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Ruedi Fries - One of the best experts on this subject based on the ideXlab platform.

  • MOESM7 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 7: Figure S6. Imputation accuracy along chromosomes 12 and 23 in Fleckvieh Cattle. a, b Correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on chromosomes 12 and 23. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. c, d Red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000 (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb). We were eventually able to impute sequence variants for BTA12 and 23 using FImpute when we discarded sequence variants that were located between 70 and 77 Mb and between 25 and 30 Mb, respectively, from the reference panel

  • MOESM3 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 3: Figure S3. Imputation accuracy along six chromosomes in Fleckvieh Cattle. a–f The correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on six chromosomes. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. Insets HD SNP coverage and sequence variant density along the chromosome. Black and red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000, (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb)

  • a frameshift mutation in gon4l is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Herma Schwarzenbache, Christine Wurmse, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, M C Langenmaye, Angelika Schnieke, G Knubbenschweize, Ruedi Fries, Hube Pausch
    Abstract:

    Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

  • A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Hermann Schwarzenbacher, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, Angelika Schnieke, Ruedi Fries, Christine Wurmser, Martin C. Langenmayer, Gabriela Knubben-schweizer, Hubert Pausch
    Abstract:

    Background Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Results Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. Conclusions A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

  • a multi trait meta analysis with imputed sequence variants reveals twelve qtl for mammary gland morphology in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Hube Pausch, Herma Schwarzenbache, Reine Emmerling, Ruedi Fries
    Abstract:

    Background The availability of whole-genome sequence data from key ancestors in bovine populations provides an exhaustive catalogue of polymorphic sites that segregate within and across Cattle breeds. Sequence variants identified from the sequenced genome of key ancestors can be imputed into animals that have been genotyped using medium- and high-density genotyping arrays. Association analysis with imputed sequences, particularly when applied to multiple traits simultaneously, is a very powerful approach to detect candidate causal variants that underlie complex phenotypes.

Herma Schwarzenbache - One of the best experts on this subject based on the ideXlab platform.

  • exploring the potential genetic heterogeneity in the incidence of hoof and leg disorders in austrian Fleckvieh and braunvieh Cattle
    bioRxiv, 2020
    Co-Authors: Arbara Kosinskaselbi, Herma Schwarzenbache, Tomasz Suchocki, Christa Eggerdanne, Magdalena Fraszczak, Joanna Szyda
    Abstract:

    Background: Genetic heterogeneity denotes the situation when different genetic architectures underlying diverse populations result in the same phenotype. In this study, we explore the nature of differences in the incidence of the number of hoof and leg disorders between Braunvieh and Fleckvieh Cattle in the context of genetic heterogeneity between the breeds. Results: Despite potentially higher power of testing due to twice as large sample size, none of the SNPs was significantly associated with the number of hoof and leg disorders in Fleckvieh, while 16 SNPs were significant in Braunvieh. The most promising candidate genes in Braunvieh are: CBLB on BTA01, which causes arthritis in rats; CAV2 on BTA04, which in effects mouse skeletal muscles; PTHLH on BTA05, which causes disease phenotypes related to the skeleton in humans, mice and zebrafish; SORCS2 on BTA06, which causes decreased susceptibility to injury in the mouse. Some of the significant SNPs (BTA01, BTA04, BTA05, BTA13, BTA16) reveal allelic heterogeneity: i.e. differences due to different allele frequencies between Fleckvieh and Braunvieh. Some of the significant regions (BTA01, BTA05, BTA13, BTA16) correlate to inter breed differences in LD structure and may thus represent false positive heterogeneity. However, positions on BTA06 (SORCS2), BTA14 and BTA24 mark Braunvieh specific regions. Conclusions: We hypothesise that the observed genetic heterogeneity of hoof and leg disorders is a by product of multigenerational differential selection of the breeds towards dairy production in the case of Braunvieh and towards beef production in the case of Fleckvieh. Based on the current data set it is no possibly to unequivocally confirm/exclude the hypothesis of genetic heterogeneity in the susceptibility to leg disorders between Fleckvieh and Braunvieh because only explore it through associations and not the causal mutations. Rationales against genetic heterogeneity comprise a limited power of detection of true associations as well as differences in the length of LD blocks and in linkage phase between breeds. On the other hand, multigenerational differential selection of the breeds and no systematic differences in LD structure between the breeds favour the heterogeneity hypothesis at some of the significant sites. Keywords: Braunvieh, feet and leg disorders, Fleckvieh, genetic heterogeneity, GWAS, linkage disequilibrium, principal components

