References of "Druet, Tom"
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See detailEfficiency of haplotype-based methods to fine-map QTLs and embryonic lethal variants affecting fertility: Illustration with a deletion segregating in Nordic Red cattle
Kadri, Naveen Kumar ULg; Sahana, Goutam; Guldbrandtsen, Bernt et al

in Livestock Science (2014), 166

Despite its importance, fertility has been declining in many cattle populations. In dairy cattle, this decline is often attributed to the negative correlation between fertility and productions traits ... [more ▼]

Despite its importance, fertility has been declining in many cattle populations. In dairy cattle, this decline is often attributed to the negative correlation between fertility and productions traits. Recent studies showed that embryonic lethal variants might also account for a non-negligible fraction of the fertility decline. Therefore identification of such embryonic lethal variants is essential to improve fertility. We herein illustrate, with an example of a large recessive lethal deletion recently identified in Nordic Red cattle, that haplotype-based method are particularly efficient to identify such embryonic lethal variants. We first show that haplotypes can be used in traditional QTL mapping approaches and that they present very high linkage disequilibrium with underlying variants. Haplotypes can also be used in scan for lack of homozygosity. Indeed,if a haplotype is associated to a recessive lethal variant, significantly fewer living individuals will be homozygote for that haplotype than expected. For both approaches, haplotype- based methods were particularly efficient. The lack of homozygosity approach achieved higher significance than the QTL approach. Only frequent variants can be detected with both approaches unless huge genotyped cohorts are available. An alternative approach would rely on identifying potential harmful variants in next-generation sequencing data followed by the genotyping of a larger population for these variants. [less ▲]

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See detailA 660-Kb Deletion with Antagonistic Effects on Fertility and Milk Production Segregates at High Frequency in Nordic Red Cattle: Additional Evidence for the Common Occurrence of Balancing Selection in Livestock
Kumar Kadri, Naveen; Sahana, Goutam; Charlier, Carole ULg et al

in PLoS Genetics (2014), 10(1), 1004049

In dairy cattle, the widespread use of artificial insemination has resulted in increased selection intensity, which has led to spectacular increase in productivity. However, cow fertility has ... [more ▼]

In dairy cattle, the widespread use of artificial insemination has resulted in increased selection intensity, which has led to spectacular increase in productivity. However, cow fertility has concomitantly severely declined. It is generally assumed that this reduction is primarily due to the negative energy balance of high-producing cows at the peak of lactation. We herein describe the fine-mapping of a major fertility QTL in Nordic Red cattle, and identify a 660-kb deletion encompassing four genes as the causative variant. We show that the deletion is a recessive embryonically lethal mutation. This probably results from the loss of RNASEH2B, which is known to cause embryonic death in mice. Despite its dramatic effect on fertility, 13%, 23% and 32% of the animals carry the deletion in Danish, Swedish and Finnish Red Cattle, respectively. To explain this, we searched for favorable effects on other traits and found that the deletion has strong positive effects on milk yield. This study demonstrates that embryonic lethal mutations account for a non-negligible fraction of the decline in fertility of domestic cattle, and that associated positive effects on milk yield may account for part of the negative genetic correlation. Our study adds to the evidence that structural variants contribute to animal phenotypic variation, and that balancing selection might be more common in livestock species than previously appreciated. [less ▲]

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See detailA missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.
Sartelet, Arnaud ULg; Stauber, Tobias; Coppieters, Wouter ULg et al

in Disease Models & Mechanisms (2014), 7

Chloride/proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal ... [more ▼]

Chloride/proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue Cattle with a severe symptomatology including peri-natal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption. [less ▲]

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See detailToward genomic prediction from whole-genome sequence data: impact of sequencing design on genotype imputation and accuracy of predictions.
Druet, Tom ULg; Macleod, I. M.; Hayes, B. J.

in Heredity (2014), 112(1), 39-47

Genomic prediction from whole-genome sequence data is attractive, as the accuracy of genomic prediction is no longer bounded by extent of linkage disequilibrium between DNA markers and causal mutations ... [more ▼]

