R Fries

Technische Universität München, München, Bavaria, Germany

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Publications (195)588.04 Total impact

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    ABSTRACT: Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes. A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P = 1.79 × 10(-5)) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2. Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.
    BMC Genomics 04/2015; 16(1). DOI:10.1186/s12864-015-1483-7 · 4.04 Impact Factor
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    ABSTRACT: Most association studies for pinpointing trait-associated variants are performed within breed. The availability of sequence data from key ancestors of several cattle breeds now enables immediate assessment of the frequency of trait-associated variants in populations different from the mapping population and their imputation into large validation populations. The objective of this study was to validate the effects of 4 putatively causative variants on milk production traits, male fertility, and stature in German Fleckvieh and Holstein-Friesian animals using targeted sequence imputation. We used whole-genome sequence data of 456 animals to impute 4 missense mutations in DGAT1, GHR, PRLR, and PROP1 into 10,363 Fleckvieh and 8,812 Holstein animals. The accuracy of the imputed genotypes exceeded 95% for all variants. Association testing with imputed variants revealed consistent antagonistic effects of the DGAT1 p.A232K and GHR p.F279Y variants on milk yield and protein and fat contents, respectively, in both breeds. The allele frequency of both polymorphisms has changed considerably in the past 20 yr, indicating that they were targets of recent selection for milk production traits. The PRLR p.S18N variant was associated with yield traits in Fleckvieh but not in Holstein, suggesting that it may be in linkage disequilibrium with a mutation affecting yield traits rather than being causal. The reported effects of the PROP1 p.H173R variant on milk production, male fertility, and stature could not be confirmed. Our results demonstrate that population-wide imputation of candidate causal variants from sequence data is feasible, enabling their rapid validation in large independent populations. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
    Journal of Dairy Science 04/2015; DOI:10.3168/jds.2015-9402 · 2.55 Impact Factor
  • 48th Annual Conference on Physiology and Pathology of Reproduction /; 02/2015
  • 48th Annual Conference on Physiology and Pathology of Reproduction /; 02/2015
  • 48th Annual Conference on Physiology and Pathology of Reproduction /; 02/2015
  • Journal of Comparative Pathology 01/2015; 152(1):58. DOI:10.1016/j.jcpa.2014.10.069 · 1.10 Impact Factor
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    ABSTRACT: The aim of the present study was to develop a reliable method to simultaneously split and biopsy valuable bovine embryos for a complete genomic evaluation (gender, polledness, and hereditary abnormalities) and to estimate the breeding value of progeny for traits of economic importance immediately after embryo recovery. A total of 208 good quality embryos collected from superovulated German Simmental animals were biopsied immediately after recovery using an inverse microscope (Zeiss, Germany) at 50× magnification with a single-use steel blade mounted on a holder (Bausch & Lomb, Germany) attached to a micromanipulator (Eppendorf, Germany). Biopsy was performed either by splitting the embryo and cutting of one-third of a half [G1: morulae (M), n=50; early blastocysts (EB), n=24; blastocysts (B), n=16], by just splitting in equal halves (G2: M, n=16; B, n=2), or by cutting of just a small biopsy of the embryo (G3: M, n=53) or of the trophoblast (G3: EB, n=19; B, n=28). Biopsied cells were immediately used for DNA amplification. Biopsied embryos (E) and demi-embryos (DE) were in vitro cultured in SOF, under mineral oil, at 39°C and 5% CO2, 5% O2, 90% N2 for 24h, after which survival was recorded. Survival rate of G1 (survival of at least 1 DE: M, 98.0%; EB, 100.0%; B, 93.8%), G2 (survival of DE: M, 75.0%; B, 100.0%), and G3 (embryo survival: M, 96.3%; EB, 100.0%; B, 96.4%) were similar, but in relation to the number of original embryo the highest ratio of DE was obtained in G1 (1.67) v. G2 (0.88) and G3 (0.97; G1:G2/G3; P<0.01). Within G1, the highest ration to the original number of embryos was by using M (1.78), followed by EB (1.75) and B (1.19; M/EB:B; P<0.05). To verify the viability of biopsied embryos some DE from G1 (1, the nonbiopsied DE, n=7, or 2, the biopsied and the nonbiopsied DE per recipient, n=21), G2 (1 DE per recipient, n=13), and G3 (1 E per recipient, n=8) were transferred after 24h of culture. Overall pregnancy rate (Day 42) of G1, G2, and G3 was 64.3, 23.1, and 50.0%, respectively (G1:G2; P<0.05). In G1, pregnancy rates (Day 42) of biopsied embryos differed significantly if either 1 or 2 DE were transferred per recipient (28.6 v. 76.2%, respectively; P<0.05). A twin pregnancy rate of 38.9% was observed by ultrasonography in recipients when 2 DE were transferred. The results suggest that high survival rates can be obtained with the G1 technique, and splitting during biopsy can increase productivity in programs aimed to evaluate the genomic constitution of early stage embryos.
