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

TY - JOUR

T1 - A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle

AU - Iso-Touru, Terhi

AU - Wurmser, Christine

AU - Venhoranta, Heli

AU - Hiltpold, Maya

AU - Savolainen, Tujia

AU - Sironen, Anu

AU - Fischer, Konrad

AU - Flisikowski, Krzysztof

AU - Fries, Ruedi

AU - Vicente-Carrillo, Alejandro

AU - Alvarez-Rodriguez, Manuel

AU - Nagy, Szabolcs

AU - Mutikainen, Mervi

AU - Peippo, Jaana

AU - Taponen, Juhani

AU - Sahana, Goutam

AU - Guldbrandtsen, Bernt

AU - Simonen, Henri

AU - Rodriguez-Martinez, Heriberto

AU - Andersson, Magnus

AU - Pausch, Hubert

PY - 2019

Y1 - 2019

N2 - Background: Cattle 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 thousands of 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 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 8557 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 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/).

AB - Background: Cattle 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 thousands of 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 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 8557 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 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/).

KW - CCDC189

KW - CILIARY

KW - Cattle

KW - DEFICIENCY

KW - DYNEIN REGULATORY COMPLEX

KW - GENERATION

KW - IN-VITRO FERTILIZATION

KW - Immotile sperm

KW - MALE-INFERTILITY

KW - MORPHOLOGY

KW - Male infertility

KW - NONSENSE MUTATION

KW - PARAMETERS

KW - SPERM MOTILITY

KW - Sterility

UR - http://www.scopus.com/inward/record.url?scp=85064220235&partnerID=8YFLogxK

U2 - 10.1186/s12864-019-5628-y

DO - 10.1186/s12864-019-5628-y

M3 - Journal article

C2 - 30975085

AN - SCOPUS:85064220235

SN - 1471-2164

VL - 20

JO - BMC Genomics

JF - BMC Genomics

IS - 1

M1 - 286

ER -