XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris).
Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sex Development (DSD) remains unknown. Of particular interest is a rare XX DSD subtype in which individuals are negative for SRY, the testis determining factor on...
Published in: | PLOS ONE |
---|---|
Main Authors: | , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2017
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pone.0186331 https://doaj.org/article/24ff92ff10bd439682ff6dbe565a1f34 |
id |
ftdoajarticles:oai:doaj.org/article:24ff92ff10bd439682ff6dbe565a1f34 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:24ff92ff10bd439682ff6dbe565a1f34 2023-05-15T15:51:08+02:00 XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). Vicki N Meyers-Wallen Adam R Boyko Charles G Danko Jennifer K Grenier Jason G Mezey Jessica J Hayward Laura M Shannon Chuan Gao Afrah Shafquat Edward J Rice Shashikant Pujar Stefanie Eggers Thomas Ohnesorg Andrew H Sinclair 2017-01-01T00:00:00Z https://doi.org/10.1371/journal.pone.0186331 https://doaj.org/article/24ff92ff10bd439682ff6dbe565a1f34 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5650465?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0186331 https://doaj.org/article/24ff92ff10bd439682ff6dbe565a1f34 PLoS ONE, Vol 12, Iss 10, p e0186331 (2017) Medicine R Science Q article 2017 ftdoajarticles https://doi.org/10.1371/journal.pone.0186331 2022-12-31T02:56:55Z Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sex Development (DSD) 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 of these phenotypes occur in the same family. This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris). Phenotypes in the canine XX DSD model are strikingly similar to those of the human XX DSD subtype. 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 C. familiaris autosome 9 (CFA9) that is associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker identified for inherited canine XX DSD. It lies upstream of SOX9 within the canine ortholog for the human disorder, which resides on 17q24. Inheritance of this 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. Our analysis of gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation in comparison to XX controls, without significant upregulation of SOX9 or other known testis pathway genes. Based on these data, a novel mechanism is proposed in which molecular lesions acting upstream of RSPO1 induce epigenomic gonadal mosaicism. Article in Journal/Newspaper Canis lupus Directory of Open Access Journals: DOAJ Articles The ''Y'' ENVELOPE(-112.453,-112.453,57.591,57.591) PLOS ONE 12 10 e0186331 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Medicine R Science Q |
spellingShingle |
Medicine R Science Q Vicki N Meyers-Wallen Adam R Boyko Charles G Danko Jennifer K Grenier Jason G Mezey Jessica J Hayward Laura M Shannon Chuan Gao Afrah Shafquat Edward J Rice Shashikant Pujar Stefanie Eggers Thomas Ohnesorg Andrew H Sinclair XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
topic_facet |
Medicine R Science Q |
description |
Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sex Development (DSD) 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 of these phenotypes occur in the same family. This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris). Phenotypes in the canine XX DSD model are strikingly similar to those of the human XX DSD subtype. 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 C. familiaris autosome 9 (CFA9) that is associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker identified for inherited canine XX DSD. It lies upstream of SOX9 within the canine ortholog for the human disorder, which resides on 17q24. Inheritance of this 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. Our analysis of gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation in comparison to XX controls, without significant upregulation of SOX9 or other known testis pathway genes. Based on these data, a novel mechanism is proposed in which molecular lesions acting upstream of RSPO1 induce epigenomic gonadal mosaicism. |
format |
Article in Journal/Newspaper |
author |
Vicki N Meyers-Wallen Adam R Boyko Charles G Danko Jennifer K Grenier Jason G Mezey Jessica J Hayward Laura M Shannon Chuan Gao Afrah Shafquat Edward J Rice Shashikant Pujar Stefanie Eggers Thomas Ohnesorg Andrew H Sinclair |
author_facet |
Vicki N Meyers-Wallen Adam R Boyko Charles G Danko Jennifer K Grenier Jason G Mezey Jessica J Hayward Laura M Shannon Chuan Gao Afrah Shafquat Edward J Rice Shashikant Pujar Stefanie Eggers Thomas Ohnesorg Andrew H Sinclair |
author_sort |
Vicki N Meyers-Wallen |
title |
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
title_short |
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
title_full |
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
title_fullStr |
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
title_full_unstemmed |
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris). |
title_sort |
xx disorder of sex development is associated with an insertion on chromosome 9 and downregulation of rspo1 in dogs (canis lupus familiaris). |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pone.0186331 https://doaj.org/article/24ff92ff10bd439682ff6dbe565a1f34 |
long_lat |
ENVELOPE(-112.453,-112.453,57.591,57.591) |
geographic |
The ''Y'' |
geographic_facet |
The ''Y'' |
genre |
Canis lupus |
genre_facet |
Canis lupus |
op_source |
PLoS ONE, Vol 12, Iss 10, p e0186331 (2017) |
op_relation |
http://europepmc.org/articles/PMC5650465?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0186331 https://doaj.org/article/24ff92ff10bd439682ff6dbe565a1f34 |
op_doi |
https://doi.org/10.1371/journal.pone.0186331 |
container_title |
PLOS ONE |
container_volume |
12 |
container_issue |
10 |
container_start_page |
e0186331 |
_version_ |
1766386186536878080 |