A. Barbat

Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2.

The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10−4) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.

Accounting for variance heterogeneity in French dairy cattle genetic evaluation

Abstract A linear mixed model assuming heterogeneous residual variances and known constant variance ratios was applied to the analysis of milk, fat, and protein yields, and fat and protein contents in the French Holstein, Montbeliarde, and Normande dairy cattle populations. The method was based on a log-linear model for residual variances. This log-linear model included a region-year fixed effect and a herd-year random effect with a within-herd autocorrelation. The estimates of this correlation coefficient varied from 0.64 to 0.92, according to trait and breed. Residual standard deviation for yields doubled over the last 20 years, whereas differences across regions were more limited and decreased over time. This model was compared with the homogeneous model and with the multiplicative model of Meuwissen et al. (1996) [Meuwissen, T.H.E., De Jong, G., Engel, B., 1996. Joint estimation of breeding values and heterogeneous variances of large data files. J. Dairy Sci. 79, 310–316]. Both heteroskedastic models provided very similar results. Accounting for heterogeneous variances had important consequences on cow ranking. Consequences on AI bull ranking were very limited, although the method affected estimated genetic trend and within birth year estimated breeding values (EBV) variability.

Environmental effects on lactation curves included in a test-day model genetic evaluation.

A large number of environmental factors affect the daily milk production of a cow. Lactation curves included in the French test-day model are modelled as a function of days in milk with semi-parametric curves (splines). The proper modelling of environmental effects in the test-day analysis was investigated using test-day records collected from the first three lactations of French Montbéliarde cows from 1988 to 2005. Four lactation-curve effects describing calving month, length of dry period, age at calving and gestation defined within parity-class were fitted. The shape of lactation curves did not depend on year of calving, which can be modelled as a constant over the whole lactation. To reduce computational requirements and time, data were pre-adjusted in a first step for fixed effects with no year interaction, and then used for genetic evaluation. Correlations for each lactation between 305-day estimates of genetic and permanent environment effects computed using pre-adjustment factors obtained at a 4-year interval were virtually one. The use of a two-step procedure had a very limited impact on the estimates of genetic and permanent environment effects. The minimum correlations with values estimated with a one-step procedure were 0.9984 and 0.9974, respectively. The knowledge of systematic environmental effects affecting the cow daily yield through lactation curves offers interesting perspectives to predict future daily milk production.

Use of an animal model for genetic evaluation of the Lacaune dairy sheep

Abstract This paper presents the characteristics and the results of an analysis of the Lacaune dairy sheep with an animal model. The analysis involved 1 003 071 lactations of parity 1 to 7, exhibited from 1978 to 1989 by 340 541 Lacaune dairy ewes. After including useful pedigrees, 492 149 females and 8231 males were evaluated for milk yield. Fat and protein yields and contents, partially recorded since 1986, were also analysed. 27 groups were defined for unknown parents only, according to the sex and birth year of their progeny. Results were consistent with those obtained with the present evaluation system (IF2). For males, the correlations between expected breeding values ranged from 0.92 to 0.98, according to the traits and the distribution of the daughters between flocks. The estimated genetic trend for milk yield was found rather insensitive to the heritability value and reached about 0.18 genetic standard deviation per year, i.e. about two thirds of the phenotypic trend and 2.2% of the production level. Some indication is given about the gain in efficiency due to the animal model.

