A nonsense mutation in TMEM95 encoding a nondescript transmembrane protein causes idiopathic male subfertility in cattle.
A nonsense mutation in TMEM95 encoding a nondescript transmembrane protein causes idiopathic male subfertility in cattle.
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DOI：
10.1371/journal.pgen.1004044
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发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Fries R
中科院分区：
文献类型：
--
作者：
Pausch H;Kölle S;Wurmser C;Schwarzenbacher H;Emmerling R;Jansen S;Trottmann M;Fuerst C;Götz KU;Fries R
在人类和模式生物中已经发现了导致男性生殖能力降低的遗传变异，其中大多数都会影响精液质量。偶尔，男性生育能力严重受损，尽管精液分析仍然没有任何明显的病理学发现（即，特发性低生育力）。在大多数牛群中，人工授精（AI）需要在授精前仔细检查所有射精。虽然异常射精被拒绝，但人工授精的成功率在AI公牛中差异很大。为了确定这种变异的遗传原因，我们进行了全基因组关联研究（GWAS）。Fleckvieh（FV）群体的7962头AI公牛可获得652，856个SNP的插补基因型。根据1530万次人工授精对男性生殖能力（MRA）进行了评估。GWAS在牛19号染色体上发现了一个强关联信号（P = 4.08 × 10 − 59）。 随后的纯合性定位显示了一个共同的1386 kb的扩展纯合性片段在40公牛繁殖性能异常差。在35，671次使用这些公牛精液样本的授精中，只有1.7%成功。繁殖性能正常的公牛没有一头是纯合的，表明隐性遗传。利用43只动物的全基因组重测序数据揭示了跨膜蛋白95编码基因TMEM95中的候选因果无义突变（rs378652941，c.483C> A，p.Cys161X），该突变随后在1990头AI公牛中得到验证。免疫组织化学研究表明，TMEM95位于精子的表面的生育力的动物，而它是缺乏精子的生育力低下的动物。这些发现意味着TMEM95的完整性是不受干扰的施肥所必需的。我们的研究结果表明，TMEM95的缺乏严重损害男性生殖性能的牛，并首次揭示了与TMEM95基因组变异相关的表型效应。雄性生育力受损是许多物种的普遍状况，通常由异常的精液质量来解释。在某些情况下，男性生育能力严重受损，尽管精液质量没有任何明显的病理发现（即，特发性男性生育力低下）。特发性男性生育力低下的遗传机制往往仍然无法解释。在本文中，我们报告了一个重复遗传变异的特发性雄性不育牛群体。我们使用650，000个全基因组SNP标记在> 7900头人工授精公牛中进行基因分型，以确定潜在的基因组区域。我们利用43只动物的全基因组重测序数据来鉴定TMEM95中编码一种无法描述的跨膜蛋白的因果性功能丧失突变。我们证明，跨膜蛋白95位于质膜的精子的生育力的动物，而它是缺乏精子的生育力低下的动物。我们的研究结果表明，完整的跨膜蛋白95是需要一个不受干扰的受精。这是第一份揭示与任何生物体中TMEM95基因组变异相关的表型效应的报告。
Genetic variants underlying reduced male reproductive performance have been identified in humans and model organisms, most of them compromising semen quality. Occasionally, male fertility is severely compromised although semen analysis remains without any apparent pathological findings (i.e., idiopathic subfertility). Artificial insemination (AI) in most cattle populations requires close examination of all ejaculates before insemination. Although anomalous ejaculates are rejected, insemination success varies considerably among AI bulls. In an attempt to identify genetic causes of such variation, we undertook a genome-wide association study (GWAS). Imputed genotypes of 652,856 SNPs were available for 7962 AI bulls of the Fleckvieh (FV) population. Male reproductive ability (MRA) was assessed based on 15.3 million artificial inseminations. The GWAS uncovered a strong association signal on bovine chromosome 19 (P = 4.08×10−59). Subsequent autozygosity mapping revealed a common 1386 kb segment of extended homozygosity in 40 bulls with exceptionally poor reproductive performance. Only 1.7% of 35,671 inseminations with semen samples of those bulls were successful. None of the bulls with normal reproductive performance was homozygous, indicating recessive inheritance. Exploiting whole-genome re-sequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c.483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. These findings imply that integrity of TMEM95 is required for an undisturbed fertilisation. Our results demonstrate that deficiency of TMEM95 severely compromises male reproductive performance in cattle and reveal for the first time a phenotypic effect associated with genomic variation in TMEM95. Impaired male fertility is a prevalent condition in many species and is often explained by aberrant semen quality. In some cases, male fertility is severely compromised although semen quality is without any apparent pathological findings (i.e., idiopathic male subfertility). The genetic mechanisms underlying idiopathic male subfertility often remain unexplained. In the present paper, we report a recessively inherited variant of idiopathic male subfertility in a cattle population. We use 650,000 genome-wide SNP markers genotyped in >7900 artificial insemination bulls to pinpoint the underlying genomic region. We take advantage of whole-genome re-sequencing data of 43 animals to identify a causal loss-of-function mutation in TMEM95 encoding a nondescript transmembrane protein. We demonstrate that transmembrane protein 95 is located at the plasma membrane of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. Our results indicate that integrity of transmembrane protein 95 is required for an undisturbed fertilisation. This is the first report to reveal a phenotypic effect associated with genomic variation in TMEM95 in any organism.
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3.5
作者：
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通讯作者：
Kirkpatrick, B. W.
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