    Reproduction Fertility and Development 12/2014; 27(1):161. DOI:10.1071/RDv27n1Ab138 · 2.58 Impact Factor
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    ABSTRACT: The aim of this study was to develop a reliable procedure for genomic evaluation of bovine embryos to determine gender, polled status, and hereditary defects within 24h after collection. German Simmental animals (n=15) were superovulated (n=25) using a standard protocol. Embryos were recovered on Day 7 (Day 0=oestrus). A total of 217 embryos (morula, n=130; early blastocyst, n=43; blastocyst, n=44) were biopsied with a steel blade attached to a micromanipulator. Biopsied cells were immediately transferred into 1µL TE buffer to a 500µL reaction tube and embryos were in vitro cultured until genomic results were available. For commonly used molecular genetic methods (e.g. 5'-exonuclease genotyping, PCR or high density genotyping) DNA amounts of 2-200ng are required. However, the DNA quantity of a single diploid cell amounts to 6 pg only. The embryo biopsies used, usually consists of 10-30 cells, necessitating an artificial amplification of the embryonic genome. Taking all vital measures to avoid external DNA contamination, isothermal whole genome amplification was performed with the REPLI-g Mini Kit (Qiagen, Valencia, CA, USA) using random hexamers and Phi29-Polymerase. Depending on the number of cells, a total DNA amount of 4-7µg was achieved. Polled status and gender was determined using PCR with subsequent gel-electrophoresis. 5'-exonuclease assays were used to obtain genotypes for the detection of genetic defects. At present, eight, mostly Simmental-specific genetic disorders can be examined: three traits associated with severe growth retardation, dwarfism (DW), Braunvieh-haplotype 2 (BH2) and stunted growth (FH2), the lethal skin disorder zinc deficiency-like syndrome (ZDL), a fertility trait bovine male subfertility (BMS), embryonic death Fleckvieh-haplotype 4 (FH4), a bleeding disorder thrombopathia (TP) and arachnomelia (A), within 24h. On average, 8.7 embryos were biopsied per embryo recovery, i.e. 93.9% of the total number of transferable embryos. Fourteen embryo samples (6.5%) totally failed during analysis, possibly due to the loss of samples. In successful analyses, gender was undetermined in two embryos; remaining embryos were 52.2% female and 47.8% male. Polled status could be analysed in 92.6% of the embryos. The analyses of embryos for possible inherited genetic disorders (healthy, heterozygote, or homozygote; n=578) were successful in 90.1%. The transfer of biopsied embryos (n=30) led to 63.3% pregnancies (Day 42). A validation of the present results has to be done as soon as the produced calves are born, demonstrating the reliability of the procedure.
