High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution.
High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution.
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DOI：
10.1371/journal.pgen.1000249
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
Korbel, Jan O.
中科院分区：
文献类型：
--
作者：
Hasin, Yehudit;Olender, Tsviya;Khen, Miriam;Gonzaga-Jauregui, Claudia;Kim, Philip M.;Urban, Alexander Eckehart;Snyder, Michael;Gerstein, Mark B.;Lancet, Doron;Korbel, Jan O.
嗅觉受体(ORs)参与气味识别，是哺乳动物最大的蛋白质超家族。在人类中，OR基因的基因组含量显著减少，反映在相对较小的谱系大小和高比例的人类假基因(∼55%)上。由于最近的几项低分辨率研究表明OR基因组座位经常受到拷贝数变异(CNV)的影响，我们推测CNV可能在人类嗅觉谱系的进化中发挥重要作用。我们使用高分辨率寡核苷酸拼接微阵列来检测851个OR基因和假基因座位上的CNV。对来自三个群体的25名有祖先的个体进行基因组DNA检测，我们发现93个OR基因座位和151个假基因座位受到CNV的影响，产生了不同人群的OR剂量马赛克。我们的数据表明，∼50%的CNV涉及多个OR，其中最大的CNV跨越11个基因座。与以前的报道不同，我们观察到在OR假基因中CNV比在完整基因中更常见，这可能是由于选择性限制和CNV形成偏差。此外，我们的结果显示，在与人类相近或在黑猩猩中缺乏一对一直系同源基因的ORs中，CNV的含量较高。有趣的是，在后者中，我们观察到CNV的损失比获得的丰富，这一发现可能与已知的人类OR谱系的减少有关。对122个样本ORs进行的定量PCR实验与微阵列结果吻合良好，并发现了另外23个CNV。重要的是，这些实验让我们发现了9个常见的缺失等位基因，它们影响了15个OR基因和5个假基因。与黑猩猩参考基因组的比较表明，所有的缺失等位基因都来自人类，因此表明人类特有的缺失对个体OR基因含量有深刻的影响。此外，这些缺失等位基因可能用于未来嗅觉个体间差异的遗传关联研究。拷贝数变异(CNV)是DNA片段的缺失和复制，是哺乳动物基因组大部分变异的原因。为了帮助阐明CNV对进化和功能的影响，我们提供了人类最大的基因超家族，即嗅觉受体(OR)基因超家族的高分辨率CNV图谱。我们的地图显示每个人的嗅觉CNV是以前报道的两倍，这表明人类的OR剂量有相当大的差异。具体地说，我们的发现表明，CNV在进化的“年轻”ORs中特别丰富，其中一些起源于人类和黑猩猩的分裂，这意味着CNV可能在持续塑造人类OR谱系的基因出生和基因丢失过程中发挥重要作用。此外，我们描述了15个显示频繁的人类特有缺失等位基因的OR基因座。此外，我们提供了最近涉及一对OR基因的非等位基因同源重组事件的证据，形成了可能具有新的气味结合特性的新的融合OR。这类事件可能潜在地与人类嗅觉检测谱系中的个别功能“洞”有关，未来的研究将解决我们的基因组变异图的特定化学感觉影响。
Olfactory receptors (ORs), which are involved in odorant recognition, form the largest mammalian protein superfamily. The genomic content of OR genes is considerably reduced in humans, as reflected by the relatively small repertoire size and the high fraction (∼55%) of human pseudogenes. Since several recent low-resolution surveys suggested that OR genomic loci are frequently affected by copy-number variants (CNVs), we hypothesized that CNVs may play an important role in the evolution of the human olfactory repertoire. We used high-resolution oligonucleotide tiling microarrays to detect CNVs across 851 OR gene and pseudogene loci. Examining genomic DNA from 25 individuals with ancestry from three populations, we identified 93 OR gene loci and 151 pseudogene loci affected by CNVs, generating a mosaic of OR dosages across persons. Our data suggest that ∼50% of the CNVs involve more than one OR, with the largest CNV spanning 11 loci. In contrast to earlier reports, we observe that CNVs are more frequent among OR pseudogenes than among intact genes, presumably due to both selective constraints and CNV formation biases. Furthermore, our results show an enrichment of CNVs among ORs with a close human paralog or lacking a one-to-one ortholog in chimpanzee. Interestingly, among the latter we observed an enrichment in CNV losses over gains, a finding potentially related to the known diminution of the human OR repertoire. Quantitative PCR experiments performed for 122 sampled ORs agreed well with the microarray results and uncovered 23 additional CNVs. Importantly, these experiments allowed us to uncover nine common deletion alleles that affect 15 OR genes and five pseudogenes. Comparison to the chimpanzee reference genome revealed that all of the deletion alleles are human derived, therefore indicating a profound effect of human-specific deletions on the individual OR gene content. Furthermore, these deletion alleles may be used in future genetic association studies of olfactory inter-individual differences. Copy-number variants (CNVs) are deletions and duplications of DNA segments, responsible for most of the genome variation in mammals. To help elucidate the impact of CNVs on evolution and function, we provide a high-resolution CNV map of the largest gene superfamily in humans, i.e., the olfactory receptor (OR) gene superfamily. Our map reveals twice as many olfactory CNVs per person than previously reported, indicating considerable OR dosage variations in humans. In particular, our findings indicate that CNVs are specifically enriched among evolutionary “young” ORs, some of which originated following the human-chimpanzee split, implying that CNVs may play an important role in the gene-birth and gene-loss processes that continuously shape the human OR repertoire. Furthermore, we describe 15 OR gene loci showing frequent human-specific deletion alleles. Additionally, we present evidence for a recent non-allelic homologous recombination event involving a pair of OR genes, forming a novel fusion OR that may harbor novel odorant-binding properties. Such events may potentially relate to individual functional “holes” in the human smell-detection repertoire, and future studies will address the specific chemosensory impact of our genomic variation map.
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