Genomic prediction from whole-genome sequence data is attractive, as the accuracy of genomic prediction is no longer bounded by extent of linkage disequilibrium between DNA markers and causal mutations affecting the trait, given the causal mutations are in the data set. A cost-effective strategy could be to sequence a small proportion of the population, and impute sequence data to the rest of the reference population. Here, we describe strategies for selecting individuals for sequencing, based on either pedigree relationships or haplotype diversity. Performance of these strategies (number of variants detected and accuracy of imputation) were evaluated in sequence data simulated through a real Belgian Blue cattle pedigree. A strategy (AHAP), which selected a subset of individuals for sequencing that maximized the number of unique haplotypes (from single-nucleotide polymorphism panel data) sequenced gave good performance across a range of variant minor allele frequencies. We then investigated the optimum number of individuals to sequence by fold coverage given a maximum total sequencing effort. At 600 total fold coverage (x 600), the optimum strategy was to sequence 75 individuals at eightfold coverage. Finally, we investigated the accuracy of genomic predictions that could be achieved. The advantage of using imputed sequence data compared with dense SNP array genotypes was highly dependent on the allele frequency spectrum of the causative mutations affecting the trait. When this followed a neutral distribution, the advantage of the imputed sequence data was small; however, when the causal mutations all had low minor allele frequencies, using the sequence data improved the accuracy of genomic prediction by up to 30%.Heredity advance online publication, 3 April 2013; doi:10.1038/hdy.2013.13. [less ▲]

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See detailError rate for imputation from the Illumina BovineSNP50 chip to the Illumina BovineHD chip.
Schrooten, Chris; Dassonneville, Romain; Ducrocq, Vincent et al

in Genetics, Selection, Evolution (2014), 46(1), 10

BACKGROUND: Imputation of genotypes from low-density to higher density chips is a cost-effective method to obtain high-density genotypes for many animals, based on genotypes of only a relatively small ... [more ▼]

BACKGROUND: Imputation of genotypes from low-density to higher density chips is a cost-effective method to obtain high-density genotypes for many animals, based on genotypes of only a relatively small subset of animals (reference population) on the high-density chip. Several factors influence the accuracy of imputation and our objective was to investigate the effects of the size of the reference population used for imputation and of the imputation method used and its parameters. Imputation of genotypes was carried out from 50 000 (moderate-density) to 777 000 (high-density) SNPs (single nucleotide polymorphisms). METHODS: The effect of reference population size was studied in two datasets: one with 548 and one with 1289 Holstein animals, genotyped with the Illumina BovineHD chip (777 k SNPs). A third dataset included the 548 animals genotyped with the 777 k SNP chip and 2200 animals genotyped with the Illumina BovineSNP50 chip. In each dataset, 60 animals were chosen as validation animals, for which all high-density genotypes were masked, except for the Illumina BovineSNP50 markers. Imputation was studied in a subset of six chromosomes, using the imputation software programs Beagle and DAGPHASE. RESULTS: Imputation with DAGPHASE and Beagle resulted in 1.91% and 0.87% allelic imputation error rates in the dataset with 548 high-density genotypes, when scale and shift parameters were 2.0 and 0.1, and 1.0 and 0.0, respectively. When Beagle was used alone, the imputation error rate was 0.67%. If the information obtained by Beagle was subsequently used in DAGPHASE, imputation error rates were slightly higher (0.71%). When 2200 moderate-density genotypes were added and Beagle was used alone, imputation error rates were slightly lower (0.64%). The least imputation errors were obtained with Beagle in the reference set with 1289 high-density genotypes (0.41%). CONCLUSIONS: For imputation of genotypes from the 50 k to the 777 k SNP chip, Beagle gave the lowest allelic imputation error rates. Imputation error rates decreased with increasing size of the reference population. For applications for which computing time is limiting, DAGPHASE using information from Beagle can be considered as an alternative, since it reduces computation time and increases imputation error rates only slightly. [less ▲]

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See detailA splice-acceptor site variant in the bovine PIGH gene causes glycosylphosphatidyl inositol deficiency and lethal arthrogryposis syndrome.
Sartelet, Arnaud ULg; Li, Wanbo; Pailhoux Eric et al

in Bayrou, Calixte; Cabaraux, Jean-François; Delguste, Catherine (Eds.) et al Proccedings of the 3rd Scientific Meetingof the Faculty of Veterinary Medecine (2013, October 11)

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See detailUse of ancestral haplotypes in Genome Wide Association Studies
Druet, Tom ULg; Farnir, Frédéric ULg

in Gondro, Cedric; van der Werf, Julius; Hayes, Ben (Eds.) Genome-Wide Association Studies and Genomic Prediction (2013)

We herein present a haplotype-based method to perform genome-wide association studies. The method relies on hidden Markov models to describe haplotypes from a population as a mosaic of a set of ancestral ... [more ▼]