    Reproduction Fertility and Development 12/2014; 27(1):247. DOI:10.1071/RDv27n1Ab316 · 2.58 Impact Factor
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    ABSTRACT: The multiplication of high-value embryos by chimera formation using asynchronic aggregation is a promising alternative to embryonic cell nuclear transfer. Single blastomeres from a donor embryo are aggregated with 2 host embryos, thus several chimeras can be constructed per donor embryo. Due to the advanced developmental stage, the donor blastomeres are likely to contribute to the inner cell mass (ICM) and later give rise to the embryo proper, whereas the host embryos form extra-embryonic tissues. To test if pairs of blastomeres from Day 5 morulae are able to form the ICM when aggregated with 2 Day 4 host embryos, we produced transgenic donor embryos carrying a fluorescent reporter gene (enhanced green fluorescent protein, eGFP) by using semen from an eGFP transgenic bull (Reichenbach et al. 2010 Transgenic Res. 19, 549-556) for in vitro fertilization and in vitro host embryos produced by a standard procedure. The zona pellucida of all embryos was removed by treatment with 1mgmL(-1) pronase. Donor embryos were assessed for eGFP expression by fluorescence microscopy and disaggregated by gentle pipetting after incubation in Mg(2+)- and Ca(2+)-free medium. Pairs of blastomeres were then placed between 2 host embryos and cultured individually in a well-of-the-well culture dish. On Day 6 after aggregation, fully developed blastocysts were assessed for eGFP fluorescence. In 3 replicates, n=30 chimeras were produced by aggregation; 13 (43%) developed to blastocysts, of which 2 (15%) showed local eGFP expression in the ICM and 7 (54%) showed a generalized expression. From the results of this study we conclude that Day 5 morulae may be multiplied in an efficient manner by using the chimera formation technique, which makes this approach applicable to ex vivo-derived embryos. In future investigations we will study the effect of using donor blastomeres from either the inside or outside of the donor morula and test the use of tetraploid host embryos to increase the rate of blastocysts with the desired genotype in the ICM. Finally, we aim to introduce this multiplication approach to the production of genotyped embryos with a genomic estimated breeding value (gEBV) and intend to produce calves with identical gEBV.
    Reproduction Fertility and Development 12/2014; 27(1):135. DOI:10.1071/RDv27n1Ab84 · 2.58 Impact Factor
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    ABSTRACT: Background Advances in human genomics have allowed unprecedented productivity in terms of algorithms, software, and literature available for translating raw next-generation sequence data into high-quality information. The challenges of variant identification in organisms with lower quality reference genomes are less well documented. We explored the consequences of commonly recommended preparatory steps and the effects of single and multi sample variant identification methods using four publicly available software applications (Platypus, HaplotypeCaller, Samtools and UnifiedGenotyper) on whole genome sequence data of 65 key ancestors of Swiss dairy cattle populations. Accuracy of calling next-generation sequence variants was assessed by comparison to the same loci from medium and high-density single nucleotide variant (SNV) arrays. Results The total number of SNVs identified varied by software and method, with single (multi) sample results ranging from 17.7 to 22.0 (16.9 to 22.0) million variants. Computing time varied considerably between software. Preparatory realignment of insertions and deletions and subsequent base quality score recalibration had only minor effects on the number and quality of SNVs identified by different software, but increased computing time considerably. Average concordance for single (multi) sample results with high-density chip data was 58.3% (87.0%) and average genotype concordance in correctly identified SNVs was 99.2% (99.2%) across software. The average quality of SNVs identified, measured as the ratio of transitions to transversions, was higher using single sample methods than multi sample methods. A consensus approach using results of different software generally provided the highest variant quality in terms of transition / transversion ratio. Conclusions Our findings serve as a reference for variant identification pipeline development in non-human organisms and help assess the implication of preparatory steps in next-generation sequencing pipelines for organisms with incomplete reference genomes (pipeline code is included). Benchmarking this information should prove particularly useful in processing next-generation sequencing data for use in genome-wide association studies and genomic selection.
