The extracellular matrix phenome across species

Abstract

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 hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish, Drosophila, and C. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagen COL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found that MSTN, CTSD, LAMB2, HSPG2, and COL11A2 and their corresponding orthologues have the most phenotypes across species. Out of the 42558 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. HighlightsO_LI7.6% of the human phenome originates from variations in matrisome genes C_LIO_LI11671 phenotypes are linked to matrisome genes of humans, mice, zebrafish, Drosophila, and C. elegans C_LIO_LIExpected top ECM phenotypes are developmental, morphological and structural phenotypes C_LIO_LINonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes C_LI