A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle

Abstract

Background: Cattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarrayderived genotypes are available for many artificial insemination bulls. Two young Nordic Red bulls delivered sperm with low progressive motility (i.e., asthenospermia) during a semen collection period of more than four months. The bulls were related through a common ancestor on both their paternal and maternal ancestry. Thus, a recessive mode of inheritance of asthenospermia was suspected.Results: Both bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98Mb segment located on bovine chromosome 25. This haplotype was not found in the homozygous state in 8,557 fertile bulls although five homozygous haplotype carriers were expected (P=0.018). Whole genome-sequencing uncovered that both asthenospermic bulls were homozygous for a mutation that disrupts a canonical 5' splice donor site of CCDC189 encoding the coiled-coil domain containing protein 189. Transcription analysis showed that the derived allele activates a cryptic splice site resulting in a frameshift and premature termination of translation. The mutated CCDC189 protein is truncated by more than 40%, thus lacking the flagellar C1a complex subunit C1a-32 that is supposed to modulate the physiological movement of the sperm flagella. The mutant allele occurs at a frequency of 2.5% in Nordic Red cattle. Conclusions:Our study in cattle uncovered that CCDC189 is required for physiological movement of sperm flagella thus enabling active progression of spermatozoa and fertilization. A direct gene test may be implemented to monitor the asthenospermiaassociated allele and prevent the birth of homozygous bulls that are infertile. Our results have been integrated in the Online Mendelian Inheritance in Animals (OMIA) database (https://omia.org/OMIA002167/9913/).

A 1-bp deletion in bovineQRICH2causes low sperm count and immotile sperm with multiple morphological abnormalities

“…These findings suggest that the 1-bp deletion does not compromise traits other than semen quality. This agrees with loss-offunction alleles in other genes with extreme testis-biased expression [8], [9], [10], [50], and corroborates findings in humans and mice with loss-of-function alleles in QRICH2 [34] suggesting that QRICH2 is dispensable for somatic development in mammals. The deviation of the haplotype encompassing the 1-bp deletion from Hardy-Weinberg proportions (P=0.03) is likely due to either selective breeding or the inability of homozygous males to contribute to the next generation rather than fatal consequences arising from homozygosity.…”

“…The routine evaluation and recording of tens-of thousands of ejaculates and millions of artificial inseminations also occasionally detect bulls with aberrant semen quality or strikingly low insemination success rates. Although diseases and environmental exposures can compromise male fertility [7], drastically reduced semen quality in individual bulls often results from monogenic disorders [8], [9], [10], [11]. Genome-wide case-control association testing facilitates pinpointing variants for such conditions.…”

Infertility due to defective sperm flagella caused by an intronic deletion in DNAH17 that perturbs splicing

“…We previously identified mutations at splice donor sites and nearby splice acceptor sites that manifest in male reproductive disorders due to aberrant splicing (Iso-Touru et al, 2019), (Hiltpold et al, 2020). Our present study reveals an intronic deletion from 5 to 17 nucleotides upstream a canonical 3' splice site that perturbs splicing as the most likely causal variant for a novel porcine sperm flagella defect.…”

“…Diseases and environmental stressors were less likely to cause the defective sperm flagella (Jurewicz et al, 2009), because the boars were maintained at a semen collection center with many other boars that produced normal semen. Idiopathic infertility and poor semen quality in healthy males may result from pathogenic alleles in genes that are specifically expressed in the male reproductive tract (Pausch et al, 2014), (Iso-Touru et al, 2019), (Pausch et al, 2016b), (Noskova et al, 2020). The eight affected boars were inbred on a common ancestor supporting the hypothesis of a shared genetic etiology.…”

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

“…Our data did not allow investigating bull fertility in natural matings. Phenotypic manifestations of the five recessive QTL detected in our study are less detrimental than effects arising from pathogenic alleles in CCDC189, ARMC3 and TMEM95 that lead to male sterility in cattle [27][28][29] . Yet, the hypothetical exclusion of bulls carrying at least one of the five detected top haplotypes in the homozygous state from breeding would significantly increase the 56-day non-return rate in cows and heifers.…”