    BMC Genomics 11/2014; 15(948). DOI:10.1186/1471-2164-15-948 · 4.04 Impact Factor
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    ABSTRACT: Background Inherited developmental diseases can cause severe animal welfare and economic problems in dairy cattle. The use of a small number of bulls for artificial insemination (AI) carries a risk that recessive defects rapidly enrich in the population. In recent years, an increasing number of Finnish Ayrshire calves have been identified with signs of ptosis, intellectual disability, retarded growth and mortality, which constitute an inherited disorder classified as PIRM syndrome. Results We established a cohort of nine PIRM-affected calves and 38 unaffected half-siblings and performed a genome-wide association study (GWAS) to map the disease to a 700-kb region on bovine chromosome 17 (p = 1.55 × 10-9). Whole genome re-sequencing of an unaffected carrier, its affected progeny and 43 other unaffected animals from another breed identified a G > A substitution mutation at the last nucleotide of exon 23 in the ubiquitin protein ligase E3B encoding gene (UBE3B). UBE3B transcript analysis revealed in-frame exon skipping in the affected animals resulting in an altered protein lacking 40 amino acids, of which 20 are located in the conserved HECT-domain, the catalytic site of the UBE3B protein. Mutation screening in 129 Ayrshire AI bulls currently used in Finland indicated a high carrier frequency (17.1%). We also found that PIRM syndrome might be connected to the recently identified AH1 haplotype, which has a frequency of 26.1% in the United States Ayrshire population. Conclusion We describe PIRM syndrome in cattle, which is associated with the mutated UBE3B gene. The bovine phenotype resembles human Kaufman oculocerebrofacial syndrome, which is also caused by mutations in UBE3B. PIRM syndrome might be connected with the recently identified AH1 haplotype, which is associated with reduced fertility in the US Ayrshire population. This study enables the development of a genetic test to efficiently reduce the high frequency of mutant UBE3B in Ayrshires, significantly improving animal health and reducing economic loss. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-890) contains supplementary material, which is available to authorized users.
    BMC Genomics 10/2014; 15(1):890. DOI:10.1186/1471-2164-15-890 · 4.04 Impact Factor
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    ABSTRACT: Background High density genotyping data are indispensable for genomic analyses of complex traits in animal and crop species. Maize is one of the most important crop plants worldwide, however a high density SNP genotyping array for analysis of its large and highly dynamic genome was not available so far. Results We developed a high density maize SNP array composed of 616,201 variants (SNPs and small indels). Initially, 57 M variants were discovered by sequencing 30 representative temperate maize lines and then stringently filtered for sequence quality scores and predicted conversion performance on the array resulting in the selection of 1.2 M polymorphic variants assayed on two screening arrays. To identify high-confidence variants, 285 DNA samples from a broad genetic diversity panel of worldwide maize lines including the samples used for sequencing, important founder lines for European maize breeding, hybrids, and proprietary samples with European, US, semi-tropical, and tropical origin were used for experimental validation. We selected 616 k variants according to their performance during validation, support of genotype calls through sequencing data, and physical distribution for further analysis and for the design of the commercially available Affymetrix® Axiom® Maize Genotyping Array. This array is composed of 609,442 SNPs and 6,759 indels. Among these are 116,224 variants in coding regions and 45,655 SNPs of the Illumina® MaizeSNP50 BeadChip for study comparison. In a subset of 45,974 variants, apart from the target SNP additional off-target variants are detected, which show only a minor bias towards intermediate allele frequencies. We performed principal coordinate and admixture analyses to determine the ability of the array to detect and resolve population structure and investigated the extent of LD within a worldwide validation panel. Conclusions The high density Affymetrix® Axiom® Maize Genotyping Array is optimized for European and American temperate maize and was developed based on a diverse sample panel by applying stringent quality filter criteria to ensure its suitability for a broad range of applications. With 600 k variants it is the largest currently publically available genotyping array in crop species. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-823) contains supplementary material, which is available to authorized users.
