CGC Canine WGS Databank
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB36030 | ENA |
REPOSITORIES: ENA
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Project description:Canine whole-genome sequences (WGS) that we have generated by the Canine Genetics Centre (CGC).
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Project description:Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sexual Development remains unknown. Of particular interest is a rare XX DSD subtype in which individuals are negative for SRY, the testis determining factor on the Y chromosome, yet develop testes or ovotestes, and both phenotypes occur in the same family. This is a naturally occurring disorder in humans and dogs (Canis lupus familiaris), and phenotypes in the canine XX DSD model are strikingly similar to those in this type of human XX DSD. The purposes of this study were to identify 1) a variant associated with XX DSD in the canine model and 2) gene expression alterations in canine embryonic gonads that could be informative to causation. Using a genome wide association study (GWAS) and whole genome sequencing (WGS), we identified a variant on Canis familiaris autosome 9 (CFA9) that is significantly associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker and candidate mutation identified for inherited canine XX DSD, and it lies within the canine ortholog for the human disorder (OMIM 278850). Inheritance of the variant indicates that XX DSD is a complex trait in which breed genetic background affects penetrance. Furthermore, the homozygous variant genotype is associated with embryonic lethality in at least one breed. Gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation without significant upregulation of SOX9 or other known testis pathway genes. A novel mechanism is proposed in which the canine XX DSD mutation acts upstream of RSPO1 to induce epigenomic gonadal mosaicism.
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