A method to delineate de novo missense variants across pathways prioritizes genes linked to autism.
A method to delineate de novo missense variants across pathways prioritizes genes linked to autism.
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DOI：
10.1126/scitranslmed.abc1739
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发表时间：
2021-05-19
影响因子：
17.1
通讯作者：
Lichtarge O
中科院分区：
文献类型：
--
作者：
Koire A;Katsonis P;Kim YW;Buchovecky C;Wilson SJ;Lichtarge O
基因型-表型关系塑造了健康和人群健康，但仍然很难预测和解释。在这里，我们在突变的环境中应用进化行动方法来揭开与自闭症谱系障碍(ASD)相关的基因和途径。进化行为通过测量适应环境中的运动，基于同源序列中的系统发育距离和替换几率来预测错义变体对蛋白质功能的影响。通过检查2384名ASD患者(先证者)的368条途径，我们发现23条途径，总共398个基因，具有从头开始的错误变异，偏向于随机地高于预期的进化行为得分，包括轴突发生、突触传递和神经发育途径。即使只使用新的候选基因，候选基因中从头开始的和遗传的错义变异对适合度的预测影响也与ASD患者的智商相关。这一方法展示了如何将进化行动方法应用于生物学，以整合队列中的错义变体，以识别导致共同表型的基因。使用这种方法，我们已经检测到了那些最有可能导致ASD发病的错义变异，并阐明了它们的表型影响。一种进化行为方法阐明了自闭症中的基因-表型关系。
Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method in mutational landscapes to unravel genes and pathways connected to autism spectrum disorder (ASD). Evolutionary action predicts the impact of missense variants on protein function by measuring motions in fitness landscapes, based on phylogenetic distances and substitution odds in homologous sequences. By examining 368 pathways across 2,384 individuals with ASD (probands), we found that 23 pathways, a total of 398 genes, had de novo missense variants biased to higher evolutionary action scores than expected by random chance, including axonogenesis, synaptic transmission, and neurodevelopmental pathways. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for using only the new gene candidates. This approach demonstrates how the evolutionary action method can be applied in biology to integrate missense variants over a cohort to identify genes contributing a shared phenotype. Using this approach, we have detected those missense variants most likely to contribute to ASD pathogenesis and have elucidated their phenotypic impact. An evolutionary action approach elucidates the genotype-phenotype relationship in autism.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
影响因子：
30.8
作者：
Chen S;Fragoza R;Klei L;Liu Y;Wang J;Roeder K;Devlin B;Yu H
通讯作者：
Yu H
错义突变热点识别神经发育障碍基因和功能域
影响因子：
25
作者：
Geisheker MR;Heymann G;Wang T;Coe BP;Turner TN;Stessman HAF;Hoekzema K;Kvarnung M;Shaw M;Friend K;Liebelt J;Barnett C;Thompson EM;Haan E;Guo H;Anderlid BM;Nordgren A;Lindstrand A;Vandeweyer G;Alberti A;Avola E;Vinci M;Giusto S;Pramparo T;Pierce K;Nalabolu S;Michaelson JJ;Sedlacek Z;Santen GWE;Peeters H;Hakonarson H;Courchesne E;Romano C;Kooy RF;Bernier RA;Nordenskjöld M;Gecz J;Xia K;Zweifel LS;Eichler EE
通讯作者：
Eichler EE