    BMC Genomics 09/2014; 15(1):823. DOI:10.1186/1471-2164-15-823 · 4.04 Impact Factor
  • 18th Annual Conference of the; 09/2014
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    ABSTRACT: Abstract Text: Advantages of using whole genome sequence data to predict genomic estimated breeding values (GEBV) include better persistence of accuracy of GEBV across generations and more accurate GEBV across breeds. The 1000 Bull Genomes Project provides a database of whole genome sequenced key ancestor bulls, for imputing sequence variant genotypes into reference sets for genomic prediction. Run 3.0 included 429 sequences, with 31.8 million variants detected. BayesRC, a new method for genomic prediction, addresses some challenges associated with using the sequence data, and takes advantage of biological information. In a dairy data set, predictions using BayesRC and imputed sequence data from 1000 Bull Genomes were 2% more accurate than with 800k data. We could demonstrate the method identified causal mutations in some cases. Further improvements will come from more accurate imputation of sequence variant genotypes and improved biological information. Keywords: Genomic prediction, whole genome sequence, biological information
    10th World Congress on Genetics Applied to Livestock Production; 08/2014
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    ABSTRACT: Sequence data were generated from 157 animals of the Fleckvieh population. A pre-phasing based approach was used to impute genotypes for 21,045,178 polymorphic sites into 10,363 target animals genotyped with high-density arrays. Imputed sequence variants were used in an association study with daughter-derived phenotypes for milk fat percentage. The association study identified ten QTL controlling fat percentage in Fleckvieh cattle. Two postulated causal variants in the DGAT1 and GHR genes yielded the most significant association signals. Sequence-based association studies for udder conformation traits demonstrated a complex genetic architecture of mammary gland development in cattle. The association studies identified eight, six and seven QTL underlying udder depth, teat length and teat thickness, respectively. Imputed sequence variants captured genetic effects at a better resolution than array-based genotypes. However, even when considering large-scale imputed sequence variants, a significant fraction of the heritability remains "missing".
    10th World Congress on Genetics Applied to Livestock Production, Vancouver, CA; 08/2014
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    ABSTRACT: Background Bovine hereditary zinc deficiency (BHZD) is an autosomal recessive disorder of cattle, first described in Holstein-Friesian animals. Affected calves suffer from severe skin lesions and show a poor general health status. Recently, eight calves with the phenotypic appearance of BHZD have been reported in the Fleckvieh cattle population. Results In spite of the similar disease phenotypes, SLC39A4, the gene responsible for BHZD in Holstein-Friesian was excluded as underlying gene for the disorder in the affected Fleckvieh calves. In order to identify the disease-associated region, genotypes of eight affected calves obtained with the Illumina BovineHD BeadChip comprising 777,962 SNPs were contrasted with the genotypes of 1,339 unaffected animals. A strong association signal was observed on chromosome 21 (P = 5.87 × 10-89). Autozygosity mapping in the eight affected animals revealed a common segment of extended homozygosity encompassing 1,023 kb (BTA 21: 70,550,045 - 71,573,501). This region contains 17 genes/transcripts, among them two genes encoding gastro-intestinal zinc transporters (CRIP1, CRIP2). However, no mutation that was compatible with recessive inheritance could be detected in these candidate genes. One of the affected calves was re-sequenced together with 42 unaffected Fleckvieh animals. Analysis of the sequencing data revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism. To confirm the causality, genotypes of the p.W215X-mutation were obtained from 3,650 animals representing three different breeds. None of the unaffected animals was homozygous for the defect allele, while all eight affected calves were homozygous. The deleterious effect of the mutation is manifested in a significantly lower survival rate of descendants from risk matings when compared with the survival rate of descendants from non-risk matings. The deleterious allele has an estimated frequency of 1.1% in the Fleckvieh population. Conclusion Our results provide strong evidence that a newly identified recessive disorder in the Fleckvieh population is caused by a nonsense mutation in PLD4, most likely resulting in an impaired function of the encoded protein. Although the phenotype of affected calves strongly resembles BHZD, a zinc deficiency resulting from malabsorption is unlikely to be responsible for the diseased Fleckvieh calves. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-623) contains supplementary material, which is available to authorized users.
