title: Neofunctionalization of the Sec1 α1,2fucosyltransferase paralogue in leporids contributes to glycan polymorphism and resistance to rabbit hemorrhagic disease virus.
abstract: RHDV (rabbit hemorrhagic disease virus), a virulent calicivirus, causes high mortalities in European rabbit populations (Oryctolagus cuniculus). It uses α1,2fucosylated glycans, histo-blood group antigens (HBGAs), as attachment factors, with their absence or low expression generating resistance to the disease. Synthesis of these glycans requires an α1,2fucosyltransferase. In mammals, there are three closely located α1,2fucosyltransferase genes rSec1, rFut2 and rFut1 that arose through two rounds of duplications. In most mammalian species, Sec1 has clearly become a pseudogene. Yet, in leporids, it does not suffer gross alterations, although we previously observed that rabbit Sec1 variants present either low or no activity. Still, a low activity rSec1 allele correlated with survival to an RHDV outbreak. We now confirm the association between the α1,2fucosyltransferase loci and survival. In addition, we show that rabbits express homogenous rFut1 and rFut2 levels in the small intestine. Comparison of rFut1 and rFut2 activity showed that type 2 A, B and H antigens recognized by RHDV strains were mainly synthesized by rFut1, and all rFut1 variants detected in wild animals were equally active. Interestingly, rSec1 RNA levels were highly variable between individuals and high expression was associated with low binding of RHDV strains to the mucosa. Co-transfection of rFut1 and rSec1 caused a decrease in rFut1-generated RHDV binding sites, indicating that in rabbits, the catalytically inactive rSec1 protein acts as a dominant-negative of rFut1. Consistent with neofunctionalization of Sec1 in leporids, gene conversion analysis showed extensive homogenization between Sec1 and Fut2 in leporids, at variance with its limited degree in other mammals. Gene conversion additionally involving Fut1 was also observed at the C-terminus. Thus, in leporids, unlike in most other mammals where it became extinct, Sec1 evolved a new function with a dominant-negative effect on rFut1, contributing to fucosylated glycan diversity, and allowing herd protection from pathogens such as RHDV.
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France; Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Kristina
authors: K
authors: Nyström
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France; CIBIO, InBIO-Research Network in Biodiversity and Evolutionary Biology, Universidade do Porto, Campus de Vairão, Rua Padre Armando Quintas, Vairão, Portugal.
authors: Joana
authors: J
authors: Abrantes
authors: CIBIO, InBIO-Research Network in Biodiversity and Evolutionary Biology, Universidade do Porto, Campus de Vairão, Rua Padre Armando Quintas, Vairão, Portugal; Departamento de Biologia, Faculdade de Ciências da Universidade do Porto, Porto, Portugal.
authors: Ana Margarida
authors: AM
authors: Lopes
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France.
authors: Béatrice
authors: B
authors: Le Moullac-Vaidye
authors: Office National de la Chasse et de la Faune Sauvage, Direction des Etudes et de la Recherche, CS 42355, Nantes, France.
authors: Stéphane
authors: S
authors: Marchandeau
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France.
authors: Jézabel
authors: J
authors: Rocher
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France; Oniris, Ecole Nationale vétérinaire, Agroalimentaire et de L'alimentation, Nantes, France.
authors: Nathalie
authors: N
authors: Ruvoën-Clouet
authors: CIBIO, InBIO-Research Network in Biodiversity and Evolutionary Biology, Universidade do Porto, Campus de Vairão, Rua Padre Armando Quintas, Vairão, Portugal; Departamento de Biologia, Faculdade de Ciências da Universidade do Porto, Porto, Portugal; CITS-Centro de Investigação em Tecnologias da Saúde, IPSN, CESPU, Gandra, Portugal.
authors: Pedro J
authors: PJ
authors: Esteves
authors: INSERM, U892; CNRS, UMR6299; Nantes University, Nantes, France.
authors: Jacques
authors: J
authors: Le Pendu
mesh_terms: D000818:Animals; D001483:Base Sequence; D017250:Caliciviridae Infections / Q000235:genetics*; D060467:Disease Resistance / Q000235:genetics; D005647:Fucosyltransferases / Q000235:genetics*; D017929:Hemorrhagic Disease Virus, Rabbit / Q000235:genetics*; D007793:Lagomorpha; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011134:Polysaccharides / Q000235:genetics*; D011817:Rabbits; D014162:Transfection
chemical_list: D011134:Polysaccharides; D005647:Fucosyltransferases