Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.
Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.
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DOI：
10.1186/s12915-022-01475-0
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发表时间：
2023-02-03
期刊：
影响因子：
5.4
通讯作者：
Moshiri, Ala
中科院分区：
文献类型：
--
作者：
Chee, Justine;Lanoue, Louise;Clary, Dave L.;Higgins, Kendall;Bower, Lynette;Flenniken, Ann;Guo, Ruolin;Adams, David;Bosch, Fatima;Braun, Robert E.;Brown, Steve D. M.;Chin, H. -J. Genie;Dickinson, Mary;Hsu, Chih-Wei;Dobbie, Michael;Gao, Xiang;Galande, Sanjeev;Grobler, Anne;Heaney, Jason;Herault, Yann;de Angelis, Martin Hrabe;Mammano, Fabio;Nutter, Lauryl M. J.;Parkinson, Helen;Qin, Chuan;Shiroishi, Toshi;Sedlacek, Radislav;Seong, J-K;Xu, Ying;Brooks, Brian;McKerlie, Colin;Lloyd, K. C. Kent;Westerberg, Henrik;Moshiri, Ala
小眼、无眼和缺损（MAC）谱系疾病包括一组在儿童视力损害中起作用的眼部畸形。虽然眼畸形的主要原因是已知的遗传性质，与80%的情况下显示功能丧失突变的眼睛发育基因OTX 2或SOX 2，遗传异常的MAC的其余情况下是不完全了解。这项研究旨在确定早期眼睛发育所需的新基因和途径。此外，胚胎发育过程中眼睛形成的途径也不完全清楚。本研究旨在通过对哺乳动物基因组的系统性正向筛选，鉴定早期眼发育所需的新基因和途径。查询国际小鼠表型分析联盟（IMPC）数据库（数据发布17.0，2022年8月1日），在小鼠胚胎中发现了74个具有遗传相关眼睛缺陷的独特敲除系（基因）。绝大多数眼部异常是小眼或无眼，这些发现与人类MAC谱疾病最相关。文献检索显示，74个品系中有27个先前发表过基因敲除小鼠模型，其中只有15个具有在原始出版物中鉴定的眼部缺陷。这12个先前发表的基因敲除没有报告的眼部异常和47个未发表的基因敲除与IMPC鉴定的眼部异常代表了59个先前与小鼠早期眼部发育无关的基因。在这59个基因中，我们确定了19个具有报告的人眼表型的基因。总体而言，IMPC数据的挖掘产生了40个以前未涉及的与哺乳动物眼睛发育相关的基因。生物信息学分析表明，几个IMPC基因共定位于几个蛋白质合成代谢和多能性途径在早期眼睛发育。值得注意的是，我们的分析表明，丝氨酸-甘氨酸途径产生甘氨酸，一个线粒体一碳供体叶酸一碳代谢（FOCM），是必不可少的眼睛形成。利用单基因敲除小鼠品系的全基因组表型筛选、STRING分析和生物信息学方法，本研究鉴定了迄今为止与MAC表型无关的基因，为研究涉及眼睛发育的新分子和细胞机制提供了模型。这些发现有可能加快这种先天性致盲疾病的诊断和治疗。在线版本包含补充材料，可通过10.1186/s12915-022-01475-0获得。
Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease. The online version contains supplementary material available at 10.1186/s12915-022-01475-0.
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影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
64.8
作者：
HILL, RE;FAVOR, J;VANHEYNINGEN, V
通讯作者：
VANHEYNINGEN, V
影响因子：
2.5
作者：
Albertson, RC;Payne-Ferreira, TL;Yelick, PC
通讯作者：
Yelick, PC
影响因子：
2.7
作者：
Burnett JB;Lupu FI;Eggenschwiler JT
通讯作者：
Eggenschwiler JT
影响因子：
64.8
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
通讯作者：
Murray SA