A marker-derived gene network reveals the regulatory role of PPARGC1A, HNF4G, and FOXP3 in intramuscular fat deposition of beef cattle

Y Ramayo-Caldas, M R S Fortes, N J Hudson, L R Porto-Neto, S Bolormaa, W Barendse, M Kelly, S S Moore, M E Goddard, S A Lehnert, A Reverter

High intramuscular fat (IMF) awards price premiums to beef producers and is associated with meat quality and flavour. Studying gene interactions and pathways that affect IMF might unveil causative physiological mechanisms and inform genomic selection, leading to increased accuracy of predictions of breeding value. To study gene interactions and pathways, a gene network was derived from genetic markers associated with direct measures of IMF, other fat phenotypes, feedlot performance and a number of meat quality traits relating to body conformation, development and metabolism that might be plausibly expected to interact with IMF biology. Marker associations were inferred from genome-wide association studies (GWAS) based on high density genotypes and 29 traits measured on 10,181 beef cattle animals from three breed types. For the network inference, SNP pairs were assessed according to the strength of the correlation between their additive association effects across the 29 traits. The co-association inferred network was formed by 2,434 genes connected by 28,283 edges. Topological network parameters suggested a highly cohesive network, in which the genes are strongly functionally interconnected. Pathway and network analyses pointed towards a trio of transcription factors (TF) as key regulators of carcass IMF: PPARGC1A, HNF4G and FOXP3. Importantly, none of these genes would have been deemed as significantly associated with IMF from the GWAS. Instead, a total of 313 network genes show significant co-association with the three TF. These genes belong to a wide variety of biological functions, canonical pathways and genetic networks linked to IMF-related phenotypes. In summary, our GWAS and network predictions are supported by the current literature and suggest a co-operative role for the three TF and other interacting genes including CAPN6, STC2, MAP2K4, EYA1, COPS5, XKR4, NR2E1, TOX, ATF1, ASPH, TGS1, and TTPA as modulators of carcass and meat quality traits in beef cattle.