Ewald, C. Y. | bioRxiv Science

bioRxiv2020

The extracellular matrix phenome across species

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

systems biology↗

bioRxiv2019

Heterogeneity in heat shock response dynamics caused by translation fidelity decline and proteostasis collapse

Genetics, environment, and stochasticity influence the rate of ageing in living organisms. Individual Caenorhabditis elegans that are genetically identical and cultured in the same environment have different lifespans, suggesting a significant role of stochasticity in ageing. We have developed a novel microfluidic methodology to measure heat-shock response as a surrogate marker for heterogeneity associated with lifespan and have quantified the heat-shock response of C. elegans at the population, single individual, and tissue levels. We have further mathematically modelled our data to identify the major drivers determining such heterogeneity. This approach demonstrates that protein translation and degradation rate constants explain the individuality of the heat-shock time-course dynamic. We observed a decline of protein turnover capacity in early adulthood, co-incidentally occurring as the predicted proteostasis collapse. We identified a decline of intestinal response as the tissue that underlies the individual heterogeneity. Additionally, we verified that individuals with enhanced translation fidelity in early adulthood live longer. Altogether, our results reveal that the stochastic onset of proteostasis collapse of somatic tissues during early adulthood reflects individual protein translation capacity underlying heterogenic ageing of isogenic C. elegans.

bioengineering↗