The structural origin of metabolic quantitative diversity.
The structural origin of metabolic quantitative diversity.
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DOI：
10.1038/srep31463
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发表时间：
2016-08-16
影响因子：
4.6
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Koshiba S;Motoike I;Kojima K;Hasegawa T;Shirota M;Saito T;Saigusa D;Danjoh I;Katsuoka F;Ogishima S;Kawai Y;Yamaguchi-Kabata Y;Sakurai M;Hirano S;Nakata J;Motohashi H;Hozawa A;Kuriyama S;Minegishi N;Nagasaki M;Takai-Igarashi T;Fuse N;Kiyomoto H;Sugawara J;Suzuki Y;Kure S;Yaegashi N;Tanabe O;Kinoshita K;Yasuda J;Yamamoto M
通过对512名人群的代谢物数量性状与全基因组序列数据的关联研究，探讨了酶结构变异与代谢表型的关系。我们确定了代谢物和非同义变体之间的五个重要关联。这些非同义变体中的四个位于参与代谢紊乱的酶中，并且对这些中度非同义变体的结构分析表明它们位于催化位点或相关调节结构域的外围区域中。相比之下，还确定了代谢物水平变化较大的两个个体，这些个体保留了罕见的变体，这导致了位于催化位点附近的非同义变体。这些结果首次证明了在人类群体中变异频率、结构位置和对表型的影响相互关联，并暗示代谢个体性和疾病易感性可能由中度变异和更有害但罕见的变异引起。
Relationship between structural variants of enzymes and metabolic phenotypes in human population was investigated based on the association study of metabolite quantitative traits with whole genome sequence data for 512 individuals from a population cohort. We identified five significant associations between metabolites and non-synonymous variants. Four of these non-synonymous variants are located in enzymes involved in metabolic disorders, and structural analyses of these moderate non-synonymous variants demonstrate that they are located in peripheral regions of the catalytic sites or related regulatory domains. In contrast, two individuals with larger changes of metabolite levels were also identified, and these individuals retained rare variants, which caused non-synonymous variants located near the catalytic site. These results are the first demonstrations that variant frequency, structural location, and effect for phenotype correlate with each other in human population, and imply that metabolic individuality and susceptibility for diseases may be elicited from the moderate variants and much more deleterious but rare variants.