Maya Hiltpold

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Hiltpold

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Maya

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0000-0002-2705-8865

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Publications 1 - 10 of 14

Optimization of Swiss dairy goat breeding programs: modelling of different variations with ZPLAN
Hiltpold, Maya; Gredler-Grandl, Birgit; Willam, A.; et al. (2017)
EAAP Book of Abstracts ~ Book of Abstracts of the 68th Annual Meeting of the European Federation of Animal Science
Leaf Length Tracker: A novel approach to analyse leaf elongation close to the thermal limit of growth in the field
Nagelmüller, Sebastian; Kirchgessner, Norbert; Yates, Steven; et al. (2016)
Journal of Experimental Botany
Leaf growth in monocot crops such as wheat and barley largely follows the daily temperature course, particularly under cold but humid springtime field conditions. Knowledge of the temperature response of leaf extension, particularly variations close to the thermal limit of growth, helps define physiological growth constraints and breeding-related genotypic differences among cultivars. Here, we present a novel method, called ‘Leaf Length Tracker’ (LLT), suitable for measuring leaf elongation rates (LERs) of cereals and other grasses with high precision and high temporal resolution under field conditions. The method is based on image sequence analysis, using a marker tracking approach to calculate LERs. We applied the LLT to several varieties of winter wheat (Triticum aestivum), summer barley (Hordeum vulgare), and ryegrass (Lolium perenne), grown in the field and in growth cabinets under controlled conditions. LLT is easy to use and we demonstrate its reliability and precision under changing weather conditions that include temperature, wind, and rain. We found that leaf growth stopped at a base temperature of 0°C for all studied species and we detected significant genotype-specific differences in LER with rising temperature. The data obtained were statistically robust and were reproducible in the tested environments. Using LLT, we were able to detect subtle differences (sub-millimeter) in leaf growth patterns. This method will allow the collection of leaf growth data in a wide range of future field experiments on different graminoid species or varieties under varying environmental or treatment conditions.
Bull fertility and semen quality are not correlated with dairy and production traits in Brown Swiss cattle
Mapel, Xena Marie; Hiltpold, Maya; Kadri, Naveen Kumar; et al. (2022)
JDS Communications
Undisturbed reproduction is key for successful breeding of beef and dairy cattle. Improving reproductive ability can be difficult because of antagonistic relationships with other economically relevant traits. In cattle, thorough investigation of female fertility revealed unfavorable genetic correlations with various production phenotypes. However, the correlation between male reproductive ability and production traits remains poorly understood. Here, we investigated the genetic relationships among and between male fertility characteristics and economically relevant traits in a population of Brown Swiss cattle. We performed GWAS with imputed genotypes at nearly 12 million sequence variants for semen quality (sperm head and tail anomalies, motility, concentration, and volume), male fertility, and 57 production phenotypes. Allele substitution effects were then correlated on a trait-by-trait basis to estimate genetic correlations. Correlations between male reproductive characteristics and traits of economic value were small and ranged from −0.0681 to 0.0787. Among the semen quality parameters, sperm motility was negatively correlated with anomalies (head: r = −0.7083 ± 0.0002; tail: r = −0.7739 ± 0.0002) and volume (r = −0.1266 ± 0.0003), whereas volume was negatively correlated with concentration (r = −0.3503 ± 0.0002). Sire nonreturn rate was negatively correlated with sperm anomalies (head: r = −0.1640 ± 0.0002; tail: r = −0.1580 ± 0.0002) and positively correlated with motility (r = 0.1598 ± 0.0002). A meta-analysis of male reproductive traits identified 2 quantitative trait loci: a previously described region on chromosome 6 showed pleiotropic effects and a novel region on chromosome 11 was associated with sperm head anomalies. In conclusion, our results suggest that selection for economically important dairy and production phenotypes has little impact on semen quality and fertility of Brown Swiss bulls.