Inbreeding and crossbreeding parameters for production and fertility traits in Holstein, Montbéliarde, and Normande cows

Breed differences and nonadditive genetic effects for milk production traits, somatic cell score (SCS), conception rate (CR), and days to first service (DFS) were estimated for Holstein × Montbéliarde and Holstein × Normande crossbreds, using an animal model adapted from the French genetic evaluation and extended to across-breed analysis. Inbreeding and breed differences were estimated from all purebred recorded cows. Only records from 1,137 herds with Holstein × Montbéliarde crossbred cows and from 1,033 herds with Holstein × Normande crossbred cows were used to estimate crossbreeding parameters. In these herds, crossbred cows represented about 13% of the total number of recorded animals compared with <1% when all herds were considered. Compared with the Montbéliarde and Normande breeds, the Holstein breed was genetically superior for production [+951kg and +2,444kg for 305-d mature-equivalent (305ME) milk, +40kg and +102kg for 305ME fat, +17kg and +54kg for 305ME protein, respectively] and inferior for fertility traits (-12 and -9% for CR, respectively). Inbreeding depression caused loss of yield for production traits (from -32 to -41kg of 305ME milk, -1.4 to -1.7kg of 305ME fat, and -1.1 to -1.3kg of 305ME protein per inbreeding percentage), a small increase in SCS (+0.001 to 0.006) and DFS (+0.12d), and a decrease in CR (-0.27 to -0.44%). Favorable heterosis effects were found for all traits (+494 to 524kg of 305ME milk, +21 to 22kg of 305ME fat, +15 to 16kg of 305ME protein, -0.05 to -0.04 SCS, +2 to 3% for CR, and -3 to 6d of DFS), to such a point that F1 crossbreds could compete with Holstein cows for milk production while having a better fertility. However, recombination losses suggested that some F1 heterosis was lost for backcross cows.

Genetic tools to improve reproduction traits in dairy cattle.

Fertility is a major concern in the dairy cattle industry and has been the subject of numerous studies over the past 20 years. Surprisingly, most of these studies focused on rough female phenotypes and, despite their important role in reproductive success, male- and embryo-related traits have been poorly investigated. In recent years, the rapid and important evolution of technologies in genetic research has led to the development of genomic selection. The generalisation of this method in combination with the achievements of the AI industry have led to the constitution of large databases of genotyping and sequencing data, as well as refined phenotypes and pedigree records. These resources offer unprecedented opportunities in terms of fundamental and applied research. Here we present five such examples with a focus on reproduction-related traits: (1) detection of quantitative trait loci (QTL) for male fertility and semen quality traits; (2) detection of QTL for refined phenotypes associated with female fertility; (3) identification of recessive embryonic lethal mutations by depletion of homozygous haplotypes; (4) identification of recessive embryonic lethal mutations by mining whole-genome sequencing data; and (5) the contribution of high-density single nucleotide polymorphism chips, whole-genome sequencing and imputation to increasing the power of QTL detection methods and to the identification of causal variants.

A missense mutation in PFAS (phosphoribosylformylglycinamidine synthase) is likely causal for embryonic lethality associated with the MH1 haplotype in Montbéliarde dairy cattle

A candidate mutation in the sex hormone binding globulin gene was proposed in 2013 to be responsible for the MH1 recessive embryonic lethal locus segregating in the Montbéliarde breed. In this follow-up study, we excluded this candidate variant because healthy homozygous carriers were observed in large-scale genotyping data generated in the framework of the genomic selection program. We fine mapped the MH1 locus in a 702-kb interval and analyzed genome sequence data from the 1,000 bull genomes project and 54 Montbéliarde bulls (including 14 carriers and 40 noncarriers). We report the identification of a strong candidate mutation in the gene encoding phosphoribosylformylglycinamidine synthase (PFAS), a protein involved in de novo purine synthesis. This mutation, located in a class I glutamine amidotransferase-like domain, results in the substitution of an arginine residue that is entirely conserved among eukaryotes by a cysteine (p.R1205C). No homozygote for the cysteine-encoding allele was observed in a large population of more than 25,000 individuals despite a 6.7% allelic frequency and 122 expected homozygotes under neutrality assumption. Genotyping of 18 embryos collected from heterozygous parents as well as analysis on nonreturn rates suggested that most homozygous carriers died between 7 and 35 d postinsemination. The identification of this strong candidate mutation will enable the accurate testing of the reproducers and the efficient selection against this lethal recessive embryonic defect in the Montbéliarde breed.