Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever
Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever
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DOI：
10.1098/rstb.2011.0299
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发表时间：
2012-03-19
影响因子：
6.3
通讯作者：
Sabeti, Pardis C.
中科院分区：
文献类型：
--
作者：
Andersen, Kristian G.;Shylakhter, Ilya;Sabeti, Pardis C.
快速进化的病毒和其他病原体可能对人类进化产生巨大影响，因为自然选择会增加提供抗病能力的遗传变异的流行。随着人类遗传变异的大型数据集的出现，我们可以在人类基因组中寻找由这些致病微生物驱动的自然选择的特征。基于这种方法，我们先前假设拉沙病毒（LASV）可能是拉沙出血热流行的西非人群中自然选择的驱动因素。在这项研究中，我们为这一概念提供了进一步的证据。通过对来自国际单倍型图谱联盟和1000个基因组联盟的全基因组数据进行选择测试，我们证明了LARGE和白细胞介素21（IL 21）这两个与LASV感染性和免疫性有关的基因的正选择证据。我们进一步定位的选择信号，使用最近开发的复合多信号的方法，内含子和这些基因的推定的调控区域。我们的研究结果表明，自然选择可能有针对性的变异，产生选择性剪接或差异基因表达的LARGE和IL 21。总体而言，我们的研究支持了这样的假设，即LASV施加的选择压力可能导致了赋予拉沙热抗性的特定等位基因的出现，并开辟了新的研究途径。
Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit.