Biology subjects

Ruedi Fries

Publications and source records attributed to Ruedi Fries.

4 recordsLinked to original sources

bioRxiv2016

A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle

BackgroundThe widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa.\n\nResultsPedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P=8.0x10-14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in the COL7A1 gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes H[o]ehenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes H[o]ehenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor.\n\nConclusionsAutosomal recessive epidermolysis bullosa in Vorderwald and Rotes H[o]ehenvieh cattle is caused by a nonsense mutation in the COL7A1 gene. Our findings demonstrate that recessive deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carriers of the defective allele. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease.

Genomics↗

bioRxiv2016

A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle

BackgroundHaplotypes 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.\n\nResultsThe 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.\n\nConclusionsA 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.

Genomics↗

bioRxiv2016

A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh cattle

BackgroundLow 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 low birth weight and size were born in 2013 in the Fleckvieh cattle population.\n\nResultsAffected calves were strikingly underweight at birth despite a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. Despite a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 SNPs and performed association testing followed by homozygosity mapping to map the 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 1bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We show that the deletion introduces intron retention and premature termination of translation, putatively resulting in a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an unnoticed carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population.\n\nConclusionsA frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh cattle. The mutation has segregated in the population for more than fifty years without being recognized as a genetic disorder. However, the widespread use of an unnoticed 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.

Genomics↗

bioRxiv2015

A multi-trait meta-analysis with imputed sequence variants reveals twelve QTL for mammary gland morphology in Fleckvieh cattle

BackgroundThe 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.\n\nResultsWe 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).\n\nConclusionsAssociation 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.

Genetics↗