    BMC Genomics 07/2014; 15(1):623. DOI:10.1186/1471-2164-15-623 · 4.04 Impact Factor
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    ABSTRACT: The 1000 bull genomes project supports the goal of accelerating the rates of genetic gain in domestic cattle while at the same time considering animal health and welfare by providing the annotated sequence variants and genotypes of key ancestor bulls. In the first phase of the 1000 bull genomes project, we sequenced the whole genomes of 234 cattle to an average of 8.3-fold coverage. This sequencing includes data for 129 individuals from the global Holstein-Friesian population, 43 individuals from the Fleckvieh breed and 15 individuals from the Jersey breed. We identified a total of 28.3 million variants, with an average of 1.44 heterozygous sites per kilobase for each individual. We demonstrate the use of this database in identifying a recessive mutation underlying embryonic death and a dominant mutation underlying lethal chrondrodysplasia. We also performed genome-wide association studies for milk production and curly coat, using imputed sequence variants, and identified variants associated with these traits in cattle.
    Nature Genetics 07/2014; 46(8):858 - 865. DOI:10.1038/ng.3034 · 29.65 Impact Factor
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    ABSTRACT: Human driven selection during domestication and subsequent breed formation has likely left detectable signatures within the genome of modern cattle. The elucidation of these signatures of selection is of interest from the perspective of evolutionary biology, and for identifying domestication-related genes that ultimately may help to further genetically improve this economically important animal. To this end, we employed a panel of more than 15 million autosomal SNPs identified from re-sequencing of 43 Fleckvieh animals. We mainly applied two somewhat complementary statistics, the integrated Haplotype Homozygosity Score (iHS) reflecting primarily ongoing selection, and the Composite of Likelihood Ratio (CLR) having the most power to detect completed selection after fixation of the advantageous allele. We find 106 candidate selection regions, many of which are harboring genes related to phenotypes relevant in domestication, such as coat coloring pattern, neurobehavioral functioning and sensory perception including KIT, MITF, MC1R, NRG4, Erbb4, TMEM132D and TAS2R16, among others. To further investigate the relationship between genes with signatures of selection and genes identified in QTL mapping studies, we use a sample of 3062 animals to perform four genome-wide association analyses using appearance traits, body size and somatic cell count. We show that regions associated with coat coloring significantly (P<0.0001) overlap with the candidate selection regions, suggesting that the selection signals we identify are associated with traits known to be affected by selection during domestication. Results also provide further evidence regarding the complexity of the genetics underlying coat coloring in cattle. This study illustrates the potential of population genetic approaches for identifying genomic regions affecting domestication-related phenotypes and further helps to identify specific regions targeted by selection during speciation, domestication and breed formation of cattle. We also show that Linkage Disequilibrium (LD) decays in cattle at a much faster rate than previously thought.
    PLoS Genetics 02/2014; 10(2):e1004148. DOI:10.1371/journal.pgen.1004148 · 8.17 Impact Factor
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    ABSTRACT: Genetic variants underlying reduced male reproductive performance have been identified in humans and model organisms, most of them compromising semen quality. Occasionally, male fertility is severely compromised although semen analysis remains without any apparent pathological findings (i.e., idiopathic subfertility). Artificial insemination (AI) in most cattle populations requires close examination of all ejaculates before insemination. Although anomalous ejaculates are rejected, insemination success varies considerably among AI bulls. In an attempt to identify genetic causes of such variation, we undertook a genome-wide association study (GWAS). Imputed genotypes of 652,856 SNPs were available for 7962 AI bulls of the Fleckvieh (FV) population. Male reproductive ability (MRA) was assessed based on 15.3 million artificial inseminations. The GWAS uncovered a strong association signal on bovine chromosome 19 (P = 4.08×10(-59)). Subsequent autozygosity mapping revealed a common 1386 kb segment of extended homozygosity in 40 bulls with exceptionally poor reproductive performance. Only 1.7% of 35,671 inseminations with semen samples of those bulls were successful. None of the bulls with normal reproductive performance was homozygous, indicating recessive inheritance. Exploiting whole-genome re-sequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c.483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. These findings imply that integrity of TMEM95 is required for an undisturbed fertilisation. Our results demonstrate that deficiency of TMEM95 severely compromises male reproductive performance in cattle and reveal for the first time a phenotypic effect associated with genomic variation in TMEM95.
