Genetic defects that occur naturally in livestock species provide valuable models for investigating the molecular mechanisms underlying rare human diseases. Livestock breeds are subject to the regular emergence of recessive genetic defects due to genetic drift and recent inbreeding. At the same time, their large population sizes provide easy access to case and control individuals and to massive amounts of pedigree, genomic and phenotypic information recorded for management and selection purposes. In this study, we investigated a lethal form of recessive chondrodysplasia observed in 21 stillborn calves of the Aubrac beef cattle breed. Detailed examinations of three affected calves revealed proximal limb shortening, epiphyseal calcific deposits, and other pathological signs consistent with human rhizomelic chondrodysplasia punctata, a rare peroxisomal disorder caused by recessive variants in one of five genes (AGPS, FAR1, GNPAT, PEX5, and PEX7). Using homozygosity mapping, whole genome sequencing of two affected individuals, and filtering for variants found in 1867 control genomes, we reduced the list of candidate variants to a single deep intronic substitution in GNPAT (NC_037355.1:g.4039268G > A on chromosome 28 of the ARS-UCD1.2 bovine genome assembly). For verification, we performed large-scale genotyping of this variant using a custom SNP array and found a perfect genotype–phenotype correlation in 21 cases and 26 of their parents, and a complete absence of homozygotes in 1195 unaffected Aubrac controls. The g.4039268A allele segregated at a frequency of 2.6

BACKGROUND:Dairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology. RESULTS:We present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates. CONCLUSIONS:The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.

Abstract Background Nine male and eight female calves born to a Normande artificial insemination bull named “Ly” were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened gestation, and stillbirth or perinatal mortality. Results Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pedigree the association between type II OI and preterm delivery, which is probably due to premature rupture of fetal membranes and has been reported in several isolated cases of type II OI in humans and cattle. Finally, analysis of perinatal mortality rates and segregation distortion supported a low level of germ cell mosaicism in Ly, with an estimate of 4.5% to 7.7% of mutant sperm and thus 63 to 107 affected calves born. These numbers contrast with the 17 cases reported and raise concerns about the underreporting of congenital defects to heredo-surveillance platforms, even for textbook genetic syndromes. Conclusions In conclusion, we describe a large animal model for a recurrent substitution in COL1A1 that is responsible for type II OI in humans. More generally, this study highlights the utility of such datasets and large half-sib families available in livestock species to characterize sporadic genetic defects.

The aim of this work was to test a surveillance protocol able to detect extended-spectrum β-lactamase (ESBL)-, cephalosporinase (AmpC)- and carbapenemase (CP)-producing gram-negative bacteria in three conveniently chosen dairy farms with known prior occurrences of ESBL- and CP-producing strains. The protocol was applied monthly for a year. At each visit, 10 healthy lactating dairy cows were rectally swabbed, and raw milk filters (RMFs) were sampled in two of the three farms. Bacterial isolation was based on a first screening step with MacConkey agar supplemented with 1 mg/L cefotaxime and commercial carbapenem-supplemented media. We failed to detect CP-producing strains but showed that ESBL-Escherichia strains, found in one farm only (13 strains), were closely associated with multi-drug resistance (12 out of 13). The limited number of conveniently selected farms and the fact that RMFs could not be retrieved from one of them limit the validity of our findings. Still, our results illustrate that ESBL-status changes monthly based on fecal swabs and negative herds should be qualified as “unsuspected” as proposed by previous authors. Although surveillance of farm statuses based on RMF analysis could theoretically allow for a better sensitivity than individual swabs, we failed to illustrate it as both farms where RMFs could be retrieved were constantly negative. Determination of CP herd-level status based on RMFs and our surveillance protocol was hindered by the presence of intrinsically resistant bacteria or strains cumulating multiple non-CP resistance mechanisms which means our protocol is not specific enough for routine monitoring of CP in dairy farms.

This report describes an outbreak of hairy vetch toxicosis afflicting a herd of cattle with a fatal cutaneous and systemic granulomatous disease. It highlights how this condition remains poorly recognized by cattle production professionals in Europe and the need for communication about vetch-associated diseases.

Post-operative pain and inflammation are normal physiological reactions to caesarean section. Their management in cattle have rarely been investigated. This surgical procedure negatively affects reproductive function with, for example, a reduction in fertility resulting in an increase in calving interval. In this multicenter clinical trial, the objective was to evaluate the impact on reproductive performance of meloxicam injected before caesarean section to manage post-operative pain and inflammation. Meloxicam is a non-steroidal anti-inflammatory drug. One hundred and twenty-seven Charolais heifers (n = 127) were recruited from 47 farms in six French veterinary practices in the Burgundy region. The heifers underwent a non-elective standardized caesarean section operation. Heifers were randomly assigned to one of two groups: meloxicam (n = 66), intravenous meloxicam injection before surgery, or control (n = 61). Reproductive performance and health information were recorded from the time of the caesarean section to the next calving or to culling. In our study, meloxicam administration before caesarean section had no effect on the incidence of retained placenta (18.2% of treated vs 25.0% of control cows, p = 0.35). The pregnancy rate was higher in treated than in control cows (83.1% vs 67.8%, p = 0.04 after multivariate analysis) and a survival analysis showed that the median calving interval was 35 days shorter in the meloxicam (t50% = 417 days) compared to the control group (t50% = 452 days, p = 0.05). A trend was also observed for culling rate to be lower in treated (4.7%) compared to control cows (13.3%, p = 0.09). In conclusion, this study suggests that there is a beneficial effect of meloxicam administration before caesarean section on reproductive performance in Charolais heifers.

La douleur chez les animaux d’élevage est une problématique de plus en plus importante dans notre société. Sa prise en charge médicale lors d’affections douloureuses est désormais incontournable mais doit être réalisée sur des bases scientifiques solides tout en respectant la réglementation sur le médicament vétérinaire. L'arsenal thérapeutique, relativement restreint, inclus les AINS, les anesthésiques locaux, les alpha-2 agonistes, la kétamine et le butorphanol (en appliquant la cascade). Les utilisations de ces molécules lors de mammites, en obstétrique, lors d'atteinte oculaire ou lors d'affections chez le veau sont présentés, en faisant le point sur les preuves de leur efficacité dans ces troubles.

La douleur chez les animaux d’élevage est une problématique de plus en plus importante dans notre société. Sa prise en charge médicale lors d’affections douloureuses est désormais incontournable mais doit être réalisée sur des bases scientifiques solides tout en respectant la réglementation sur le médicament vétérinaire. L'arsenal thérapeutique, relativement restreint, inclus les AINS, les anesthésiques locaux, les alpha-2 agonistes, la kétamine et le butorphanol (en appliquant la cascade). Les utilisations de ces molécules lors de mammites, en obstétrique, lors d'atteinte oculaire ou lors d'affections chez le veau sont présentés, en faisant le point sur les preuves de leur efficacité dans ces troubles.