Genetic parameters, GWAS and selection perspective on gestation length in 16 French cattle breeds.

In this paper, we present a comprehensive study of gestation length (GL) in 16 cattle breeds by using large genotype and animal record databases. Data included over 20 million gestations since 2000 and genotypes from one million calves. The study addressed the GL variability within and between breeds, estimation of its direct and maternal heritability coefficients, association with fitness and several economic traits, and QTL detection. The breed average GL varied from 279.7 to 294.4 d, in Holstein and Blonde d'Aquitaine breeds, respectively. Standard deviations per breed were similar and ranged from 5.2 to 5.8 d. Direct heritability (i.e., for GL defined as a trait of the calf) was moderate to high (h2 = 0.40 to 0.67), whereas the maternal heritability was low (0.04 to 0.06). Extreme breeding values for GL were strongly associated with a higher mortality during the first 2 d of life and were associated with milk production of dams for dairy breeds and precocity of females. Finally, several QTL were detected affecting GL with cumulated effects up to a few days, and at least 2 QTL were found to be shared between different breeds. Our study highlights the risks that would be associated with selection toward a reduced gestation length. Further genomic studies are needed to identify the causal variants, and their association with juvenile mortality and other economic traits.

Relationship between feed efficiency and slaughter traits of French Charolais bulls.

Improving feed efficiency is of interest to French beef producers so as to increase their profitability. To enable this improvement through selection, genetic correlations with production traits need to be quantified. The objective of this study was to estimate the genetic parameters for growth, feed efficiency (FE), and slaughter performance of young beef bulls of the French Charolais breed. Three feed efficiency criteria were calculated: residual feed intake (RFI), residual gain (RG), and ratio of FE. Data on feed intake, growth, and FE were available for 4,675 Charolais bulls tested in performance test stations and fed with pelleted diet. Between 1985 and 1989, 60 among 510 of these bulls were selected to procreate one generation of 1,477 progeny bulls which received the same pelleted diet at the experimental farm in Bourges. In addition to feed intake, growth, and FE traits, these terminal bulls also had slaughter traits of carcass yield, carcass composition, and weight of visceral organs collected. Genetic parameters were estimated using linear mixed animal models. Between performance test bulls and terminal bulls, the genetic correlation of RFI was 0.80 ± 0.18; it was 0.70 ± 0.21 for RG and 0.46 ± 0.20 for FE. For carcass traits, RFI was negatively correlated with carcass yield (-0.18 ± 0.14) and muscle content (-0.47 ± 0.14) and positively with fat content (0.48 ± 0.13). Conversely, RG and FE were positively correlated with carcass yield and muscle content and negatively with fat content. For the three FE criteria, efficient animals had leaner carcass. For visceral organs (as a proportion of empty body weight), RFI was genetically correlated with the proportions of the 5th quarter (0.51 ± 0.17), internal fat (0.36 ± 0.14), abomasum (0.46 ± 0.20), intestines (0.38 ± 0.17), liver (0.36 ± 0.16), and kidneys (0.73 ± 0.11). Conversely, RG and FE were negatively associated with these traits. The high-energy expenditure associated with the high-protein turnover in visceral organs may explain this opposite relationship between FE and the proportion of visceral organs. Selection for final weight and RFI increased growth and FE in progeny, and also improved carcass yield and muscle content in the carcass. To conclude, determinations of growth and feed intake in performance test stations are effective to select bulls to improve their growth, FE, and muscle content in carcass.

Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions.

A missense variant in the coil1A domain of the keratin 25 gene is associated with the dominant curly hair coat trait (Crd) in horse.

BACKGROUND: Curly horses present a variety of curl phenotypes that are associated with various degrees of curliness of coat, mane, tail and ear hairs. Their origin is still a matter of debate and several genetic hypotheses have been formulated to explain the diversity in phenotype, including the combination of autosomal dominant and recessive alleles. Our purpose was to map the autosomal dominant curly hair locus and identify the causal variant using genome-wide association study (GWAS) and whole-genome sequencing approaches. RESULTS: A GWAS was performed using a Bayesian sparse linear mixed model, based on 51 curly and 19 straight-haired French and North American horses from 13 paternal families genotyped on the Illumina EquineSNP50 BeadChip. A single strong signal was observed on equine chromosome 11, in a region that encompasses the type I keratin gene cluster. This region was refined by haplotype analysis to a segment including 36 genes, among which are 10 keratin genes (KRT-10, -12, -20, -23, -24, -25, -26, -27, -28, -222). To comprehensively identify candidate causal variants within all these genes, whole-genome sequences were obtained for one heterozygous curly stallion and its straight-haired son. Among the four non-synonymous candidate variants identified and validated in the curly region, only variant g.21891160G>A in the KRT25 gene (KRT25:p.R89H) was in perfect agreement with haplotype status in the whole pedigree. Genetic association was then confirmed by genotyping a larger population consisting of 353 horses. However, five discordant curly horses were observed, which carried neither the variant nor the main haplotype associated with curliness. Sequencing of KRT25 for two discordant horses did not identify any other deleterious variant, which suggests locus rather than allelic heterogeneity for the curly phenotype. CONCLUSIONS: We identified the KRT25:p.R89H variant as responsible for the dominant curly trait, but a second dominant locus may also be involved in the shape of hairs within North American Curly horses.

Insights into the genetic variation of maternal behavior and suckling performance of continental beef cows.

BACKGROUND: In beef cattle, maternal care is critical for calf survival and growth. Our objective was to evaluate the major sources of additive genetic variation in maternal behavior and suckling performance in two genetically close beef breeds. METHODS: Maternal performance was assessed based on maternal behavior (MB), milk yield (MY) and udder swelling score (US) of 1236 Blonde d'Aquitaine cows and 1048 Limousin cows. MB was scored just after calving to describe the intensity of the dam's protective behavior towards her calf. Most of the cows were genotyped using the low-density chip EuroG10K BeadChip, and imputed to the high-density 770K panel within breed. Genetic parameters for each trait were estimated for each breed under a multi-trait best linear unbiased prediction animal model. Genomic analysis was performed for each breed using the high-density genotypes and a Bayesian variable selection method. RESULTS: Heritabilities were low for MB (0.11-0.13), intermediate for MY (0.33-0.45) and high for US (0.47-0.64). Genetic correlations between the traits ranged from 0.31 to 0.58 and 0.72 to 0.99 for the Blonde d'Aquitaine and Limousin breeds, respectively. Two quantitative trait loci (QTL) were detected for MB in Blonde d'Aquitaine with NPY1R and ADRA2A as candidate causative genes. Thirty to 56 QTL were detected for MY and US in both breeds and 12 candidate genes were identified as having a role in the genetic variation of suckling performance. Since very few pleiotropic QTL were detected, there was little biological explanation for the moderate (0.57) to very high (0.99) genetic correlations estimated between MY and US in the Blonde d'Aquitaine and Limousin cows, respectively. In Blonde d'Aquitaine, the correlation was largely due to the pleiotropic QTL detected in the region upstream of the CG gene, while in Limousin, this region was only identified for US, thus attesting the difference in genetic architecture between the breeds. CONCLUSIONS: Our findings question the assumption that two populations that have close genetic links share many QTL. Nevertheless, we identified four candidate genes that may explain a substantial amount of the genetic variation in suckling performance of these two breeds.

Detection of quantitative trait loci for maternal traits using high-density genotypes of Blonde d'Aquitaine beef cattle.

BACKGROUND: The genetic determinism of the calving and suckling performance of beef cows is little known whereas these maternal traits are of major economic importance in beef cattle production systems. This paper aims to identify QTL regions and candidate genes that affect maternal performance traits in the Blonde d'Aquitaine breed. Three calving performance traits were studied: the maternal effect on calving score from field data, the calving score and pelvic opening recorded in station for primiparous cows. Three other traits related to suckling performance were also analysed: the maternal effect on weaning weight from field data, milk yield and the udder swelling score recorded in station for primiparous cows. A total of 2,505 animals were genotyped from various chip densities and imputed in high density chips for 706,791 SNP. The number of genotyped animals with phenotypes ranged from 1,151 to 2,284, depending on the trait considered. RESULTS: QTL detections were performed using a Bayes C approach. Evidence for a QTL was based on Bayes Factor values. Putative candidate genes were proposed for the QTL with major evidence for one of the six traits and for the QTL shared by at least two of the three traits underlying either calving or suckling performance. Nine candidate genes were proposed for calving performance among the nine highlighted QTL regions. The neuroregulin gene on chromosome 27 was notably identified as a very likely candidate gene for maternal calving performance. As for suckling abilities, seven candidate genes were identified among the 15 highlighted QTL. In particular, the Group-Specific Component gene on chromosome 6, which encodes vitamin D binding protein, is likely to have a major effect on maternal weaning weight in the Blonde d'Aquitaine breed. This gene had already been linked to milk production and clinical mastitis in dairy cattle. CONCLUSION: In the near future, these QTL findings and the preliminary proposals of candidate genes which act on the maternal performance of beef cows should help to identify putative causal mutations based on sequence data from different cattle breeds.

