Regulation of sex determination in mice by a non-coding genomic region

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 reversa...

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Bibliographic Details
Published in:Genetics (Austin) 2014-07, Vol.197 (3), p.885-897
Main Authors: Arboleda, Valerie A, Fleming, Alice, Barseghyan, Hayk, Délot, Emmanuèle, Sinsheimer, Janet S, Vilain, Eric
Format: Article
Language:English
Subjects:
Animals
Breeding
Chromosomes
Chromosomes, Mammalian - genetics
DNA, Intergenic - genetics
Epigenetics
Female
Founder Effect
Genetic research
Genome - genetics
Genomics
Heterozygote
Homozygote
Investigations
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mus domesticus
Polymorphism, Single Nucleotide - genetics
Regulatory Sequences, Nucleic Acid - genetics
Rodents
Sex Determination Processes - genetics
Sexes
SOX9 Transcription Factor - metabolism
Time Factors
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Summary: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.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1534/genetics.113.160259