Background: Atypical external genitalia are often a sign of reproductive organ pathologies and infertility with both environmental or genetic causes, including karyotypic abnormalities. Genome-wide association studies (GWAS) provide a means for identifying chromosomal regions harboring deleterious DNA-variants causing such phenotypes. We performed a GWAS to unravel the causes of incidental cases of atypically small vulvae in German Landrace gilts. Results: A case-control GWAS involving Illumina porcine SNP60 BeadChip-called genotypes of 17 gilts with atypically small vulvae and 1,818 control animals (fertile German Landrace sows) identified a significantly associated region on the X-chromosome (P = 8.81×10^-43). Inspection of whole-genome sequencing data in the critical area allowed us to pinpoint a likely causal variant in the form of a nonsense mutation of bone morphogenetic protein-15 (Sscrofa11.1_X:g.44618787C>T, BMP15:p.R212X). The mutant allele occurs at a frequency of 6.2% in the German Landrace breeding population. Homozygous gilts exhibit underdeveloped, most likely not functional ovaries and are not fertile. Male carriers do not seem to manifest defects. Heterozygous sows produce 0.41±0.02 (P=4.5×10^-83) piglets more than wildtype animals. However, the mutant allele's positive effect on litter size accompanies a negative impact on lean meat growth. Conclusion: Our results provide an example for the power of GWAS in identifying the genetic causes of a fuzzy phenotype and add to the list of natural deleterious BMP15 mutations that affect fertility in a dosage-dependent manner, the first time in a poly-ovulatory species. We advise eradicating the mutant allele from the German Landrace breeding population since the adverse effects on the lean meat growth outweigh the larger litter size in heterozygous sows.

中文翻译：

---

骨形态发生蛋白15（BMP15）的无意义突变会导致猪的不育和产仔数增加。

背景：不典型的外生殖器通常是生殖器官病变和不育的标志，有环境或遗传原因，包括核型异常。全基因组关联研究（GWAS）提供了一种方法，用于鉴定具有导致此类表型的有害DNA变异的染色体区域。我们进行了GWAS分析，以揭示德国长白猪后备母猪非典型小外阴的偶然病例。结果：病例对照GWAS涉及Illumina猪SNP60 BeadChip，称为17个具有非典型小外阴的后备母猪的基因型和1,818只对照动物（可育的德国长白猪），在X染色体上发现了显着相关的区域（P = 8.81×10 ^-43）。通过检查关键区域的全基因组测序数据，我们可以精确定位骨形态发生蛋白-15（Sscrofa11.1_X：g.44618787C> T，BMP15：p.R212X）的无义突变形式。突变等位基因在德国地方品种育种种群中的发生频率为6.2％。纯合的后备母猪表现出发育不足的卵巢，很可能不是功能性卵巢，并且不育。男性携带者似乎没有表现出缺陷。杂合母猪产生0.41±0.02（P = 4.5×10 ^-83）仔猪多于野生型动物。但是，突变等位基因对产仔数的正面影响对瘦肉的生长产生负面影响。结论：我们的结果提供了一个实例，证明了GWAS在识别模糊表型的遗传原因方面的功效，并将其添加到以排毒方式影响生育力的自然有害BMP15突变列表中，这是多排卵物种中的首次。我们建议根除德国长白繁殖种群的突变等位基因，因为对瘦肉生长的不利影响超过杂合母猪更大的窝产仔数。