A nonsense mutation of bone morphogenetic protein-15 (BMP15) causes both infertility and increased litter size in pigs

Flossmann, Gabriele; Wurmser, Christine; Pausch, Hubert; Tenghe, Amabel; Dodenhoff, J.; Dahinten, Günther; Götz, Kay-Uwe; Ruß, Ingolf; Fries, R.

doi:10.1186/s12864-020-07343-x

Cited by 8 publications

(6 citation statements)

References 33 publications

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“…Our meta-analyses approach using imputed sequence variants revealed six QTL of which five were associated with multiple traits. Several porcine pleiotropic loci are underpinned by heterozygous loss-of-function alleles that may have fatal consequences in the homozygous state [ 49 – 51 ]. Pleiotropic QTL have also been described in pigs for highly correlated traits [ 31 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs

et al. 2023

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Background Genetic correlations between complex traits suggest that pleiotropic variants contribute to trait variation. Genome-wide association studies (GWAS) aim to uncover the genetic underpinnings of traits. Multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS enable detecting variants associated with multiple phenotypes. In this study, we used array-derived genotypes and phenotypes for 24 reproduction, production, and conformation traits to explore differences between the two methods and used imputed sequence variant genotypes to fine-map six quantitative trait loci (QTL). Results We considered genotypes at 44,733 SNPs for 5,753 pigs from the Swiss Large White breed that had deregressed breeding values for 24 traits. Single-trait association analyses revealed eleven QTL that affected 15 traits. Multi-trait association testing and the meta-analysis of the single-trait GWAS revealed between 3 and 6 QTL, respectively, in three groups of traits. The multi-trait methods revealed three loci that were not detected in the single-trait GWAS. Four QTL that were identified in the single-trait GWAS, remained undetected in the multi-trait analyses. To pinpoint candidate causal variants for the QTL, we imputed the array-derived genotypes to the sequence level using a sequenced reference panel consisting of 421 pigs. This approach provided genotypes at 16 million imputed sequence variants with a mean accuracy of imputation of 0.94. The fine-mapping of six QTL with imputed sequence variant genotypes revealed four previously proposed causal mutations among the top variants. Conclusions Our findings in a medium-size cohort of pigs suggest that multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS provide very similar results. Although multi-trait association methods provide a useful overview of pleiotropic loci segregating in mapping populations, the investigation of single-trait association studies is still advised, as multi-trait methods may miss QTL that are uncovered in single-trait GWAS.

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Section: Discussionmentioning

confidence: 99%

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs

et al. 2023

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“…Numerous studies have demonstrated the essential role of BMP15/Bmp15 during the ovulatory period in mammals. Mutant models in mice and pigs, 6,13 as well as natural mutations of the BMP15 gene in humans and sheep, 7,10,11 have been linked with ovulatory defects. Also vaccination against BMP15 using synthetic peptides caused phenotypes in sheep and cattle 73,74 .…”

Section: Discussionmentioning

confidence: 99%

“…These species‐specific features reported for BMP15 / Bpm15 mutant variants seem associated to the species' reproductive strategy, generally resulting in more severe ovarian phenotypes in mono‐ versus poly‐ovulatory species 12 . However, a recent study in pig has shown, for the first time, natural BMP15 mutations clearly affecting fertility in a poly‐ovulatory species 13 . In teleost fish (animal group with high egg production capacity), the zebrafish bmp15 knockout is the only mutant model available to date.…”

Section: Introductionmentioning

confidence: 97%

Loss of bmp15 function in the seasonal spawner Atlantic salmon results in ovulatory failure