Multi-breed and multi-trait co-association analysis of meat tenderness and other meat quality traits in three French beef cattle breeds.

BACKGROUND: Studies to identify markers associated with beef tenderness have focused on Warner-Bratzler shear force (WBSF) but the interplay between the genes associated with WBSF has not been explored. We used the association weight matrix (AWM), a systems biology approach, to identify a set of interacting genes that are co-associated with tenderness and other meat quality traits, and shared across the Charolaise, Limousine and Blonde d'Aquitaine beef cattle breeds. RESULTS: Genome-wide association studies were performed using ~500K single nucleotide polymorphisms (SNPs) and 17 phenotypes measured on more than 1000 animals for each breed. First, this multi-trait approach was applied separately for each breed across 17 phenotypes and second, between- and across-breed comparisons at the AWM and functional levels were performed. Genetic heterogeneity was observed, and most of the variants that were associated with WBSF segregated within rather than across breeds. We identified 206 common candidate genes associated with WBSF across the three breeds. SNPs in these common genes explained between 28 and 30 % of the phenotypic variance for WBSF. A reduced number of common SNPs mapping to the 206 common genes were identified, suggesting that different mutations may target the same genes in a breed-specific manner. Therefore, it is likely that, depending on allele frequencies and linkage disequilibrium patterns, a SNP that is identified for one breed may not be informative for another unrelated breed. Well-known candidate genes affecting beef tenderness were identified. In addition, some of the 206 common genes are located within previously reported quantitative trait loci for WBSF in several cattle breeds. Moreover, the multi-breed co-association analysis detected new candidate genes, regulators and metabolic pathways that are likely involved in the determination of meat tenderness and other meat quality traits in beef cattle. CONCLUSIONS: Our results suggest that systems biology approaches that explore associations of correlated traits increase statistical power to identify candidate genes beyond the one-dimensional approach. Further studies on the 206 common genes, their pathways, regulators and interactions will expand our knowledge on the molecular basis of meat tenderness and could lead to the discovery of functional mutations useful for genomic selection in a multi-breed beef cattle context.

Whole-genome sequencing identifies a homozygous deletion encompassing exons 17 to 23 of the integrin beta 4 gene in a Charolais calf with junctional epidermolysis bullosa.

BACKGROUND: Since 2010, four Charolais calves with a congenital mechanobullous skin disorder that were born in the same herd from consanguineous matings were reported to us. Clinical and histopathological examination revealed lesions that are compatible with junctional epidermolysis bullosa (JEB). RESULTS: Fifty-four extended regions of homozygosity (>1 Mb) were identified after analysing the whole-genome sequencing (WGS) data from the only case available for DNA sampling at the beginning of the study. Filtering of variants located in these regions for (i) homozygous polymorphisms observed in the WGS data from eight healthy Charolais animals and (ii) homozygous or heterozygous polymorphisms found in the genomes of 234 animals from different breeds did not reveal any deleterious candidate SNPs (single nucleotide polymorphisms) or small indels. Subsequent screening for structural variants in candidate genes located in the same regions identified a homozygous deletion that includes exons 17 to 23 of the integrin beta 4 (ITGB4), a gene that was previously associated with the same defect in humans. Genotyping of a second case and of six parents of affected calves (two sires and four dams) revealed a perfect association between this mutation and the assumed genotypes of the individuals. Mining of Illumina BovineSNP50 Beadchip genotyping data from 6870 Charolais cattle detected only 44 heterozygous animals for a 5.6-Mb haplotype around ITGB4 that was shared with the carriers of the mutation. Interestingly, none of the 16 animals genotyped for the deletion carried the mutation, which suggests a rather recent origin for the mutation. CONCLUSIONS: In conclusion, we successfully identified the causative mutation for a very rare autosomal recessive mutation with only one case by exploiting the most recent DNA sequencing technologies.