  • on the genomic regions associated with milk lactose in Fleckvieh Cattle
    Journal of Dairy Science, 2019
    Co-Authors: Angela Costa, Herma Schwarzenbache, C Fuers, Gabo Meszaros, Joha Solkne, M Penasa
    Abstract:

    ABSTRACT Lactose is a sugar uniquely found in mammals' milk and it is the major milk solid in bovines. Lactose yield (LY, kg/d) is responsible for milk volume, whereas lactose percentage (LP) is thought to be more related to epithelial integrity and thus to udder health. There is a paucity of studies that have investigated lactose at the genomic level in dairy cows. This paper aimed to improve our knowledge on LP and LY, providing new insights into the significant genomic regions affecting these traits. A genome-wide association study for LP and LY was carried out in Fleckvieh Cattle by using bulls' deregressed estimated breeding values of first lactation as pseudo-phenotypes. Heritabilities of first-lactation test-day LP and LY estimated using linear animal models were 0.38 and 0.25, respectively. A total of 2,854 bulls genotyped with a 54K SNP chip were available for the genome-wide association study; a linear mixed model approach was adopted for the analysis. The significant SNP of LP were scattered across the whole genome, with signals on chromosomes 1, 2, 3, 7, 12, 16, 18, 19, 20, 28, and 29; the top 4 significant SNP explained 4.90% of the LP genetic variance. The signals were mostly in regions or genes with involvement in molecular intra- or extracellular transport; for example, CDH5, RASGEF1C, ABCA6, and SLC35F3. A significant region within chromosome 20 was previously shown to affect mastitis or somatic cell score in Cattle. As regards LY, the significant SNP were concentrated in fewer regions (chromosomes 6 and 14), related to mastitis/somatic cell score, immune response, and transport mechanisms. The 5 most significant SNP for LY explained 8.45% of genetic variance and more than one-quarter of this value has to be attributed to the variant within ADGRB1. Significant peaks in target regions remained even after adjustment for the 2 most significant variants previously detected on BTA6 and BTA14. The present study is a prelude for deeper investigations into the biological role of lactose for milk secretion and volume determination, stressing the connection with genes regulating intra- or extracellular trafficking and immune and inflammatory responses in dairy cows. Also, these results improve the knowledge on the relationship between lactose and udder health; they support the idea that LP and its derived traits are potential candidates as indicators of udder health in breeding programs aimed to enhance cows' resistance to mastitis.

  • a missense mutation in tubd1 is associated with high juvenile mortality in braunvieh and Fleckvieh Cattle
    BMC Genomics, 2016
    Co-Authors: Herma Schwarzenbache, Joha Urgstalle, F Seefried, Christine Wurmse, Monika Hilbe, Simone Jung, C Fuers, Nora Dinhopl, Herbe Weissenbock, M. Doležal
    Abstract:

    Background Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh Cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated.

