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 multiple species to define their extracellular matrix phenomes. By using the 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 >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 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.

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

“…extracellular matrix (ECM) proteins. Cytoskeleton remodeling often leads to ECM remodeling, a process important for mechanotransduction and healthy aging (Ewald et al, 2015;Ewald, 2019;Statzer and Ewald, 2020). We also observed a strong longevity-associated enrichment for ECM components in the kidney transcriptomics (Figure 3), highlighting mechanotransduction as a process potentially involved in longevity.…”

Extracellular matrix gene expression signatures as cell type and cell state identifiers

“…In this regard, the fact that we observed evolutionary conserved matreotypes, in homologous cell types of mice and chicken highlights the potential of model organisms research. Identification of conserved orthologous ECM-based genotype-phenotype interactions might thus inform human biology or delineate novel ECM-related drug targets promoting healthy aging [57] , [58] .…”

Youthful and age‐related matreotypes predict drugs promoting longevity

“…The human matrisome encompasses 1027 protein‐encoding genes that either form the ECM, such as collagens, glycoproteins, and proteoglycans; associate with ECM ( e.g ., TGFβ, Wnts, and cytokines); or remodel the ECM ( e.g ., matrix metalloproteinases (MMPs)) (Naba et al, 2016 ). The matrisome represents about 4% of the human genome and is functionally implicated in about 8% of the total 7037 unique human phenotypes (Statzer & Ewald, 2020 ). Age‐related phenotypes rank among the top matrisome‐phenotypic categories across species (Ewald, 2019 ; Taha & Naba, 2019 ).…”