Two-stage genome-wide association study for the identification of causal variants underlying hoof disorders in cattle.

Feet and legs disorders influence dairy cattle breeding by their effect on animal welfare, economic losses due to lower production and fertility, costs of treatment, and problems with herd management. In our study, we estimated heritabilities and performed a 2-step GWAS for 3 traits describing hoof health: hoof health status defined by a veterinarian (HSV), hoof health status defined by a claw trimmer (HSC), and the total number of hoof disorders (NHD), scored in 1,998 Fleckvieh and 979 Braunvieh cows. The individuals were genotyped with a high-density (HD) panel consisting of 76,934 SNP. For significant genomic regions, the SNP information was enhanced by SNP imputed from the whole-genome sequence of Fleckvieh and Braunvieh bulls from the 1000 Bulls Genome project. The heritabilities were estimated to be 0.035 for HSV, 0.249 for HSC, and 0.279 for NHD. Based on the first-stage GWAS with SNP from the HD panel, 7 significant genomic regions on 6 chromosomes were defined: (1) 120 SNP spanning 15,522 bp on BTA1, including the TOPBP1 gene; (2) 4,139 SNP spanning 1,426,046 bp on BTA7, including the RIOK2 and RGMB genes; (3) 167 SNP spanning 167,352 bp on BTA13, including the C13H20orf194 gene; (4) 2 regions on BTA14, one harboring 1,071 SNP spanning 380,024 bp, including RRM2B and NCALD, and the other comprising 632 SNP spanning 385,111 bp, including STK3; (5) 328 SNP on BTA15, spanning 235,567 bp between FAM168A and PLEKHB1; and (6) 1,549 SNP on BTA22, spanning 596,101 bp in the neighborhood of PTPRG. Then, we conducted a second-stage GWAS based on SNP from whole-genome sequences within the significant regions obtained in the first stage of the analysis. For HSV, the highest additive effect was estimated for 23 SNP located within a region on BTA15, close to FAM168A, corresponding to a predicted gene sequence. For HSC, the highest additive effect was attributed to 44 SNP located within a region of BTA22 corresponding to 4 predicted gene sequences, with rs135082893 within a sequence encoding a microRNA. Another potential causal mutation for HSC was rs134142607 on BTA13, within the exon of C13H20orf194. For NHD, 33 SNP with the highest estimated effect were located on BTA7 within a region of a predicted gene positioned between RIOK2 and RGMB. On BTA14, all significant SNP were located in introns of STK3, which is responsible for the "abnormal gait" phenotype in mice.

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

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.

Single-step genomic evaluation for growth traits in a Mexican Braunvieh cattle population.

OBJECTIVE: The objective was to compare (pedigree-based) best linear unbiased prediction (BLUP), genomic BLUP (GBLUP), and single-step GBLUP (ssGBLUP) methods for genomic evaluation of growth traits in a Mexican Braunvieh cattle population. METHODS: Birth (BW), weaning (WW), and yearling weight (YW) data of a Mexican Braunvieh cattle population were analyzed with BLUP, GBLUP, and ssGBLUP methods. These methods are differentiated by the additive genetic relationship matrix included in the model and the animals under evaluation. The predictive ability of the model was evaluated using random partitions of the data in training and testing sets, consistently predicting about 20% of genotyped animals on all occasions. For each partition, the Pearson correlation coefficient between adjusted phenotypes for fixed effects and non-genetic random effects and the estimated breeding values (EBV) were computed. RESULTS: The random contemporary group (CG) effect explained about 50%, 45%, and 35% of the phenotypic variance in BW, WW, and YW, respectively. For the three methods, the CG effect explained the highest proportion of the phenotypic variances (except for YW-GBLUP). The heritability estimate obtained with GBLUP was the lowest for BW, while the highest heritability was obtained with BLUP. For WW, the highest heritability estimate was obtained with BLUP, the estimates obtained with GBLUP and ssGBLUP were similar. For YW, the heritability estimates obtained with GBLUP and BLUP were similar, and the lowest heritability was obtained with ssGBLUP. Pearson correlation coefficients between adjusted phenotypes for non-genetic effects and EBVs were the highest for BLUP, followed by ssBLUP and GBLUP. CONCLUSION: The successful implementation of genetic evaluations that include genotyped and non-genotyped animals in our study indicate a promising method for use in genetic improvement programs of Braunvieh cattle. Our findings showed that simultaneous evaluation of genotyped and non-genotyped animals improved prediction accuracy for growth traits even with a limited number of genotyped animals.

Exploring the Potential Genetic Heterogeneity in the Incidence of Hoof Disorders in Austrian Fleckvieh and Braunvieh Cattle.

