associated with drug resistance, in addition to two novel signals observed in multiple countries that have yet to be explored in detail. Additionally, we investigate relatedness networks over the selected loci and determine that one of these sweeps has spread between continents while the other has arisen independently in different countries. IBD analysis of microorganisms using isoRelate can be used for exploring population structure, positive selection and haplotype distributions, and will be a valuable tool for monitoring disease control and elimination efforts of many diseases.