We herein present a haplotype-based method to perform genome-wide association studies. The method relies on hidden Markov models to describe haplotypes from a population as a mosaic of a set of ancestral haplotypes. For a given position in the genome, haplotypes deriving from the same ancestral haplotype are also likely to carry the same risk alleles. Therefore, the model can be used in several applications such as haplotype reconstruction, imputation, association studies or genomic predictions. We illustrate then the model with two applications: the fine-mapping of a QTL affecting live weight in cattle and association studies in a stratified cattle population. Both applications show the potential of the method and the high linkage disequilibrium between ancestral haplotypes and causative variants. [less ▲]

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See detailScan for selective sweeps associated with muscular devolpment in Belgian Blue beef cattle
Druet, Tom ULg; Ahariz, Naïma ULg; Cambisano, Nadine ULg et al

Poster (2013, February)

The Belgian Blue beef cattle is well known for its double muscling phenotype resulting from fixation of a deletion in the myostatin gene. Since this fixation, further intensive selection for muscular ... [more ▼]

The Belgian Blue beef cattle is well known for its double muscling phenotype resulting from fixation of a deletion in the myostatin gene. Since this fixation, further intensive selection for muscular development has been particularly succesful. This response to selection might be due to fixation of more genetic variants increasing muscular development. In the present study, we search for selective sweeps in the Belgian Blue genome which might result from the fixation of such variants. To that end we used data from 593 sires genotyped with the BovineHD SNP array. In addition, we used the Belgian Blue dual purpose and the Holstein breeds as controls. We first performed scans for regions of complete homozygosity resulting from fixation. Large fixed regions were found around major genes known to be fixed in the Belgian Blue cattle breed (MSTN, PLAG1 and MC1R) but no other regions of the same magnitude was found. Among the smaller identified regions, only few of them were unique to the Belgian Blue breed. Statistical tests based on long range haplotype information were also implemented, revealing large regions in the genome of reduced haplotype homozygosity specific to the Belgian Blue breed. Some of these regions corresponded to known major genes (MSTN, roan locus, PLAG1 or MC1R) while other regions were new. To determine whether these regions might be the result of selection for muscular development, we performed association studies for muscular development. None of the identified QTL matched with the regions of reduced haplotype homozygosity and the largest QTLs did not presented evidence of strong selective sweeps. These results suggest that the response to selection for muscular development in Belgian Blue beef cattle is probably the result of polygenic selection. [less ▲]

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See detailIdentification of large selective sweeps associated with major genes in cattle.
Druet, Tom ULg; Perez-Pardal, L.; Charlier, Carole ULg et al

in Animal Genetics (2013), 44(6), 758-62

Selection for new favorable variants can lead to selective sweeps. However, such sweeps might be rare in the evolution of different species for which polygenic adaptation or selection on standing ... [more ▼]

Selection for new favorable variants can lead to selective sweeps. However, such sweeps might be rare in the evolution of different species for which polygenic adaptation or selection on standing variation might be more common. Still, strong selective sweeps have been described in domestic species such as chicken lines or dog breeds. The goal of our study was to use a panel of individuals from 12 different cattle breeds genotyped at high density (800K SNPs) to perform a whole-genome scan for selective sweeps defined as unexpectedly long stretches of reduced heterozygosity. To that end, we developed a hidden Markov model in which one of the hidden states corresponds to regions of reduced heterozygosity. Some unexpectedly long regions were identified. Among those, six contained genes known to affect traits with simple genetic architecture such as coat color or horn development. However, there was little evidence for sweeps associated with genes underlying production traits. [less ▲]

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See detailA missense mutation in the ClC-7 chloride channel causes hamartomas with osteopetrosis in cattle.
Sartelet, Arnaud ULg; Stauber, Tobias; Coppieters, Wouter ULg et al

Conference (2012, October 19)

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See detailA missense mutation in the ClC-7 chloride channel causes hamartomas with osteopetrosis in cattle.
Sartelet, Arnaud ULg; Stauber, Tobias; Druet, Tom ULg et al

Conference (2012, June 05)

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See detailAncestral haplotype-based association mapping with generalized linear mixed models accounting for stratification
Zhang, Zhiyan; Guillaume, François; Sartelet, Arnaud ULg et al

in Bioinformatics (2012), 28(19), 2467-2473

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See detailA splice site variant in the bovine RNF11 gene compromises growth and regulation of the inflammatory response.
Sartelet, Arnaud ULg; Druet, Tom ULg; Michaux, Charles ULg et al

in PLoS Genetics (2012), 15(3), 1002581

We herein report association mapping of a locus on bovine chromosome 3 that underlies a Mendelian form of stunted growth in Belgian Blue Cattle. By resequencing positional candidates, we identify the ... [more ▼]