Genetic heterogeneity denotes the situation when different genetic architectures underlying diverse populations result in the same phenotype. In this study, we explore the genetic background underlying differences in the incidence of hoof disorders between Braunvieh and Fleckvieh cattle in the context of genetic heterogeneity between the breeds. Despite potentially higher power of testing due to twice as large sample size, none of the SNPs was significantly associated with the total number of hoof disorders in Fleckvieh, while 15 SNPs were significant in Braunvieh. The most promising candidate genes in Braunvieh were as follows: CBLB on BTA1, which causes arthritis in rats; CAV2 on BTA4, which affects skeletal muscles in mice; PTHLH on BTA5, which causes disease phenotypes related to the skeleton in humans, mice, and zebrafish; and SORCS2 on BTA6, which causes decreased susceptibility to injury in mice. Some of the significant SNPs (BTA1, BTA4, BTA5, BTA13, and BTA16) revealed allelic heterogeneity-i.e., different allele frequencies between Fleckvieh and Braunvieh. Some of the significant regions (BTA1, BTA5, BTA13, and BTA16) correlated to inter-breed differences in linkage disequilibrium (LD) structure and may thus represent false-positive heterogeneity. However, positions on BTA6 (SORCS2), BTA14, and BTA24 mark Braunvieh-specific regions. We hypothesize that the observed genetic heterogeneity of hoof disorders is a by-product of different selection goals defined for the analyzed breeds-toward dairy production in Braunvieh and toward beef production in Fleckvieh. Based on the current dataset, it is not possible to unequivocally confirm or exclude the hypothesis of genetic heterogeneity in the susceptibility to hoof disorders between Fleckvieh and Braunvieh. The main reason for the problem is that the potential heterogeneity was explored through SNP-phenotype associations and not through causal mutations, due to a limited SNP density offered by the SNP-chip. The rationale against genetic heterogeneity comprises 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, different selection goals defined for the analyzed breeds accompanied by no systematic, genome-wide differences in LD structure between the breeds favor the heterogeneity hypothesis at some smaller genomic regions.

Big dairy data to unravel effects of environmental, physiological and morphological factors on milk production of mountain-pastured Braunvieh cows.

The transhumance system, which consists in moving animals to high mountain pastures during summer, plays a considerable role in preserving both local biodiversity and traditions, as well as protecting against natural hazard. In cows, particularly, milk production is observed to decline as a response to food shortage and climatic stress, leading to atypical lactation curves that are barely described by current lactation models. Here, we relied on 5 million monthly milk records from over 200 000 Braunvieh and Original Braunvieh cows to devise a new model accounting for transhumance, and test the influence of environmental, physiological and morphological factors on cattle productivity. Counter to expectations, environmental conditions in the mountain showed a globally limited impact on milk production during transhumance, with cows in favourable conditions producing only 10% more compared with cows living in detrimental conditions, and with precipitation in spring and altitude revealing to be the most production-affecting variables. Conversely, physiological factors such as lactation number and pregnancy stage presented an important impact over the whole lactation cycle with 20% difference in milk production, and alter the way animals respond to transhumance. Finally, the considered morphological factors (cow height and foot angle) presented a smaller impact during the whole lactation cycle (10% difference in milk production). The present findings help to anticipate the effect of climate change and to identify problematic environmental conditions by comparing their impact with the effect of factors that are known to influence lactation.

Impact of US Brown Swiss genetics on milk quality from low-input herds in Switzerland: Interactions with season.

This study investigated the effect of, and interactions between, US Brown Swiss (BS) genetics and season on milk yield, basic composition and fatty acid profiles, from cows on low-input farms in Switzerland. Milk samples (n = 1,976) were collected from 1,220 crossbreed cows with differing proportions of BS, Braunvieh and Original Braunvieh genetics on 40 farms during winter-housing and summer-grazing. Cows with more BS genetics produced more milk in winter but not in summer, possibly because of underfeeding potentially high-yielding cows on low-input pasture-based diets. Cows with more Original Braunvieh genetics produced milk with more (i) nutritionally desirable eicosapentaenoic and docosapentaenoic acids, throughout the year, and (ii) vaccenic and α-linolenic acids, total omega-3 fatty acid concentrations and a higher omega-3/omega-6 ratio only during summer-grazing. This suggests that overall milk quality could be improved by re-focussing breeding strategies on cows' ability to respond to local dietary environments and seasonal dietary changes.

Impact of US Brown Swiss genetics on milk quality from low-input herds in Switzerland: interactions with grazing intake and pasture type.

This study investigated the effect of, and interactions between, contrasting crossbreed genetics (US Brown Swiss [BS] × Improved Braunvieh [BV] × Original Braunvieh [OB]) and feeding regimes (especially grazing intake and pasture type) on milk fatty acid (FA) profiles. Concentrations of total polyunsaturated FAs, total omega-3 FAs and trans palmitoleic, vaccenic, α-linolenic, eicosapentaenoic and docosapentaenoic acids were higher in cows with a low proportion of BS genetics. Highest concentrations of the nutritionally desirable FAs, trans palmitoleic, vaccenic and eicosapentaenoic acids were found for cows with a low proportion of BS genetics (0-24% and/or 25-49%) on high grazing intake (75-100% of dry matter intake) diets. Multivariate analysis indicated that the proportion of OB genetics is a positive driver for nutritionally desirable monounsaturated and polyunsaturated FAs while BS genetics proportion was positive driver for total and undesirable individual saturated FAs. Significant genetics × feeding regime interactions were also detected for a range of FAs.