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, sp...
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| creator | Hiltpold, Maya Niu, Guanglin Kadri, Naveen Kumar Crysnanto, Danang Fang, Zih-Hua Spengeler, Mirjam Schmitz-Hsu, Fritz Fuerst, Christian Schwarzenbacher, Hermann Seefried, Franz R. Seehusen, Frauke Witschi, Ulrich Schnieke, Angelika Fries, Ruedi Bollwein, Heinrich Flisikowski, Krzysztof Pausch, Hubert |
| description | 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.
Author summary
In cattle farming, artificial insemination is the most common method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers of 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel ex |
| doi_str_mv | 10.1371/journal.pgen.1008804 |
| format | Article |
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Author summary
In cattle farming, artificial insemination is the most common method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers of 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008804</identifier><identifier>PMID: 32407316</identifier><language>eng</language><publisher>SAN FRANCISCO: Public Library Science</publisher><subject>Analysis ; Animal models ; Artificial insemination ; Biology and Life Sciences ; Bulls (Cattle) ; Cattle ; Chromosome 6 ; Chromosomes ; Composition ; Fertility ; Genetic aspects ; Genetics & Heredity ; Genomes ; Genotypes ; Haplotypes ; Heritability ; Life Sciences & Biomedicine ; Medicine and Health Sciences ; Motility ; Physiological aspects ; Quantitative trait loci ; Science & Technology ; Semen ; Single nucleotide polymorphisms ; Sperm ; Straw ; Success</subject><ispartof>PLoS genetics, 2020-05, Vol.16 (5), p.e1008804-e1008804, Article 1008804</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Hiltpold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Hiltpold et al 2020 Hiltpold et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>27</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000538052400010</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c726t-88f14e27cd8252b5a1d03c3705de9a97f7d08ba1c17f9dc6fafc2077b0977dff3</citedby><cites>FETCH-LOGICAL-c726t-88f14e27cd8252b5a1d03c3705de9a97f7d08ba1c17f9dc6fafc2077b0977dff3</cites><orcidid>0000-0002-0501-6760 ; 0000-0002-5683-5379 ; 0000-0003-4444-9371 ; 0000-0002-2705-8865 ; 0000-0003-4396-2747 ; 0000-0002-2799-3896 ; 0000-0002-0225-8772 ; 0000-0001-9713-3376 ; 0000-0002-4657-1787 ; 0000-0001-5599-8558 ; 0000-0003-4715-7307 ; 0000-0001-9629-5533 ; 0000-0003-1982-5101</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252675/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252675/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2118,2932,23875,27933,27934,28257,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32407316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>O'Bryan, Moira K.</contributor><creatorcontrib>Hiltpold, Maya</creatorcontrib><creatorcontrib>Niu, Guanglin</creatorcontrib><creatorcontrib>Kadri, Naveen Kumar</creatorcontrib><creatorcontrib>Crysnanto, Danang</creatorcontrib><creatorcontrib>Fang, Zih-Hua</creatorcontrib><creatorcontrib>Spengeler, Mirjam</creatorcontrib><creatorcontrib>Schmitz-Hsu, Fritz</creatorcontrib><creatorcontrib>Fuerst, Christian</creatorcontrib><creatorcontrib>Schwarzenbacher, Hermann</creatorcontrib><creatorcontrib>Seefried, Franz R.</creatorcontrib><creatorcontrib>Seehusen, Frauke</creatorcontrib><creatorcontrib>Witschi, Ulrich</creatorcontrib><creatorcontrib>Schnieke, Angelika</creatorcontrib><creatorcontrib>Fries, Ruedi</creatorcontrib><creatorcontrib>Bollwein, Heinrich</creatorcontrib><creatorcontrib>Flisikowski, Krzysztof</creatorcontrib><creatorcontrib>Pausch, Hubert</creatorcontrib><title>Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility</title><title>PLoS genetics</title><addtitle>PLOS GENET</addtitle><addtitle>PLoS Genet</addtitle><description>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.