  • a missense mutation in tubd1 is associated with high juvenile mortality in braunvieh and Fleckvieh Cattle
    BMC Genomics, 2016
    Co-Authors: Herma Schwarzenbache, Joha Urgstalle, F Seefried, Christine Wurmse, Monika Hilbe, Simone Jung, C Fuers, Nora Dinhopl, Herbe Weissenbock, M. Doležal
    Abstract:

    Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh Cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated. The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome databases. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than the average in Braunvieh Cattle resulting in a depletion of BH2 homozygous adult animals (P = 9.3x10−12). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. The availability of sequence data of 236 animals from diverse bovine populations revealed that the missense mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed high juvenile mortality of homozygous calves (P = 2.2x10−15). Our findings show that the putative disease allele is located on an ancestral haplotype that segregates in Braunvieh and Fleckvieh Cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly resulting from defective cilia in the respiratory tract. A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh Cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh Cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed Cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia.

  • a frameshift mutation in gon4l is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Herma Schwarzenbache, Christine Wurmse, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, M C Langenmaye, Angelika Schnieke, G Knubbenschweize, Ruedi Fries, Hube Pausch
    Abstract:

    Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

Hube Pausch - One of the best experts on this subject based on the ideXlab platform.

  • MOESM3 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 3: Figure S3. Imputation accuracy along six chromosomes in Fleckvieh Cattle. a–f The correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on six chromosomes. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. Insets HD SNP coverage and sequence variant density along the chromosome. Black and red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000, (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb)

  • MOESM7 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 7: Figure S6. Imputation accuracy along chromosomes 12 and 23 in Fleckvieh Cattle. a, b Correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on chromosomes 12 and 23. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. c, d Red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000 (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb). We were eventually able to impute sequence variants for BTA12 and 23 using FImpute when we discarded sequence variants that were located between 70 and 77 Mb and between 25 and 30 Mb, respectively, from the reference panel

  • a frameshift mutation in gon4l is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Herma Schwarzenbache, Christine Wurmse, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, M C Langenmaye, Angelika Schnieke, G Knubbenschweize, Ruedi Fries, Hube Pausch
    Abstract:

    Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

  • clinical and biochemical signs in Fleckvieh Cattle with genetically confirmed fanconi bickel syndrome Cattle homozygous for Fleckvieh haplotype 2
    Berliner Und Munchener Tierarztliche Wochenschrift, 2016
    Co-Authors: Joha Urgstalle, Herma Schwarzenbache, Angelika Url, Hube Pausch, Monika Egerbache, Thomas Wittek
    Abstract:

    Abstract Fanconi-Bickel Syndrome (FBS) is an autosomal recessive disorder of the carbohydrate metabolism, which has been reported in human and some animals (OMIA 000366-9913). In Fleckvieh Cattle it is caused by mutations in SLC2A2, a gene encoding for glucose transporter protein 2 (GLUT2), which is primarily expressed in liver, kidney, pancreas and intestines. The causal mutation resides in a previously reported Fleckvieh Haplotype 2 (FH-2). FH-2 homozygous individuals are rare, but due to widespread use of heterozygous bulls in artificial insemination, heterozygous animals are likely to be present in a larger number in the Cattle population. Two clinical cases of Fleckvieh Cattle with a syndrome resembling the phenotypic appearance of FBS are presented in the present study describing the association between the clinical manifestations of FBS and the postulated frameshift mutation in bovine SLC2A2. Clinical examination showed poor growth, retarded development, polyuria, and polydipsia. Laboratory analyses showed an increased plasma glucose but normal insulin concentration and increased renal glucose excretion. Histopathological examination of kidney and liver samples revealed massively increased liver glycogen storage and nephrosis. Sires of both cases were tested positive for being heterozygous carriers for the same frameshift mutation in SLC2A2 as was originally reported in Fleckvieh Cattle. DNA of both cases described was analyzed and Sanger sequencing confirmed homozygosity for the frameshift mutation in SLC2A2.

  • a multi trait meta analysis with imputed sequence variants reveals twelve qtl for mammary gland morphology in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Hube Pausch, Herma Schwarzenbache, Reine Emmerling, Ruedi Fries
    Abstract:

    Background The availability of whole-genome sequence data from key ancestors in bovine populations provides an exhaustive catalogue of polymorphic sites that segregate within and across Cattle breeds. Sequence variants identified from the sequenced genome of key ancestors can be imputed into animals that have been genotyped using medium- and high-density genotyping arrays. Association analysis with imputed sequences, particularly when applied to multiple traits simultaneously, is a very powerful approach to detect candidate causal variants that underlie complex phenotypes.