We herein report association mapping of a locus on bovine chromosome 3 that underlies a Mendelian form of stunted growth in Belgian Blue Cattle. By resequencing positional candidates, we identify the causative c124-2A>G splice variant in intron 1 of the RNF11 gene, for which all affected animals are homozygous. We make the remarkable observation that 26% of healthy Belgian Blue animals carry the corresponding variant. We demonstrate in a prospective study design that approximately one third of homozygous mutants die prematurely with major inflammatory lesions, hence explaining the rarity of growth-stunted animals despite the high frequency of carriers. We provide preliminary evidence that heterozygous advantage for an as of yet unidentified phenotype may have caused a selective sweep accounting for the high frequency of the RNF11 c124-2A>G mutation in Belgian Blue Cattle. [less ▲]

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See detailSerial translocation by means of circular intermediates underlies colour sidedness in cattle.
Durkin, Keith ULg; Coppieters, Wouter ULg; Drogemuller, Cord et al

in Nature (2012), 482(7383), 81-4

Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik ... [more ▼]

Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism. [less ▲]

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See detailLDSO: A program to simulate pedigrees and molecular information under various evolutionary forces
Ytournel, F.; Teyssèdre, S.; Roldan, D. et al

in Journal of Animal Breeding & Genetics (2012), 129(5), 417-421

Simulations are a major tool to evaluate new statistical methods and optimize experimental designs in the genomic era. However, this can only be achieved when the simulations are close enough to reality ... [more ▼]

Simulations are a major tool to evaluate new statistical methods and optimize experimental designs in the genomic era. However, this can only be achieved when the simulations are close enough to reality, as well as diverse enough to be realistic. For mapping studies, it is thus critical to re-create as much as possible the forces generating linkage (mutation, random drift, changes in population sizes, selection and pedigree structure) and the mechanisms producing trait genetic architecture (additivity, dominance, epistasis). We present here a computer program (ldso) simulating these phenomena. Optional outputs provide statistics on the linkage disequilibrium (LD) structure and the identity by descent between chromosomal segments, facilitating further data analyses. Furthermore, ldso enables the simulation of genomic data in known pedigrees, which sticks as precisely as possible to recent population history and structures of the long-range LD, allowing optimization of fine-mapping strategies. © 2012 Blackwell Verlag GmbH. [less ▲]

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See detailEstimating age of admixture in a cattle population based on SNP chip data
Frkonja, A.; Druet, Tom ULg; Gredler, B. et al

in Acta Agriculturae Slovenica (2012), 100(SUPPL.3), 115-119

The aim of this study was to predict individual age of admixture in the crossbred Swiss Fleckvieh population. We checked how well the method is dealing with recent admixture with high throughput single ... [more ▼]

The aim of this study was to predict individual age of admixture in the crossbred Swiss Fleckvieh population. We checked how well the method is dealing with recent admixture with high throughput single nucleotide polymorphism data from the bovine 50K SNP Chip. A total of 101 Red Holstein, 91 Simmental, and 308 crossed animals were available for analysis. Age of admixture was derived from the complete pedigree and molecular markers. The method applied (using SABER software) based on Markov-hidden Markov model was able to derive age of admixture similar to estimates of pedigree data, however the values were often overestimated. Of 21 investigated cases, results from SNP data reflected paternal and maternal age of admixture well for 9 cases but provided results out of range for the other 12 cases. Alternative methods based on breed-specific haplotype blocks need to be evaluated in the future. [less ▲]

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See detailGenetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle.
Sandor, Cynthia ULg; Li, Wanbo ULg; Coppieters, Wouter ULg et al

in PLoS Genetics (2012), 8(7), 1002854

We use >250,000 cross-over events identified in >10,000 bovine sperm cells to perform an extensive characterization of meiotic recombination in male cattle. We map Quantitative Trait Loci (QTL ... [more ▼]

We use >250,000 cross-over events identified in >10,000 bovine sperm cells to perform an extensive characterization of meiotic recombination in male cattle. We map Quantitative Trait Loci (QTL) influencing genome-wide recombination rate, genome-wide hotspot usage, and locus-specific recombination rate. We fine-map three QTL and present strong evidence that genetic variants in REC8 and RNF212 influence genome-wide recombination rate, while genetic variants in PRDM9 influence genome-wide hotspot usage. [less ▲]

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