Author summary
In cattle farming, artificial insemination is the most common method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers of 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.</description><subject>Analysis</subject><subject>Animal models</subject><subject>Artificial insemination</subject><subject>Biology and Life Sciences</subject><subject>Bulls (Cattle)</subject><subject>Cattle</subject><subject>Chromosome 6</subject><subject>Chromosomes</subject><subject>Composition</subject><subject>Fertility</subject><subject>Genetic aspects</subject><subject>Genetics & Heredity</subject><subject>Genomes</subject><subject>Genotypes</subject><subject>Haplotypes</subject><subject>Heritability</subject><subject>Life Sciences & Biomedicine</subject><subject>Medicine and Health Sciences</subject><subject>Motility</subject><subject>Physiological aspects</subject><subject>Quantitative trait loci</subject><subject>Science & Technology</subject><subject>Semen</subject><subject>Single nucleotide 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of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility</title><author>Hiltpold, Maya ; Niu, Guanglin ; Kadri, Naveen Kumar ; Crysnanto, Danang ; Fang, Zih-Hua ; Spengeler, Mirjam ; Schmitz-Hsu, Fritz ; Fuerst, Christian ; Schwarzenbacher, Hermann ; Seefried, Franz R. ; Seehusen, Frauke ; Witschi, Ulrich ; Schnieke, Angelika ; Fries, Ruedi ; Bollwein, Heinrich ; Flisikowski, Krzysztof ; Pausch, Hubert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-88f14e27cd8252b5a1d03c3705de9a97f7d08ba1c17f9dc6fafc2077b0977dff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Analysis</topic><topic>Animal models</topic><topic>Artificial insemination</topic><topic>Biology and Life Sciences</topic><topic>Bulls (Cattle)</topic><topic>Cattle</topic><topic>Chromosome 6</topic><topic>Chromosomes</topic><topic>Composition</topic><topic>Fertility</topic><topic>Genetic aspects</topic><topic>Genetics & Heredity</topic><topic>Genomes</topic><topic>Genotypes</topic><topic>Haplotypes</topic><topic>Heritability</topic><topic>Life Sciences & Biomedicine</topic><topic>Medicine and Health Sciences</topic><topic>Motility</topic><topic>Physiological aspects</topic><topic>Quantitative trait loci</topic><topic>Science & Technology</topic><topic>Semen</topic><topic>Single nucleotide polymorphisms</topic><topic>Sperm</topic><topic>Straw</topic><topic>Success</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hiltpold, Maya</creatorcontrib><creatorcontrib>Niu, Guanglin</creatorcontrib><creatorcontrib>Kadri, Naveen Kumar</creatorcontrib><creatorcontrib>Crysnanto, Danang</creatorcontrib><creatorcontrib>Fang, Zih-Hua</creatorcontrib><creatorcontrib>Spengeler, Mirjam</creatorcontrib><creatorcontrib>Schmitz-Hsu, 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Abstracts</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hiltpold, Maya</au><au>Niu, Guanglin</au><au>Kadri, Naveen Kumar</au><au>Crysnanto, Danang</au><au>Fang, Zih-Hua</au><au>Spengeler, Mirjam</au><au>Schmitz-Hsu, Fritz</au><au>Fuerst, Christian</au><au>Schwarzenbacher, Hermann</au><au>Seefried, Franz R.</au><au>Seehusen, Frauke</au><au>Witschi, Ulrich</au><au>Schnieke, Angelika</au><au>Fries, Ruedi</au><au>Bollwein, Heinrich</au><au>Flisikowski, Krzysztof</au><au>Pausch, Hubert</au><au>O'Bryan, Moira K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility</atitle><jtitle>PLoS genetics</jtitle><stitle>PLOS GENET</stitle><addtitle>PLoS Genet</addtitle><date>2020-05-14</date><risdate>2020</risdate><volume>16</volume><issue>5</issue><spage>e1008804</spage><epage>e1008804</epage><pages>e1008804-e1008804</pages><artnum>1008804</artnum><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>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.
Author summary
In cattle farming, artificial insemination is the most common method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers of 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence of WDR19 encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing in WDR19 is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.</abstract><cop>SAN FRANCISCO</cop><pub>Public Library Science</pub><pmid>32407316</pmid><doi>10.1371/journal.pgen.1008804</doi><tpages>27</tpages><orcidid>https://orcid.org/0000-0002-0501-6760</orcidid><orcidid>https://orcid.org/0000-0002-5683-5379</orcidid><orcidid>https://orcid.org/0000-0003-4444-9371</orcidid><orcidid>https://orcid.org/0000-0002-2705-8865</orcidid><orcidid>https://orcid.org/0000-0003-4396-2747</orcidid><orcidid>https://orcid.org/0000-0002-2799-3896</orcidid><orcidid>https://orcid.org/0000-0002-0225-8772</orcidid><orcidid>https://orcid.org/0000-0001-9713-3376</orcidid><orcidid>https://orcid.org/0000-0002-4657-1787</orcidid><orcidid>https://orcid.org/0000-0001-5599-8558</orcidid><orcidid>https://orcid.org/0000-0003-4715-7307</orcidid><orcidid>https://orcid.org/0000-0001-9629-5533</orcidid><orcidid>https://orcid.org/0000-0003-1982-5101</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2020-05, Vol.16 (5), p.e1008804-e1008804, Article 1008804 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_2479458852 |
| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central |
| subjects | Analysis Animal models Artificial insemination Biology and Life Sciences Bulls (Cattle) Cattle Chromosome 6 Chromosomes Composition Fertility Genetic aspects Genetics & Heredity Genomes Genotypes Haplotypes Heritability Life Sciences & Biomedicine Medicine and Health Sciences Motility Physiological aspects Quantitative trait loci Science & Technology Semen Single nucleotide polymorphisms Sperm Straw Success |
| title | Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility |
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