Infertility due to defective sperm flagella caused by an intronic deletion in DNAH17 that perturbs splicing
Poublan-Couzardot, Adéla; Hiltpold, Maya; Janett, Fredi; et al. (2021)
Genetics
Artificial insemination in pig (Sus scrofa domesticus) breeding involves the evaluation of the semen quality of breeding boars. Ejaculates that fulfill predefined quality requirements are processed, diluted and used for inseminations. Within short time, eight Swiss Large White boars producing immotile sperm that had multiple morphological abnormalities of the sperm flagella were noticed at a semen collection center. The eight boars were inbred on a common ancestor suggesting that the novel sperm flagella defect is a recessive trait. Transmission electron microscopy cross-sections revealed that the immotile sperm had disorganized flagellar axonemes. Haplotype-based association testing involving microarray-derived genotypes at 41,094 SNPs of six affected and 100 fertile boars yielded strong association (P = 4.22 × 10−15) at chromosome 12. Autozygosity mapping enabled us to pinpoint the causal mutation on a 1.11 Mb haplotype located between 3,473,632 and 4,587,759 bp. The haplotype carries an intronic 13-bp deletion (Chr12:3,556,401–3,556,414 bp) that is compatible with recessive inheritance. The 13-bp deletion excises the polypyrimidine tract upstream exon 56 of DNAH17 (XM_021066525.1: c.8510–17_8510–5del) encoding dynein axonemal heavy chain 17. Transcriptome analysis of the testis of two affected boars revealed that the loss of the polypyrimidine tract causes exon skipping which results in the in-frame loss of 89 amino acids from DNAH17. Disruption of DNAH17 impairs the assembly of the flagellar axoneme and manifests in multiple morphological abnormalities of the sperm flagella. Direct gene testing may now be implemented to monitor the defective allele in the Swiss Large White population and prevent the frequent manifestation of a sterilizing sperm tail disorder in breeding boars.
Genetic Characterization of Impaired Sperm Quality and Insemination Success in Brown Swiss Bulls
Hiltpold, Maya (2022)
Male fertility is an important factor in reproductive success which is crucial for the survival of a sexually reproducing lineage or species. In mammals, male reproduction is complex and needs many physiological processes to be successful for reaching sexual maturity, spermatogenesis, sperm maturation, finding and mating a female in heat, and ejaculation of the sperm and the seminal plasma. In the female reproductive tract, the viable and fertile sperm need to be able to reach the place of fertilization. Changes in sperm physiology like hyperactivation, capacitation, and acrosome reaction are required to occur at the correct place and in coordination with the female mate. All those processes are influenced and controlled to a certain extent by genetic variants. Reproduction is as well crucial for livestock farming. Because of the wide-spread use of artificial insemination, records of sperm quality and insemination success are available for many bulls. Linking this phenotypic information with SNP array and whole-genome genotypes enables to quantify heritability and map trait associated loci and candidate causal variants. This thesis investigated genetic variation affecting male fertility traits in Brown Swiss (BSW) dairy cattle using comprehensive semen quality and insemination success records. Chapter 2 reports on a recessive quantitative trait locus (QTL) for sperm motility, sperm head and tail morphology, and insemination success that is located within a 2.38 Mb segment of extended homozygosity on bovine chromosome 6. Haplotype-based genome-wide association testing between high density level SNP array data (607,511 SNPs) and various semen quality phenotypes from 794 BSW bulls revealed strong association at the QTL region. Homozygosity for the top QTL haplotype reduces insemination success by 0.99 phenotypic standard deviations. Whole-genome sequencing data of 42 BSW bulls showed that a synonymous variant (BTA6:58373887C>T, rs474302732) in WDR19 was compatible with the inheritance of the top haplotype. Although annotated as a synonymous variant, the investigation of transcriptome data revealed that it activates a cryptic splice site leading to the truncation of three evolutionarily conserved amino acids from the protein. WD repeat-containing protein 19 is part of the intraflagellar transport complex that is essential for the formation and physiological function of motile cilia and flagella. Impaired function of this protein