EIF2S2 Retroposition into IRF2BP2 Underlies Fleece Variation in Sheep through the Formation of a Long Endogenous Double-Stranded RNA

International audience; Fleece variation, in composition and structure, observed in mammals is a consequence of a strong selective pressure for fiber production after domestication. Wild species with double coated fleece produced a variety of breeds with single coated fleece. In sheep, these two categories discriminate primitive sheep from woolly modern sheep (Ovis aries). Nowadays, fleece variation is segregating in the Romane breed with lambs owning a coat either long and hairy (characteristic of ancestral sheep) or short and woolly (typical to domestic sheep). Here we report that the “woolly” allele results from the insertion of an antisense EIF2S2 (Eukaryotic Translation Initiation Factor 2, Subunit 2 Beta) retrogene (called asEIF2S2) into the 3’ UTR of the IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) gene leading to an abnormal IRF2BP2 transcript. We provide evidence that this chimeric IRF2BP2/asEIF2S2 messenger, by targeting the genuine sense EIF2S2 RNA and creating a long endogenous double-stranded RNA, alters the expression of EIF2S2 mRNA. This is the first example, to our knowledge of a phenotype arising from the modulation of messengers accumulation via a RNA-RNA hybrid itself generated through a retroposition gene mechanism. Altogether our results bring new insights on (i) the mammalian hair morphogenesis with the identification of EIF2S2 and IRF2BP2 as novel key regulators and (ii) the sheep population history thanks to the characterization of the molecular origin of an evolutionary phenotypic variation. Furthermore, these findings will contribute to a sustainable sheep production system since lambs carrying a hairy fleece are more adapted and robust to environmental harsh conditions.