title: Regulation of sex determination in mice by a non-coding genomic region.
abstract: To identify novel genomic regions that regulate sex determination, we utilized the powerful C57BL/6J-Y(POS) (B6-Y(POS)) model of XY sex reversal where mice with autosomes from the B6 strain and a Y chromosome from a wild-derived strain, Mus domesticus poschiavinus (Y(POS)), show complete sex reversal. In B6-Y(POS), the presence of a 55-Mb congenic region on chromosome 11 protects from sex reversal in a dose-dependent manner. Using mouse genetic backcross designs and high-density SNP arrays, we narrowed the congenic region to a 1.62-Mb genomic region on chromosome 11 that confers 80% protection from B6-Y(POS) sex reversal when one copy is present and complete protection when two copies are present. It was previously believed that the protective congenic region originated from the 129S1/SviMJ (129) strain. However, genomic analysis revealed that this region is not derived from 129 and most likely is derived from the semi-inbred strain POSA. We show that the small 1.62-Mb congenic region that protects against B6-Y(POS) sex reversal is located within the Sox9 promoter and promotes the expression of Sox9, thereby driving testis development within the B6-Y(POS) background. Through 30 years of backcrossing, this congenic region was maintained, as it promoted male sex determination and fertility despite the female-promoting B6-Y(POS) genetic background. Our findings demonstrate that long-range enhancer regions are critical to developmental processes and can be used to identify the complex interplay between genome variants, epigenetics, and developmental gene regulation.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Arboleda
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088.
authors.forename: Alice
authors.initials: A
authors.lastname: Fleming
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088.
authors.forename: Hayk
authors.initials: H
authors.lastname: Barseghyan
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088.
authors.forename: Emmanuèle
authors.initials: E
authors.lastname: Délot
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088 Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088 Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7088 evilain@ucla.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
mesh_terms: D000818:Animals; D001947:Breeding; D033481:Chromosomes, Mammalian / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D016678:Genome / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000378:metabolism; D019849:Sex Determination Processes / Q000235:genetics*; D013997:Time Factors
chemical_list: D021901:DNA, Intergenic; D055758:SOX9 Transcription Factor
keywords: congenic; disorders of sex development; gonad; sex determination; sex reversal; testis