is likely causal for the impaired motility and lower fertility in the homozygous state. Surprisingly, the variant has a high frequency of 24% in the BSW population, leading to an expected proportion of 5.8% of all bulls carrying the variant in homozygous state assuming random mating at this locus. Even subtle reductions in sperm quality due to genetic aetiology can reduce insemination success. Chapter 3 revealed four additional recessive QTL for insemination success in Brown Swiss cattle located on BTA1, 18, 25, and 26. By conditioning the haplotype-based genome wide association study on the known QTL on BTA6, the additional signals were stronger and only then met the significance threshold in case of the QTL on BTA18 and 25. The top associated haplotypes segregate at rather high frequency (0.18, 0.34, 0.09, and 0.26) in the BSW population. They reduce the insemination success by 0.80, 0.28, 1.09, and 0.52 phenotypic standard deviations, for BTA1, BTA18, BTA25, and BTA26, respectively. Possible reasons for the reduced insemination success were investigated using comprehensive sperm quality data. However, only the QTL on BTA1 is associated with an increased proportion of sperm with an abnormal head shape, possibly explaining the mechanism of reduced insemination success in homozygous bulls. We screened for candidate variants using whole-genome sequence variants of 125 bulls with insemination success phenotypes and imputed sequence variants for all bulls with phenotypes. A missense variant in SPATA16 (spermatogenesis associated protein 16) was strongly associated with this QTL. But non-coding variants were stronger associated, suggesting that regulatory variants are more likely to be causal for the QTL variation. None of the other QTL showed an association with any of the analysed sperm quality traits. Coding candidate variants compatible with the top haplotypes were located in ENSBTAG00000006717 (encoding ATP-binding cassette sub-family A member 3-like protein) and VWA3A (encoding von Willebrand factor A domain-containing protein 3A) on BTA25 and in ENSBTAG00000019919 (bovine ortholog of CFAP46 encoding cilia and flagella associated protein 46) on BTA26. Likewise, non-coding variants were stronger associated, e.g., a variant downstream SYCE1 (synaptonemal complex central element protein 1) on BTA26. In summary, this chapter showed that recessive QTL explain a considerable fraction of quantitative variation of male fertility in BSW bulls. Chapter 4 reports on a recessive loss-of-function variant in QRICH2 leading to male infertility in vivo because of immotile sperm with abnormal flagellum and head morphology. In sperm quality data of 70,990 ejaculates from 1343 BS collected at the Swiss artificial insemination centre Swissgenetics, we recognized 7 bulls that never produced ejaculates suitable for artificial inseminations and that had severely impaired semen quality. Among those, one bull presented severe oligoasthenoteratozoospermia. Whole-genome sequence screening and comparison with 397 fertile bulls revealed a 1-bp deletion in QRICH2 (glutamine rich 2) causing a frameshift and a premature stop codon (BTA19:55436705TC>T, ENSBTAT00000018337.1:c.4929del) that was homozygous only in this infertile bull. Through mapping the 1-bp deletion to a SNP array genotype derived haplotype segregating at a frequency of 5% in the BSW population, we identified a second bull that was homozygous for the 1-bp deletion. Confirming the disorder of the first bull, this bull produced immotile sperm with multiple morphological abnormalities of the flagella and head at low sperm concentration. The most frequent abnormality observed in the ejaculates of this bull were shortened, abnormally shaped flagella. Transmission electron microscopy imaging revealed that the ultrastructure of the sperm flagella was affected, often resulting in incomplete microtubule structures and a generally disorganized assembly of the sperm flagella. Bulls homozygous for the 1-bp deletion can now be identified early on through customized genotyping. This thesis leveraged comprehensive genotype and phenotype data to study the effects of genetic variation on male fertility traits in cattle. Different approaches were applied to detect 5 QTL affecting insemination success and one loss-of-function variant leading to severely disturbed sperm quality. All six QTL/variants are recessively inherited which implies that the fertility is only impaired in homozygous bulls. As heterozygous carrier bulls and females are not affected, such recessive