Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

Cui, Leilei; Yang, Bin; Xiao, Shijun; Gao, Jun; Baud, Amelie; Graham, Delyth; McBride, Martin; Dominiczak, Anna; Schafer, Sebastian; Lopez Aumatell, Regina; Mont, Carme; Fernandez Teruel, Albert; Hübner, Norbert; Flint, Jonathan; Mott, Richard; Huang, Lusheng

doi:http://dx.doi.org/10.1186/s13059-023-03060-2

Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

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Cui L, Yang B, Xiao S, Gao J, Baud A, Graham D, McBride M, Dominiczak A, Schafer S, Aumatell RL, Mont C, Teruel AF, Hübner N, Flint J, Mott R, Huang L. Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing. Genome Biol. 2023 Sep 29;24(1):215. DOI: 10.1186/s13059-023-03060-2

Abstract

Background: Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. Results: We systematically investigate both dominance-here representing any non-additive within-locus interaction-and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. Conclusions: Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.