Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression

ABSTRACT

Allele-specific expression (ASE) is a phenomenon where one allele is preferentially expressed over the other. Genetic and epigenetic factors cause ASE by altering the final allelic composition of a gene’s product, leading to expression imbalances that can have functional consequences on phenotypes. Environmental signals also impact allele-specific gene regulation, but how they contribute to this crosstalk remains understudied. Here, we explored how allelic genotype, parent-of-origin, tissue type, sex, and dietary fat simultaneously influence ASE biases in a F₁ reciprocal cross mouse model. Male and female mice from a F₁ reciprocal cross of the LG/J and SM/J strains were fed a high-fat or low-fat diet. We harnessed strain-specific variants to distinguish between two classes of ASE: parent-of-origin dependent (unequal expression based on an allele’s parental origin) and sequence dependent (unequal expression based on an allele’s nucleotide identity). We present a comprehensive genome-wide map of ASE patterns across three metabolically-relevant tissues and nine environmental contexts. We find that both ASE classes are highly dependent on tissue type and environmental context. They vary across metabolic tissues, between males and females, and in response to dietary fat levels. Surprisingly, we also find several genes with inconsistent ASE biases that switched direction across tissues and/or contexts (e.g. SM/J biased in one cohort, LG/J biased in another). Together, our results provide novel insights into how genetic, epigenetic, and environmental mechanisms govern allele-specific gene regulation, which is an essential step towards deciphering the genotype to phenotype map.