Genetic architecture of natural variation of cardiac performance from flies to humans.
Genetic architecture of natural variation of cardiac performance from flies to humans.
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DOI：
10.7554/elife.82459
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发表时间：
2022-11-16
期刊：
影响因子：
7.7
通讯作者：
Perrin L
中科院分区：
文献类型：
--
作者：
Saha S;Spinelli L;Castro Mondragon JA;Kervadec A;Lynott M;Kremmer L;Roder L;Krifa S;Torres M;Brun C;Vogler G;Bodmer R;Colas AR;Ocorr K;Perrin L
破译人类心脏疾病的遗传结构至关重要，但其潜在的复杂性是一个主要障碍。我们研究了果蝇遗传参考小组（DGRP）测序的近交系心脏性能的自然变化。全基因组关联研究（GWAS）确定了与心脏特征自然变异相关的遗传网络，用于了解受影响的分子和细胞过程。我们发现的非编码变异体用于绘制潜在的非编码调控区域，进而用于预测转录因子（tf）结合位点。同源tf，其中许多本身具有与心脏功能变化相关的多态性，也通过心脏特异性敲除得到验证。此外，我们表明，与心脏性能变异性相关的自然变异影响了一组与平均性状相关的基因重叠，但通过同一基因的不同变异。此外，我们发现表型变异也与基因调控网络的自然变异有关。更重要的是，我们记录了与果蝇和人类心脏表型相关的基因之间的相关性，这支持了从节肢动物到哺乳动物调节成年心脏功能的保守遗传结构。具体来说，PAX9和EGR2在两种模型中都在心律调节中发挥了作用，这表明在果蝇中发现的心功能自然变化的特征可以加速在人类中的发现。
Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome-wide associations studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict transcription factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart-specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.
果蝇心脏功能障碍的遗传变异。
影响因子：
3.7
作者：
Ocorr, Karen A.;Crawley, Timothy;Gibson, Greg;Bodmer, Rolf
通讯作者：
Bodmer, Rolf