The relationship between gene co-expression network connectivity and phenotypic prediction sheds light at the core of the omnigenic theory

Abstract Recent literature on the differential role of genes within networks, including the omnigenic model, distinguishes core from peripheral genes in the layout underlying phenotypes. Cores are typically few, each of them highly contributes to phenotypic variation, but because they are so few, they altogether only explain a small part of trait heritability. In contrast, peripherals, each of small influence, are so numerous that they finally lead phenotypic variation. We collected and sequenced RNA from 459 European black poplars and built co-expression networks to define core and peripheral genes as the most and least connected ones. We computed the role of each of these gene sets in the prediction of phenotypes and showed that cores contribute additively to phenotypes, consistent with a downstream position in a biological cascade, while peripherals interact to influence phenotypes, consistent with an upstream position. Quantitative and population genetics analyses further revealed that cores are more expressed than peripherals but they tend to vary less and to be more differentiated between populations suggesting that they are more constrained by natural selection. Our work is the first attempt to integrate core and peripheral terminologies from co-expression networks and omnigenic theory. In the end, we showed, that there seems to be a strong overlap between them, with core genes from co-expression networks likely being a mixture of integrative hubs with a direct effect on phenotype in agreement with the omnigenic theory, and master regulators which control the overall metabolic flow towards the phenotype.