    PLoS Genetics 01/2014; 10(1):e1004044. DOI:10.1371/journal.pgen.1004044 · 8.17 Impact Factor
  • H Pausch, R Fries
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    ABSTRACT: The implementation of high-throughput genotyping arrays in routine applications in livestock breeding programs yields genotypes for a large number of single nucleotide polymorphisms (SNPs). Dense SNP information enables both genomic predictions and the identification of quantitative trait loci (QTL) via genome-wide association studies(GWAS). Current genome-wide analyses of cattle populations rely on genotypes of 45,000 SNPs. We demonstrate that increasing the marker density only marginallyincreases the power of GWAS in the Fleckvieh population. However, sufficiently sized samples are crucial for successful genome-wide analyses of complex traits. Using phenotypes for milkfat percentage, we highlight that the identification of QTL that explain a small fraction (< 1%) of the genetic variation only, requires genotypes of several thousands of individuals. Identifying the underlying genomic variation is mandatory to permanently integrate QTL information in breeding programs. A key factor for the identification of causal trait variants is the availability of sequencing data of a population's key animals. Sequence-derived variants can be imputed for any individual with high-density genotypes. This enables to perform sequence-based association studies and to directly test putatively causal variants for association with phenotypes of interest.
    Züchtungskunde 01/2014; 86(1):47-57. · 0.25 Impact Factor

Publication Stats

6k Citations
588.04 Total Impact Points

Institutions

  • 1996–2015
    • Technische Universität München
      • • Chair of Plant Breeding
      • • Chair of Buildings Physics
      München, Bavaria, Germany
  • 2003–2010
    • Bayerische Landesanstalt für Landwirtschaft
      • Institut für Landtechnik und Tierhaltung
      Freysing, Bavaria, Germany
  • 1986–2010
    • Eawag: Das Wasserforschungs-Institut des ETH-Bereichs
      Duebendorf, Zurich, Switzerland
  • 2009
    • Helmholtz Zentrum München
      München, Bavaria, Germany
  • 2005
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
  • 2004
    • Justus-Liebig-Universität Gießen
      • Institute of Animal Breeding and Genetics
      Gieben, Hesse, Germany
  • 2001–2004
    • Georg-August-Universität Göttingen
      • Institute of Veterinary Medicine
      Göttingen, Lower Saxony, Germany
    • University of Jyväskylä
      • Department of Biological and Environmental Science
      Jyväskylä, Province of Western Finland, Finland
  • 1998–2002
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
    • St. Jude Children's Research Hospital
      • Department of Tumor Cell Biology
      Memphis, Tennessee, United States
  • 1999
    • Okayama University
      • Department of Biology
      Okayama, Okayama, Japan
    • University of Ottawa
      • Department of Biology
      Ottawa, Ontario, Canada
  • 1997
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
  • 1995
    • INO - Istituto Nazionale di Ottica
      Florens, Tuscany, Italy
  • 1994
    • Hochschule für Technik Zürich
      Zürich, Zurich, Switzerland
    • University of Iowa
      Iowa City, Iowa, United States
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 1992–1994
    • ETH Zurich
      Zürich, Zurich, Switzerland