Simone Jung - One of the best experts on this subject based on the ideXlab platform.

  • a missense mutation in tubd1 is associated with high juvenile mortality in braunvieh and Fleckvieh Cattle
    BMC Genomics, 2016
    Co-Authors: Herma Schwarzenbache, Joha Urgstalle, F Seefried, Christine Wurmse, Monika Hilbe, Simone Jung, C Fuers, Nora Dinhopl, Herbe Weissenbock, M. Doležal
    Abstract:

    Background Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh Cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated.

  • a missense mutation in tubd1 is associated with high juvenile mortality in braunvieh and Fleckvieh Cattle
    BMC Genomics, 2016
    Co-Authors: Herma Schwarzenbache, Joha Urgstalle, F Seefried, Christine Wurmse, Monika Hilbe, Simone Jung, C Fuers, Nora Dinhopl, Herbe Weissenbock, M. Doležal
    Abstract:

    Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh Cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated. The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome databases. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than the average in Braunvieh Cattle resulting in a depletion of BH2 homozygous adult animals (P = 9.3x10−12). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. The availability of sequence data of 236 animals from diverse bovine populations revealed that the missense mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed high juvenile mortality of homozygous calves (P = 2.2x10−15). Our findings show that the putative disease allele is located on an ancestral haplotype that segregates in Braunvieh and Fleckvieh Cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly resulting from defective cilia in the respiratory tract. A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh Cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh Cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed Cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia.

  • a frameshift mutation in gon4l is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Herma Schwarzenbache, Christine Wurmse, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, M C Langenmaye, Angelika Schnieke, G Knubbenschweize, Ruedi Fries, Hube Pausch
    Abstract:

    Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

  • A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Hermann Schwarzenbacher, Simone Jung, Krzysztof Flisikowski, Lubica Misurova, Angelika Schnieke, Ruedi Fries, Christine Wurmser, Martin C. Langenmayer, Gabriela Knubben-schweizer, Hubert Pausch
    Abstract:

    Background Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh Cattle population. Results Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population. Conclusions A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh Cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.

  • a missense mutation in tubd1 is associated with high juvenile mortality in braunvieh and Fleckvieh Cattle
    bioRxiv, 2016
    Co-Authors: Herma Schwarzenbache, Joha Urgstalle, F Seefried, Christine Wurmse, Monika Hilbe, Simone Jung, C Fuers, Nora Dinhopl, Herbe Weissenbock, M. Doležal
    Abstract:

    Background: Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh Cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated. Results: The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome databases. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than the average in Braunvieh Cattle resulting in a depletion of BH2 homozygous adult animals (P=9.3x10-12). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. The availability of sequence data of 236 animals from diverse bovine populations revealed that the missense mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed high juvenile mortality of homozygous calves (P=2.2x10-15). Our findings show that the putative disease allele is located on an ancestral haplotype that segregates in Braunvieh and Fleckvieh Cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly resulting from defective cilia in the respiratory tract. Conclusions: A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh Cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh Cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed Cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia.

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  • MOESM3 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 3: Figure S3. Imputation accuracy along six chromosomes in Fleckvieh Cattle. a–f The correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on six chromosomes. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. Insets HD SNP coverage and sequence variant density along the chromosome. Black and red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000, (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb)

  • MOESM7 of Evaluation of the accuracy of imputed sequence variant genotypes and their utility for causal variant detection in Cattle
    2017
    Co-Authors: Hube Pausch, Ruedi Fries, Reine Emmerling, Iona Macleod, Phil Owma, Hans Daetwyle, Michael Goddard
    Abstract:

    Additional file 7: Figure S6. Imputation accuracy along chromosomes 12 and 23 in Fleckvieh Cattle. a, b Correlation between true and imputed genotypes for sequence variants located within successive 1-Mb windows on chromosomes 12 and 23. Different colours and symbols represent correlation coefficients obtained using different imputation scenarios. c, d Red colours represent the number of SNPs that were included in the BovineHD Bead Chip (HD) and sequence (Seq) variants (×1000 (K)) that were polymorphic in the multi-breed reference population, respectively, per million basepairs (Mb). We were eventually able to impute sequence variants for BTA12 and 23 using FImpute when we discarded sequence variants that were located between 70 and 77 Mb and between 25 and 30 Mb, respectively, from the reference panel

  • a multi trait meta analysis with imputed sequence variants reveals twelve qtl for mammary gland morphology in Fleckvieh Cattle
    Genetics Selection Evolution, 2016
    Co-Authors: Hube Pausch, Herma Schwarzenbache, Reine Emmerling, Ruedi Fries
    Abstract:

    Background The availability of whole-genome sequence data from key ancestors in bovine populations provides an exhaustive catalogue of polymorphic sites that segregate within and across Cattle breeds. Sequence variants identified from the sequenced genome of key ancestors can be imputed into animals that have been genotyped using medium- and high-density genotyping arrays. Association analysis with imputed sequences, particularly when applied to multiple traits simultaneously, is a very powerful approach to detect candidate causal variants that underlie complex phenotypes.

  • MOESM2 of Systematic genotyping of groups of cows to improve genomic estimated breeding values of selection candidates
    2016
    Co-Authors: Laura Plieschke, Christia Edel, Eduardo Pimentel, Reine Emmerling, Jรถ Ennewitz, Kay-uwe Gรถtz
    Abstract:

    Additional file 2: Figure S2. Distribution of the allele frequencies. (A) Simulated data, approximately 38,000 segregating SNPs; (B) Real data on Fleckvieh Cattle, approximately 41,000 segregating SNPs

  • a multi trait meta analysis with imputed sequence variants reveals twelve qtl for mammary gland morphology in Fleckvieh Cattle
    bioRxiv, 2015
    Co-Authors: Hube Pausch, Herma Schwarzenbache, Reine Emmerling, Ruedi Fries
    Abstract:

    Background: The availability of whole-genome sequence data from key ancestors provides an exhaustive catalogue of polymorphic sites segregating within and across Cattle breeds. Sequence variants from key ancestors can be imputed in animals that have been genotyped using medium- and high-density genotyping arrays. Association analysis with imputed sequences, particularly if applied to multiple traits simultaneously, is a very powerful approach to revealing candidate causal variants underlying complex phenotypes. Results: We used whole-genome sequence data from 157 key ancestors of the German Fleckvieh population to impute 20 561 798 sequence variants in 10 363 animals that had (partly imputed) array-derived genotypes at 634 109 SNP. The imputed sequence data were enriched for rare variants. Association studies with imputed sequence variants were performed using seven correlated udder conformation traits as response variables. The calculation of an approximate multi-trait test statistic enabled us to detect twelve major QTL (P<2.97 x 10-9) controlling different aspects of mammary gland morphology. Imputed sequence variants were the most significantly associated at eleven QTL, whereas the top association signal at a QTL on BTA14 resulted from an array-derived variant. Seven QTL were associated with multiple phenotypes. Most QTL were located in non-coding regions of the genome in close neighborhood, however, to plausible candidate genes for mammary gland morphology (SP5, GC, NPFFR2, CRIM1, RXFP2, TBX5, RBM19, ADAM12). Conclusions: Association analysis with imputed sequence variants allows QTL characterization at maximum resolution. Multi-trait approaches can reveal QTL that are not detected in single-trait association studies. Most QTL for udder conformation traits were located in non-coding elements of the genome suggesting regulatory mutations to be the major determinants of variation in mammary gland morphology in Cattle.