Digenic inheritance in medical genetics.
Digenic inheritance in medical genetics.
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DOI：
10.1136/jmedgenet-2013-101713
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发表时间：
2013-10
影响因子：
4
通讯作者：
Schäffer AA
中科院分区：
文献类型：
--
作者：
Schäffer AA
双基因遗传（DI）是遗传复杂疾病的最简单的遗传形式。与成千上万的单基因突变导致人类疾病的报道相比，只有几十种人类疾病表型在某些谱系中有DI的证据。高通量测序（HTS）的出现使得识别单基因疾病原因变得更简单，并且可以类似地简化DI的证明，因为人们可以同时在同一样本中发现两个基因的突变。然而，到2012年，我只能找到一个使用HTS的人类DI的例子;在那个例子中，HTS只发现了两个基因中的第二个。为了探索期望与现实之间的差距，我试图收集所有具有狭义定义的人类DI的例子，并根据收集到的证据的类型以及是否有复制来对它们进行分类。两个强有力的趋势是候选基因的知识和蛋白质-蛋白质相互作用（PPI）的知识在大多数已发表的人类DI的例子中是有帮助的。相比之下，遗传连锁分析的定位方法在鉴定人类DI的潜在基因方面大多不成功。基于经验数据，我建议将HTS与不断增长的已建立PPI网络相结合，可能会加快未来人类DI的发现，并加强证据。
Digenic inheritance (DI) is the simplest form of inheritance for genetically complex diseases. By contrast with the thousands of reports that mutations in single genes cause human diseases, there are only dozens of human disease phenotypes with evidence for DI in some pedigrees. The advent of high-throughput sequencing (HTS) has made it simpler to identify monogenic disease causes and could similarly simplify proving DI because one can simultaneously find mutations in two genes in the same sample. However, through 2012, I could find only one example of human DI in which HTS was used; in that example, HTS found only the second of the two genes. To explore the gap between expectation and reality, I tried to collect all examples of human DI with a narrow definition and characterise them according to the types of evidence collected, and whether there has been replication. Two strong trends are that knowledge of candidate genes and knowledge of protein–protein interactions (PPIs) have been helpful in most published examples of human DI. By contrast, the positional method of genetic linkage analysis, has been mostly unsuccessful in identifying genes underlying human DI. Based on the empirical data, I suggest that combining HTS with growing networks of established PPIs may expedite future discoveries of human DI and strengthen the evidence for them.
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