title: TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse.
abstract: Genome-wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X-linked meiosis-specific gene, promotes meiotic recombination and chromosomal synapsis. Here, we report that TEX11 is mutated in infertile men with non-obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non-causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X-linked Tex11 gene, providing genetic evidence for the X-to-autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome-wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Infertility Center of St. Louis, St. Luke's Hospital, St. Louis, MO, USA.
authors.forename: Sherman
authors.initials: S
authors.lastname: Silber
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.affiliation: Department of Urology, Boston University Medical Center, Boston, MA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oates
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Marszalek
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Skaletsky
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Brown
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA Duke-Nus Graduate Medical School Singapore, Singapore City, Singapore.
authors.forename: Steve
authors.initials: S
authors.lastname: Rozen
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Page
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA pwang@vet.upenn.edu.
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D053713:Azoospermia / Q000235:genetics*; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D011995:Recombination, Genetic
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D050505:Mutant Proteins; C000598435:TEX11 protein, human
keywords: X chromosome; chromosomal synapsis; infertility; meiosis; recombination