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中科院徐书华等揭示人类疾病基因特征

2011/12/30 来源:科学网
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国际著名学术期刊《人类分子遗传学》在线发表了中科院上海生命科学研究院计算生物学所徐书华和金力研究组的研究成果。该研究系统分析了人类疾病相关基因的特征,并与其他各类基因进行了全面比较。

近日,国际著名学术期刊《人类分子遗传学》在线发表了中科院上海生命科学研究院计算生物学所徐书华和金力研究组的研究成果。该研究系统分析了人类疾病相关基因的特征,并与其他各类基因进行了全面比较。这对认识人类疾病基因的特性,了解致病遗传变异的产生、基因组分布、自然选择和进化机制,以及理解疾病基因表达和调控网络模式有重要理论意义,对研究复杂疾病的实验设计也具参考价值。

传统上,遗传类疾病可分为罕见的孟德尔遗传病和较常见的复杂疾病。孟德尔遗传病往往由单基因控制,在人群中的发病率很低,表现出很强的家族聚集性,如镰刀性贫血、白化病、色盲等,其单基因变异效应较强。复杂疾病往往受多个基因控制,在人群中发病率高,如癌症、高血压、糖尿病等,其遗传模式复杂,每个基因变异的效应很弱。

然而,此次研究人员通过对最新的遗传类疾病基因数据库分析发现,孟德尔遗传病基因和复杂疾病基因并不像通常的分类那样界限分明。相反,两类疾病基因存在大量的重叠,即与两类疾病共同关联的基因(双联基因),而且比基于统计学随机假设的预期数目多出8倍。研究人员对已知的人类基因进行了分类,包括双联基因、必需基因、单基因疾病基因、复杂疾病基因和其他基因。

研究者发现,双联基因和复杂疾病基因都受到了近期的正向自然选择,而必需基因和单基因疾病基因受到较强的负向选择。对物种间差异数据分析表明,必需基因总是最保守,这支持必需基因在漫长的进化史中总是受到最强的负向选择;而双联基因在保守性上排在第二位,提示其在进化中也受到较强的负向选择。

同时,该研究比较了各类基因在基因表达模式、基因结构等方面的差异。研究人员推测,双联基因的很多特征和它们在复杂疾病和单基因疾病中的双重作用相关。

这是首个对双联基因特征进行系统分析的研究,结果同时也对其他四类基因的特征有新的认识。比如该研究发现,很多复杂疾病基因落在拷贝数变异区域,表明拷贝数变异可能在多种复杂疾病的遗传因素中起重要作用。

 

A Systematic Characterization of Genes Underlying both Complex and Mendelian Diseases

Wenfei Jin, Pengfei Qin, Haiyi Lou, Li Jin, Shuhua Xu

Traditionally, genetic disorders have been classified as either Mendelian or complex diseases. This nosology has greatly benefited genetic counseling and the development of gene mapping strategies. However, based on two well-established databases, we identified that 54% (524 of 968) of the Mendelian diseases genes were also involved in complex diseases, and this kind of genes has not been systematically analyzed. Here, we classified human genes into five categories: Mendelian and complex diseases (MC) genes, Mendelian but not complex diseases (MNC) genes, complex but not Mendelian diseases (CNM) genes, essential genes and OTHER genes. Firstly, we found that MC genes were associated with more diseases and phenotypes, and were involved in more complex protein-protein interaction network than MNC or CNM genes on average. Secondly, MC genes encoded the longest proteins and had the highest transcript count among all gene categories. Especially, tissue specificity of MC genes was much higher than that of any other gene categories (P< 7.5×10-5), although their expression level was similar to that of essential genes. Thirdly, evidences from different aspects supported that MC genes have been subjected to both purifying and positive selection. Interestingly, functions of some human disease genes might be different from those of their orthologous genes in non-primate-mammalians since they were even less conserved than OTHER genes. The significant over-representation of CNVs in CNM genes suggested the important roles of CNVs in complex diseases. In brief, our study not only revealed the characteristics of MC genes, but also provided new insights into the other four gene categories.

文献链接:http://hmg.oxfordjournals.org/content/early/2011/12/20/hmg.ddr599.abstract?sid=1ac12eb3-d57d-4b8f-8373-10b0bc4c134f

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