References of "Druet, Tom"
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See detailA Random Forests Framework for Modeling Haplotypes as Mosaics of Reference Haplotypes
Faux, Pierre; Geurts, Pierre ULiege; Druet, Tom ULiege

in Frontiers in Genetics (2019)

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See detailRZooRoH: An R package to characterize individual genomic autozygosity and identify homozygous-by-descent segments
Bertrand, Amandine ULiege; Kadri, N. K.; Flori, L. et al

in Methods in Ecology and Evolution (2019)

Identifying homozygous-by-descent (HBD) regions in individual genomes is highly valuable to infer the recent history of populations and to provide insights into trait architecture. Here, we present the ... [more ▼]

Identifying homozygous-by-descent (HBD) regions in individual genomes is highly valuable to infer the recent history of populations and to provide insights into trait architecture. Here, we present the RZooRoH R-package that implements an efficient and accurate model-based approach to identify HBD segments. The underlying hidden Markov model partitions the genome-wide individual autozygosity into different age-related HBD classes while accounting for genotyping errors and genetic map information. The RZooRoH package is user-friendly and versatile, accepting either genotyping or sequencing (including low-coverage) data in various formats. Through numerical maximization and parallelization, computational performances were improved compared to our initial Fortran implementation of the model. The package allows to evaluate and compare various models defined by their number of HBD classes and it also provides several graphical functions that help interpretation of the results. RZooRoH is an efficient tool that proves particularly suited for sub-optimal datasets (e.g. low marker density, individual low-coverage sequencing, uneven marker spacing) and for individuals from populations with complex demographic histories. RZooRoH is available from CRAN: https://CRAN.R-project.org/package=RZooRoH. © 2019 The Authors. Methods in Ecology and Evolution © 2019 British Ecological Society [less ▲]

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See detailOn the path to recovery : characterizing inbreeding in the European Bison with a model-based approach
Druet, Tom ULiege; Flori, Laurence; Olénski, Kamel et al

Conference (2018, December 15)

When two alleles from the same individual descend from a single allele in an ancestor, they form an homozygous-by-descent (HBD) or autozygous segment. Increased autozygosity is frequently associated with ... [more ▼]

When two alleles from the same individual descend from a single allele in an ancestor, they form an homozygous-by-descent (HBD) or autozygous segment. Increased autozygosity is frequently associated with negative effects on fitness. Population bottlenecks or founder effects can dramatically increase autozygosity levels. We recently developped a model-based approach to identify HBD segments that is particularly valuable when marker information is sparser (e.g., low-fold sequencing experiments, low marker density, marker recruitment bias). This hidden Markov model is also useful when the data is not uniform (variable genotyping errors, marker spacing or recombinations rates). Overall the approach is beneficial in situations encountered in wild organisms. Here, we use our model to characterize individual autozygosity in the restored European Bison. After complete extinction in the wild, restoration programs started as soon as 1929 using only twelve founders kept in European zoos and private breeding centers and leading to the sucessfull restoration of two genetic lines, the lowland and lowland-Caucasian lines. To characterize inbreeding we used a bovine genotyping array encompassing more than 700,000 SNPs. Only 22,602 SNPs were conserved after data filtering. Despite the sparse marker information, we estimated high inbreeding levels (0.30 to 0.40) consistent with pedigree estimates. Many long HBD segments (up to 120 Mb) associated with recent common ancestors, approximately 4 to 32 generations in the past, were identified. Their distribution is compatible with a recent bottleneck. The results obtained with this sparse genotyping data were validated with whole genome sequence data from two individuals. Overall, the presented approach is still efficient when the number of informative markers is reduced compared to traditional high-density genotyping arrays and can also be used with genotyping-by-sequencing data. The same strategy can be applied to wild populations for which the history is not well documented. [less ▲]

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See detailOn the path to recovery: characterizing inbreeding in the European Bison with a model-based approach
Druet, Tom ULiege; Flori, Laurence; Bertrand, Amandine ULiege et al

Scientific conference (2018, December 07)

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See detailA model-based approach to characterize individual autozygosity at both global and local genomic scales
Druet, Tom ULiege; Gautier, Mathieu

Conference (2018, August 29)

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See detailHigh resolution mapping of cross-over events in cattle using NGS data
Kadri, Naveen Kumar ULiege; Harland, Chad; Charlier, Carole ULiege et al

in Proceedings of the World Congress on Genetics Applied to Livestock Production (2018, February 15)

High resolution mapping of cross-over events in cattle using NGS data Keywords: recombination, cattle, NGS Homologous recombination plays an important role in proper segregation of homologues in the first ... [more ▼]

