Statzer Cyril, Ewald Collin Y
Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine, Schwerzenbach, Zürich CH-8603, Switzerland.
Matrix Biol Plus. 2020 Jun 23;8:100039. doi: 10.1016/j.mbplus.2020.100039. eCollection 2020 Nov.
Extracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across multiple species to define their extracellular matrix phenomes. By using the previously defined matrisomes of humans, mice, zebrafish, and , we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (, ) and fibrillin () are each associated with >150 distinct phenotypes in humans, whereas collagen , Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found that , and and their corresponding orthologues have the most phenotypes across species. Out of the 42,551 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases.
细胞外基质对于细胞和机体功能至关重要。最近的全基因组和全表型关联研究开始揭示与基因变异相关的广泛表型谱。然而，与细胞外基质基因中的基因变异相关的所有表型的表型组或谱尚不清楚。在此，我们分析了跨多个物种的超过两百万条记录的基因型与表型关系，以定义它们的细胞外基质表型组。通过使用先前定义的人类、小鼠、斑马鱼等的基质体，我们发现细胞外基质表型组占整个表型组的3%至10%。胶原蛋白（如、）和原纤蛋白（）在人类中各自与超过150种不同的表型相关，而胶原蛋白、Wnt和音猬因子（shh）信号在其他物种中主要相关。我们确定了基质体基因的表型指纹，发现、及其相应的直系同源物在跨物种中具有最多的表型。在具有已定义基质体的五个物种的42551个独特的基质体基因型与表型关系中，我们构建了相互作用网络，以识别与直系同源物表型和新表型相关的潜在分子成分。因此，我们的网络提供了一个框架来预测未评估的表型及其潜在的分子相互作用。这些框架为基质体基因型与表型关系提供了信息，并可能为研究人类表型和疾病提供复杂的生物模型系统选择。
