Ohnologs are overrepresented in pathogenic copy number mutations
Ohnologs are overrepresented in pathogenic copy number mutations
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DOI：
10.1073/pnas.1309324111
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发表时间：
2014-01-07
影响因子：
11.1
通讯作者：
Collier, David A.
中科院分区：
文献类型：
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作者：
McLysaght, Aoife;Makino, Takashi;Collier, David A.
许多罕见的拷贝数变异（CNV），包括缺失和重复，与发育障碍有关，包括精神分裂症、自闭症、智力障碍和癫痫。致病性可能源自 CNV 基因座内包含的一种或多种基因的剂量敏感性。为了了解病理生理学，需要确定每个 CNV 内的特定致病基因。在本研究中，我们检验了以下假设：ohnologs（祖先全基因组复制事件后保留的基因，通常对剂量敏感）在致病性 CNV 中比例过高。我们选择了三组与拷贝数致病性有关的基因：（i）罕见疾病相关 CNV 内的基因定位，（ii）负遗传选择下新生 CNV 内的基因，以及（iii）通过临床阵列比较基因组杂交研究鉴定为潜在致病性的基因。我们比较了这些基因组和对照基因之间的 ohnologs 比例，映射到未知与疾病相关的 CNV。我们发现，无论 CNV 是如何鉴定的，在映射到致病性 CNV 的基因中，ohnolog 明显过多，超过 90% 的基因含有 ohnolog，而对照 CNV >100 kb，只有约 30% 含有 ohnolog。在一些 CNV 中，例如 del15p11.2 (CYFIP1) 和 dup/del16p13.11 (NDE1)，最可能的先前候选基因也是 ohnolog，基因 VIPR2 和 NRXN1 也是如此，它们均在不含其他基因的短 CNV 中发现。我们的结果支持这样的假设：ohnologs代表基因组的关键剂量敏感元件，可能是致病性CNV观察到的一些有害表型的原因，因此是易于识别的候选基因以供进一步研究。
A number of rare copy number variants (CNVs), including both deletions and duplications, have been associated with developmental disorders, including schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study.