Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus

Crosses between the two North American rodent species Peromyscus polionotus (PO) and Peromyscus maniculatus (BW) yield parent-of-origin effects on bot h embryonic and placental growth(1,2). The two species are approximately th e same size, but a female BW crossed with a male PO produces offspring that are smaller than either parent. In the reciprocal cross, the offspring are oversized and typically die before birth. Rare survivors are exclusively f emale, consistent with Haldane's rule, which states that in instances of hy brid sterility or inviability, the heterogametic sex tends to be more sever ely affected(3). To understand these sex- and parent-of-origin-specific pat terns of overgrowth, we analysed reciprocal backcrosses. Our studies reveal that hybrid inviability is partially due to a maternally expressed X-linke d PO locus and an imprinted paternally expressed autosomal BW locus. In add ition, the hybrids display skewing of X-chromosome inactivation in favour o f the expression of the BW X chromosome. The most severe overgrowth is acco mpanied by widespread relaxation of imprinting of mostly paternally express ed genes. Both genetic and epigenetic mechanisms underlie hybrid inviabilit y in Peromyscus and hence have a role in the establishment and maintenance of reproductive isolation barriers in mammals.