Crespo,

Fjelldal,

Hansen

et al. 2024

The FASEB Journal

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Bone morphogenetic protein 15 (BMP15) is an oocyte‐specific growth factor important for successful female reproduction in mammals. While mutations in BMP15/Bmp15 cause ovulatory deficiency and/or infertility in certain mammalian species, loss of bmp15 in zebrafish, a continuous spawner and the only bmp15 knockout model in fish to date, results in complete arrest of follicle development and later female‐to‐male sex reversal, preventing to examine effects on ovulation/fertilization. Here, we used Atlantic salmon, a seasonal spawner, and generated bmp15 mutants to investigate ovarian development and fertility. Histological and morphometric analyses revealed that in biallelic frameshift (bmp15 fs/fs) mutant ovaries, folliculogenesis started earlier, resulting in an advanced development compared to wild‐type (WT) controls, accompanied by a weaker expression of the (early) oocyte‐specific factor figla. This precocious ovarian development was followed in bmp15 fs/fs females by enhanced follicle atresia during vitellogenic stages. Although genes involved in steroid synthesis and signaling (star, cyp11b, cyp17a1 and esr1) were dramatically higher in late vitellogenic bmp15 fs/fs mutant ovaries, estradiol‐17β plasma levels were lower than in WT counterparts, potentially reflecting compensatory changes at the level of ovarian gene expression. At spawning, bmp15 fs/fs females displayed lower gonado‐somatic index values and reduced oocyte diameter, and the majority (71.4%), showed mature non‐ovulating ovaries with a high degree of atresia. The remaining (28.6%) females spawned eggs but they either could not be fertilized or, upon fertilization, showed severe malformations and embryonic mortality. Our results show that Bmp15 is required for proper follicle recruitment and growth and later ovulatory success in Atlantic salmon, providing an alternative candidate target to induce sterility in farmed salmon. Moreover, since loss of bmp15 in salmon, in contrast to zebrafish, does not result in female‐to‐male sex change, this is the first mutant model in fish allowing further investigations on Bmp15‐mediated functions in the ovulatory period.

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“…Thus far, 35,384 QTLs have been identified in pigs according to pigQTLdb, of which 3315 QTLs are associated with reproduction ( , 25 April 2022). In pigs, GWAS has identified numerous SNPs significantly associated with growth traits [ 4 , 5 ], meat quality [ 6 , 7 ], feed efficiency [ 8 , 9 ], semen traits [ 10 , 11 ], coat color [ 12 , 13 ], genetic defects [ 14 , 15 ], disease susceptibility [ 16 , 17 ], and microbial phenotypes [ 18 ]. However, most of them were genotyped based on SNP microarrays, and the density of markers is a key factor affecting GWAS efficiency [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Study on Reproductive Traits Using Imputation-Based Whole-Genome Sequence Data in Yorkshire Pigs

Sun

Xiao

Jiang

et al. 2023

Genes

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Reproductive traits have a key impact on production efficiency in the pig industry. It is necessary to identify the genetic structure of potential genes that influence reproductive traits. In this study, a genome-wide association study (GWAS) based on chip and imputed data of five reproductive traits, namely, total number born (TNB), number born alive (NBA), litter birth weight (LBW), gestation length (GL), and number of weaned (NW), was performed in Yorkshire pigs. In total, 272 of 2844 pigs with reproductive records were genotyped using KPS Porcine Breeding SNP Chips, and then chip data were imputed to sequencing data using two online software programs: the Pig Haplotype Reference Panel (PHARP v2) and Swine Imputation Server (SWIM 1.0). After quality control, we performed GWAS based on chip data and the two different imputation databases by using fixed and random model circulating probability unification (FarmCPU) models. We discovered 71 genome-wide significant SNPs and 25 potential candidate genes (e.g., SMAD4, RPS6KA2, CAMK2A, NDST1, and ADCY5). Functional enrichment analysis revealed that these genes are mainly enriched in the calcium signaling pathway, ovarian steroidogenesis, and GnRH signaling pathways. In conclusion, our results help to clarify the genetic basis of porcine reproductive traits and provide molecular markers for genomic selection in pig breeding.

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A nonsense mutation of bone morphogenetic protein-15 (BMP15) causes both infertility and increased litter size in pigs

Cited by 8 publications

References 33 publications

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs

Loss of bmp15 function in the seasonal spawner Atlantic salmon results in ovulatory failure

Genome-Wide Association Study on Reproductive Traits Using Imputation-Based Whole-Genome Sequence Data in Yorkshire Pigs

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