Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease
Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease
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DOI：
10.1101/gr.127738.111
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发表时间：
2012-03-01
期刊：
影响因子：
7
通讯作者：
Hahn, Matthew W.
中科院分区：
文献类型：
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作者：
Casola, Claudio;Zekonyte, Ugne;Hahn, Matthew W.
建立引起遗传疾病的DNA突变的分子基础对于理解人类遗传疾病的起源，性质和临床后遗症至关重要。大多数与疾病相关的突变构成了单基本取代，以及由DNA复制误差和修复受损碱的修复产生的短缺失和/或插入。然而，病理突变也可以通过寄生虫序列之间的非相互重组事件引入，这种现象称为腹膜间基因转化率（IGC）。到目前为止，IGC事件与20多个人类基因的病理有关。然而，人类基因组中的大量重复基因序列意味着更多与疾病相关的突变可以通过IGC起源。在这里，我们使用了全基因组计算方法来鉴定来自IGC事件的疾病相关突变。我们的方法揭示了数百个可能由IGC引起的已知病理突变。此外，我们确定了由IGC产生的遗传性疾病突变的数十个高信任病例，与分析的所有基因相似。与此类突变相关的供体序列的大约一半是功能性寄生基因，这表明上皮相互作用或差异表达模式将决定对重复基因之间特定取代的适用性的影响。此外，我们确定了数千个迄今未描述的且可能通过IGC引起的有害突变。我们的发现揭示了间间基因转化对人遗传疾病范围的影响的程度。
Establishing the molecular basis of DNA mutations that cause inherited disease is of fundamental importance to understanding the origin, nature, and clinical sequelae of genetic disorders in humans. The majority of disease-associated mutations constitute single-base substitutions and short deletions and/or insertions resulting from DNA replication errors and the repair of damaged bases. However, pathological mutations can also be introduced by non reciprocal recombination events between paralogous sequences, a phenomenon known as interlocus gene conversion (IGC). IGC events have thus far been linked to pathology in more than 20 human genes. However, the large number of duplicated gene sequences in the human genome implies that many more disease-associated mutations could originate via IGC. Here, we have used a genome-wide computational approach to identify disease-associated mutations derived from IGC events. Our approach revealed hundreds of known pathological mutations that could have been caused by IGC. Further, we identified several dozen high-confidence cases of inherited disease mutations resulting from IGC in similar to 1% of all genes analyzed. About half of the donor sequences associated with such mutations are functional paralogous genes, suggesting that epistatic interactions or differential expression patterns will determine the impact upon fitness of specific substitutions between duplicated genes. In addition, we identified thousands of hitherto undescribed and potentially deleterious mutations that could arise via IGC. Our findings reveal the extent of the impact of interlocus gene conversion upon the spectrum of human inherited disease.