Autosomal recessive loci contribute significantly to quantitative variation of male fertility in a dairy cattle population.

BACKGROUND: Cattle are ideally suited to investigate the genetics of male fertility. Semen from individual bulls is used for thousands of artificial inseminations for which the fertilization success is monitored. Results from the breeding soundness examination and repeated observations of semen quality complement the fertility evaluation for each bull. RESULTS: In a cohort of 3881 Brown Swiss bulls that had genotypes at 683,609 SNPs, we reveal four novel recessive QTL for male fertility on BTA1, 18, 25, and 26 using haplotype-based association testing. A QTL for bull fertility on BTA1 is also associated with sperm head shape anomalies. All other QTL are not associated with any of the semen quality traits investigated. We perform complementary fine-mapping approaches using publicly available transcriptomes as well as whole-genome sequencing data of 125 Brown Swiss bulls to reveal candidate causal variants. We show that missense or nonsense variants in SPATA16, VWA3A, ENSBTAG00000006717 and ENSBTAG00000019919 are in linkage disequilibrium with the QTL. Using whole-genome sequence data, we detect strong association (P = 4.83 × 10- 12) of a missense variant (p.Ile193Met) in SPATA16 with male fertility. However, non-coding variants exhibit stronger association at all QTL suggesting that variants in regulatory regions contribute to variation in bull fertility. CONCLUSION: Our findings in a dairy cattle population provide evidence that recessive variants may contribute substantially to quantitative variation in male fertility in mammals. Detecting causal variants that underpin variation in male fertility remains difficult because the most strongly associated variants reside in poorly annotated non-coding regions.

Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility.

Cattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 x 10-27), head (P = 2.0 x 10-44) and tail anomalies (P = 7.2 x 10-49) and insemination success (P = 9.9 x 10-13). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 x 10-32) in an independent cohort of 2481 Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24% in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle.

Genetic parameters for semen production traits in Swiss dairy bulls.

Variance components (VC) were estimated for the semen production trait ejaculate volume, sperm concentration and sperm motility in the Swiss cattle breeds Brown Swiss (BS), Original Braunvieh (OB), Holstein (HO), Red-Factor-Carrier (RF), Red Holstein (RH), Swiss Fleckvieh (SF) and Simmental (SI). For this purpose, semen production traits from 2,617 bulls with 124,492 records were used. The data were collected in the years 2000-2012. The model for genetic parameter estimation across all breeds included the fixed effects age of bull at collection, year of collection, month of collection, number of collection per bull and day, interval between consecutive collections, semen collector, bull breed as well as a random additive genetic component and a permanent environmental effect. The same model without a fixed breed effect was used to estimate VC and repeatabilities separately for each of the breeds BS, HO, RH, SF and SI. Estimated heritabilities across all breeds were 0.42, 0.25 and 0.09 for ejaculate volume, sperm concentration and sperm motility, respectively. Different heritabilities were estimated for ejaculate volume (0.42; 0.45; 0.49; 0.40; 0.10), sperm concentration (0.34; 0.30; 0.20; 0.07; 0.23) and number of semen portions (0.18; 0.30; 0.04; 0.14; 0.04) in BS, HO, RH, SF and SI breed, respectively. The phenotypic and genetic correlations across all breeds between ejaculate volume and sperm concentration were negative (-0.28; -0.56). The other correlations across all breeds were positive. The phenotypic and genetic correlations were 0.01 and 0.19 between sperm motility and ejaculate volume, respectively. Between sperm motility and sperm concentration, the phenotypic and genetic correlations were 0.20 and 0.36, respectively. The results are consistent with other analyses and show that genetic improvement through selection is possible in bull semen production traits.