Long-term persistence of both functional and non-functional alleles at the leukocyte immunoglobulin-like receptor A3 (LILRA3) locus suggests balancing selection
Long-term persistence of both functional and non-functional alleles at the leukocyte immunoglobulin-like receptor A3 (LILRA3) locus suggests balancing selection
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DOI：
10.1007/s00439-006-0152-y
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发表时间：
2006-05-01
期刊：
影响因子：
5.3
通讯作者：
Yabe, T
中科院分区：
文献类型：
--
作者：
Hirayasu, K;Ohashi, J;Yabe, T
白细胞免疫球蛋白样受体（LILR）家族由13个基因座组成，在这些基因中已经确定了许多变异。据报道，LILR基因的一些多态性与类风湿关节炎和多发性硬化症等疾病的易感性有关。LILRA3是LILR基因之一，由于6.7 kb的缺失，在不同人群中表现出存在或缺失的差异。在这项研究中，LILRA3基因的变异筛选显示，日本人的LILRA3缺失6.7 kb的等位基因频率较高（71%），与其他人群的报道频率相反。此外，我们在内含子1中发现了一个剪接受体突变，等位基因频率为19%，导致三个剪接异构体交替。令人惊讶的是，所有这些同工异构体都被发现在外显子3中含有过早终止密码子（ptc）。总的来说，大约80%的日本人缺乏功能性的LILRA3等位基因。最大似然聚结分析表明，功能等位基因和含ptc等位基因这两个主要谱系在人类中维持了275万年。这些结果促使我们假设平衡选择维持了LILRA3位点的功能和非功能等位基因。这一假设与在世界范围内存在功能性LILRA3等位基因时检测到6.7 kb的LILRA3缺失的观察结果是一致的。
The leukocyte immunoglobulin-like receptor (LILR) family consists of 13 loci, and a number of variations have been identified in these genes. Some polymorphisms of the LILR genes are reported to be associated with susceptibility to diseases such as rheumatoid arthritis and multiple sclerosis. LILRA3, one of the LILR genes, exhibits a presence or absence variation due to a 6.7-kb deletion in various populations. In this study, variation screening of the LILRA3 gene revealed high allele frequency of the 6.7-kb LILRA3 deletion (71%) in Japanese, in contrast to the frequency reported for the other populations. In addition, we identified a splice acceptor mutation in intron 1 with allele frequency of 19%, resulting in three alternatively spliced isoforms. Surprisingly, all of these isoforms were found to contain premature termination codons (PTCs) in the exon 3. Taken together, approximately 80% of Japanese lack functional LILRA3 alleles. The maximum likelihood coalescent analysis suggested that two major lineages, functional alleles and PTC-containing alleles, have been maintained for 2.75 million years in humans. These results prompted us to hypothesize that balancing selection had maintained both the functional and non-functional alleles at the LILRA3 locus. This hypothesis is consistent with the observation that the 6.7-kb LILRA3 deletion is detected worldwide in the presence of functional LILRA3 alleles.