XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris).
XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris).
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DOI：
10.1371/journal.pone.0186331
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sinclair AH
中科院分区：
文献类型：
--
作者：
Meyers-Wallen VN;Boyko AR;Danko CG;Grenier JK;Mezey JG;Hayward JJ;Shannon LM;Gao C;Shafquat A;Rice EJ;Pujar S;Eggers S;Ohnesorg T;Sinclair AH
性别决定机制的研究已经取得了显著进展，但许多性发育障碍（DSD）的原因仍然未知。特别令人感兴趣的是一种罕见的XX DSD亚型，其中个体对Y染色体上的睾丸决定因子SRY呈阴性，但发育睾丸或卵睾丸，并且这两种表型发生在同一家族中。这是一种自然发生的疾病，在人类（智人）和狗（C。familiaris）。犬XX DSD模型中的表型与人XX DSD亚型的表型惊人相似。本研究的目的是鉴定1）犬模型中与XX DSD相关的变体和2）犬胚胎性腺中可能提供因果关系信息的基因表达改变。利用全基因组关联研究（GWAS）和全基因组测序（WGS），我们鉴定了C.在犬模型和受影响的纯种犬中，与XX DSD相关的家族常染色体9（CFA 9）。这是第一个遗传性犬XX DSD的标记。它位于人类疾病的犬直系同源物中SOX 9的上游，位于17 q24。这一变异的遗传表明XX DSD是一个复杂的性状，其中品种遗传背景影响着遗传率。此外，在至少一个品种中，纯合变异基因型与胚胎致死性相关。我们对犬模型中存在XX DSD风险的胚胎性腺中的基因表达研究（RNA-seq和PRO-seq）进行了分析，发现与XX对照组相比，RSPO 1显著下调，而SOX 9或其他已知睾丸途径基因没有显著上调。基于这些数据，提出了一种新的机制，其中作用于RSPO 1上游的分子病变诱导表观基因组性腺镶嵌。
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.
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影响因子：
9.8
作者：
Boyko AR;Quignon P;Li L;Schoenebeck JJ;Degenhardt JD;Lohmueller KE;Zhao K;Brisbin A;Parker HG;vonHoldt BM;Cargill M;Auton A;Reynolds A;Elkahloun AG;Castelhano M;Mosher DS;Sutter NB;Johnson GS;Novembre J;Hubisz MJ;Siepel A;Wayne RK;Bustamante CD;Ostrander EA
通讯作者：
Ostrander EA
影响因子：
4.5
作者：
Auton A;Rui Li Y;Kidd J;Oliveira K;Nadel J;Holloway JK;Hayward JJ;Cohen PE;Greally JM;Wang J;Bustamante CD;Boyko AR
通讯作者：
Boyko AR
影响因子：
3.5
作者：
Chassot, Anne-Amandine;Ranc, Fariba;Chaboissier, Marie-Christine
通讯作者：
Chaboissier, Marie-Christine
影响因子：
48
作者：
Danko CG;Hyland SL;Core LJ;Martins AL;Waters CT;Lee HW;Cheung VG;Kraus WL;Lis JT;Siepel A
通讯作者：
Siepel A
影响因子：
30.8
作者：
Benko, Sabina;Fantes, Judy A.;Lyonnet, Stanislas
通讯作者：
Lyonnet, Stanislas