alleles can segregate undetected for a long time in the population. Monitoring known alleles and putting constraints on future inbreeding are possible approaches to counteract the negative effects on male fertility. Reduced sperm quality and a higher proportion of ejaculates per bull not meeting the requirements for artificial insemination can be indicative of a genetic defect and the detected reduction of sperm quality might just be the tip of the iceberg of the overall effect. The effect of QTL reducing sperm quality and insemination success is likely underestimated using records from artificial insemination bulls as ejaculates and bulls not meeting the minimum quality requirements are excluded from breeding. Minimum quality requirements and the exclusion of bulls with low sperm quality are thus as well useful when dealing with genetic aetiology of impaired sperm quality.
A 1-bp deletion in bovine QRICH2 causes low sperm count and immotile sperm with multiple morphological abnormalities
Hiltpold, Maya; Janett, Fredi; Mapel, Xena Marie; et al. (2022)
Genetics Selection Evolution
BACKGROUND: Semen quality and insemination success are monitored in artificial insemination bulls to ensure high male fertility rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced 12 ejaculates with an aberrantly small number of sperm (0.2 ± 0.2 × 109 sperm per mL) which were mostly immotile due to multiple morphological abnormalities. RESULTS: The genome of this bull was sequenced at a 12× coverage to investigate a possible genetic cause. Comparing the sequence variant genotypes of this bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of the QRICH2 gene which encodes the glutamine rich 2 protein, as a compelling candidate causal variant. This 1-bp deletion causes a frameshift in translation and a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subject to nonsense-mediated mRNA decay. The 1-bp deletion resides in a 675-kb haplotype that includes 181 single nucleotide polymorphisms (SNPs) from the Illumina BovineHD Bead chip. This haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. Our analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities that primarily affect the sperm flagellum and, to a lesser extent, the sperm head. CONCLUSIONS: A recessive loss-of-function allele of the bovine QRICH2 gene likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls for this allele. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.
Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility
Hiltpold, Maya; Niu, Guanglin; Kadri, Naveen Kumar; et al. (2020)
PLoS Genetics
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.
Quantitative variation of male fertility in Brown Swiss cattle is shaped by autosomal recessive loci
Hiltpold, Maya; Kadri, Naveen Kumar; Janett, Fredi; et al. (2021)
EAAP Book of Abstracts ~ Book of Abstracts of the 72nd Annual Meeting of the European Federation of Animal Science
A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle
Iso-Touru, Terhi; Wurmser, Christine; Venhoranta, Heli; et al. (2019)
BMC Genomics
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/).
Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Mapel, Xena Marie; Kadri, Naveen Kumar; Leonard, Alexander; et al. (2024)
Nature Communications
Breeding bulls are well suited to investigate inherited variation in male fertility because they are genotyped and their reproductive success is monitored through semen analyses and thousands of artificial inseminations. However, functional data from relevant tissues are lacking in cattle, which prevents fine-mapping fertility-associated genomic regions. Here, we characterize gene expression and splicing variation in testis, epididymis, and vas deferens transcriptomes of 118 mature bulls and conduct association tests between 414,667 molecular phenotypes and 21,501,032 genome-wide variants to identify 41,156 regulatory loci. We show broad consensus in tissue-specific and tissue-enriched gene expression between the three bovine tissues and their human and murine counterparts. Expression- and splicing-mediating variants are more than three times as frequent in testis than epididymis and vas deferens, highlighting the transcriptional complexity of testis. Finally, we identify genes (WDR19, SPATA16, KCTD19, ZDHHC1) and molecular phenotypes that are associated with quantitative variation in male fertility through transcriptome-wide association and colocalization analyses.

Publications 1 - 10 of 14

Maya Hiltpold

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