Whole-genome de novo sequencing reveals genomic variants associated with differences of sex development in SRY negative pigs.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-09-02 DOI:10.1186/s13293-024-00644-w
Jinhua Wu, Shuwen Tan, Zheng Feng, Haiquan Zhao, Congying Yu, Yin Yang, Bingzhou Zhong, Wenxiao Zheng, Hui Yu, Hua Li
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引用次数: 0

Abstract

Background: Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. In more than 50% of human DSD cases, a molecular diagnosis is not available. In intensively farmed pig populations, the incidence of XX DSD pigs is relatively high, leading to economic losses for pig breeders. Interestingly, in the majority of 38, XX DSD pigs, gonads still develop into testis-like structures or ovotestes despite the absence of the testis-determining gene (SRY). However, the current understanding of the molecular background of XX DSD pigs remains limited.

Methods: Anatomical and histological characteristics of XX DSD pigs were analysed using necropsy and HE staining. We employed whole-genome sequencing (WGS) with 10× Genomics technology and used de novo assembly methodology to study normal female and XX DSD pigs. Finally, the identified variants were validated in 32 XX DSD pigs, and the expression levels of the candidate variants in the gonads of XX DSD pigs were further examined.

Results: XX DSD pigs are characterised by the intersex reproductive organs and the absence of germ cells in the seminiferous tubules of the gonads. We identified 4,950 single-nucleotide polymorphisms (SNPs) from non-synonymous mutations in XX DSD pigs. Cohort validation results highlighted two specific SNPs, "c.218T > C" in the "Interferon-induced transmembrane protein 1 gene (IFITM1)" and "c.1043C > G" in the "Newborn ovary homeobox gene (NOBOX)", which were found exclusively in XX DSD pigs. Moreover, we verified 14 candidate structural variants (SVs) from 1,474 SVs, identifying a 70 bp deletion fragment in intron 5 of the WW domain-containing oxidoreductase gene (WWOX) in 62.5% of XX DSD pigs. The expression levels of these three candidate genes in the gonads of XX DSD pigs were significantly different from those of normal female pigs.

Conclusion: The nucleotide changes of IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment of the WWOX were the most dominant variants among XX DSD pigs. This study provides a theoretical basis for better understanding the molecular background of XX DSD pigs. DSD are conditions affecting development of the gonads or genitalia. These disorders can happen in many different types of animals, including pigs, goats, dogs, and people. In people, DSD happens in about 0.02-0.13% of births, and in pigs, the rate is between 0.08% and 0.75%. Pigs have a common type of DSD where the animal has female chromosomes (38, XX) but no SRY gene, which is usually found on the Y chromosome in males. XX DSD pigs may look like both males and females on the outside and have testis-like or ovotestis (a mix of ovary and testis) gonads inside. XX DSD pigs often lead to not being able to have piglets, slower growth, lower chance of survival, and poorer meat quality. Here, we used a method called whole-genome de novo sequencing to look for variants in the DNA of XX DSD pigs. We then checked these differences in a larger group of pigs. Our results reveal the nucleotide changes in IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment in intron 5 of the WWOX, all linked to XX DSD pigs. The expression levels of these three genes were also different in the gonads of XX DSD pigs compared to normal female pigs. These variants are expected to serve as valuable molecular markers for XX DSD pigs. Because pigs are a lot like humans in their genes, physiology, and body structure, this research could help us learn more about what causes DSD in people.

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全基因组从头测序揭示了与 SRY 阴性猪性别发育差异相关的基因组变异。
背景:性别发育差异(DSD)是指染色体、性腺或表型性别不典型的先天性疾病。超过 50% 的人类 DSD 病例无法进行分子诊断。在集约化养殖的猪群中,XX DSD 猪的发病率相对较高,给养猪户造成了经济损失。有趣的是,在大多数 38 XX DSD 猪中,尽管没有睾丸决定基因(SRY),但性腺仍然发育成睾丸样结构或卵巢。然而,目前对XX DSD猪分子背景的了解仍然有限:方法:通过尸体解剖和 HE 染色分析了 XX DSD 猪的解剖学和组织学特征。我们利用 10× 基因组学技术进行了全基因组测序(WGS),并使用从头组装方法研究了正常雌性猪和 XX DSD 猪。最后,在 32 头 XX DSD 猪身上验证了所发现的变异,并进一步研究了候选变异在 XX DSD 猪性腺中的表达水平:结果:XX DSD猪的特点是生殖器官无性,性腺的曲细精管中没有生殖细胞。我们从XX DSD猪的非同义突变中鉴定出4950个单核苷酸多态性(SNPs)。队列验证结果表明,"干扰素诱导跨膜蛋白 1 基因(IFITM1)"中的 "c.218T > C "和 "新生卵巢同源染色体基因(NOBOX)"中的 "c.1043C > G "这两个特定的 SNP 只存在于 XX DSD 猪体内。此外,我们还从 1,474 个 SV 中验证了 14 个候选结构变异(SV),在 62.5% 的 XX DSD 猪中发现了含 WW domain 的氧化还原酶基因(WWOX)内含子 5 中的 70 bp 缺失片段。这三个候选基因在XX DSD猪性腺中的表达水平与正常雌性猪有显著差异:结论:IFITM1(c.218T > C)、NOBOX(c.1043 C > G)和WWOX的一个70 bp缺失片段的核苷酸变化是XX DSD猪中最主要的变异。这项研究为更好地了解 XX DSD 猪的分子背景提供了理论依据。DSD是影响性腺或生殖器发育的疾病。这些疾病可发生在许多不同类型的动物身上,包括猪、山羊、狗和人。人的 DSD 发生率约为 0.02%-0.13%,而猪的发生率为 0.08%-0.75%。猪有一种常见的 DSD,即动物有雌性染色体(38,XX),但没有 SRY 基因,而 SRY 基因通常存在于雄性猪的 Y 染色体上。XX DSD 猪外表看起来既像雄性也像雌性,但体内却有类似睾丸或卵睾(卵巢和睾丸的混合体)的性腺。XX DSD 猪通常会导致无法产仔、生长缓慢、存活率低和肉质较差。在这里,我们使用了一种名为全基因组从头测序的方法来寻找XX DSD猪DNA中的变异。然后,我们在更大的猪群中检验了这些差异。我们的结果显示,IFITM1(c.218T > C)、NOBOX(c.1043 C > G)和 WWOX 内含子 5 中一个 70 bp 缺失片段的核苷酸变化都与 XX DSD 猪有关。与正常母猪相比,这三个基因在 XX DSD 猪性腺中的表达水平也有所不同。这些变异有望成为 XX DSD 猪的重要分子标记。由于猪在基因、生理和身体结构方面与人类非常相似,这项研究可以帮助我们更多地了解导致人类 DSD 的原因。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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