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

Iso-Touru, T.; Wurmser, C.; Venhoranta, H.; Hiltpold, M.; Savolainen, T.; Sironen, A.; Fischer, K.; Flisikowski, K.; Fries, R.; Vicente-Carrillo, A.; Alvarez-Rodriguez, M.; Nagy, S.; Mutikainen, M.; Peippo, J.; Taponen, J.; Sahana, G.; Guldbrandtsen, B.; Simonen, H.; Rodriguez-Martinez, H.; Andersson, M.; Pausch, H.

doi:10.1101/472282

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bioRxiv · 10.1101/472282

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

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Abstract

BackgroundCattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarray-derived 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. ResultsBoth bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50 Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98 Mb 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. ConclusionsOur 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 asthenospermia-associated 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/).

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Iso-Touru, T., Wurmser, C., Venhoranta, H., Hiltpold, M., Savolainen, T., Sironen, A., Fischer, K., Flisikowski, K., Fries, R., Vicente-Carrillo, A., Alvarez-Rodriguez, M., Nagy, S., Mutikainen, M., Peippo, J., Taponen, J., Sahana, G., Guldbrandtsen, B., Simonen, H., Rodriguez-Martinez, H., Andersson, M., Pausch, H.. 2018-11-19. A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle. https://doi.org/10.1101/472282

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