High resolution mapping of cross-over events in cattle using NGS data Keywords: recombination, cattle, NGS Homologous recombination plays an important role in proper segregation of homologues in the first meiotic division. Failure in proper segregation results in aneuploidy, which is a leading cause for pregnancy loss in humans. Recently, global recombination rate has been studied in large cattle populations genotyped with SNP arrays ( 50K). However, the fine-scale resolution of these studies remained limited as a result of the relatively low marker density. Here we report high-resolution mapping of cross-over (CO) events in a cattle pedigree using whole genome sequence data. We carry out an extensive cleaning of our sequence data to remove errors (errors in the genome build, sequencing errors and presence of CNVs) that dramatically inflate CO counts. Using 5 million high quality sequence variants we identify 3,880 CO events in 155 male gametes and 3,088 CO events in 124 female gametes. The median resolution of the identified COs was 34 kb with about 70% of the events mapped to an interval less than 100 kb. The male and female map lengths were estimated at 27.5 M and 23.8 M respectively. Consistent with previous studies in cattle, we find higher recombination rate in males and higher frequency of COs at chromosome ends. Interestingly, compared to the map lengths estimated from SNP chip we find an increase of 3.7 and 2.7 M in male and female maps respectively. Despite the cleaning efforts, we cannot determine at this time whether the increased in map lengths correspond to CO missed with genotyping arrays, to spurious CO identified with NGS data (due to unidentified sources of errors) or both. [less ▲]

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See detailA model-based approach to characterize individual inbreeding at both global and local genomic scales.
Druet, Tom ULiege; Gautier, M.

in Molecular Ecology (2017), 26

Inbreeding results from the mating of related individuals and may be associated with reduced fitness because it brings together deleterious variants in one individual. In general, inbreeding is estimated ... [more ▼]

Inbreeding results from the mating of related individuals and may be associated with reduced fitness because it brings together deleterious variants in one individual. In general, inbreeding is estimated with respect to an arbitrary base population consisting of ancestors that are assumed unrelated. We herein propose a model-based approach to estimate and characterize individual inbreeding at both global and local genomic scales by assuming the individual genome is a mosaic of homozygous-by-descent (HBD) and non-HBD segments. The HBD segments may originate from ancestors tracing back to different periods in the past defining distinct age-related classes. The lengths of the HBD segments are exponentially distributed with class-specific parameters reflecting that inbreeding of older origin generates on average shorter stretches of observed homozygous markers. The model is implemented in a hidden Markov model framework that uses marker allele frequencies, genetic distances, genotyping error rates and the sequences of observed genotypes. Note that genotyping errors, low-fold sequencing or genotype-by-sequencing data are easily accommodated under this framework. Based on simulations under the inference model, we show that the genomewide inbreeding coefficients and the parameters of the model are accurately estimated. In addition, when several inbreeding classes are simulated, the model captures them if their ages are sufficiently different. Complementary analyses, either on data sets simulated under more realistic models or on human, dog and sheep real data, illustrate the range of applications of the approach and how it can reveal recent demographic histories among populations (e.g., very recent bottlenecks or founder effects). The method also allows to clearly identify individuals resulting from extreme consanguineous matings. [less ▲]

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See detailEstimation and characterization of individual genomic inbreeding in Belgian Blue beef cattle
Sole Berga, Marina ULiege; Gori, Ann-Stephan ULiege; Faux, Pierre et al

Conference (2017, August)

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See detailIdentification and management of recessive genetic defects in Belgian Blue beef cattle
Druet, Tom ULiege; Sartelet, Arnaud ULiege; Hubin, Xavier et al

Conference (2017, August)

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See detailAge-based partitioning of individual genomic inbreeding levels in Belgian Blue cattle.
Sole Berga, Marina ULiege; Gori, Ann-Stephan ULiege; Faux, Pierre et al

in Genetics, Selection, Evolution (2017), 49(1), 92

BACKGROUND: Inbreeding coefficients can be estimated either from pedigree data or from genomic data, and with genomic data, they are either global or local (when the linkage map is used). Recently, we ... [more ▼]

BACKGROUND: Inbreeding coefficients can be estimated either from pedigree data or from genomic data, and with genomic data, they are either global or local (when the linkage map is used). Recently, we developed a new hidden Markov model (HMM) that estimates probabilities of homozygosity-by-descent (HBD) at each marker position and automatically partitions autozygosity in multiple age-related classes (based on the length of HBD segments). Our objectives were to: (1) characterize inbreeding with our model in an intensively selected population such as the Belgian Blue Beef (BBB) cattle breed; (2) compare the properties of the model at different marker densities; and (3) compare our model with other methods. RESULTS: When using 600 K single nucleotide polymorphisms (SNPs), the inbreeding coefficient (probability of sampling an HBD locus in an individual) was on average 0.303 (ranging from 0.258 to 0.375). HBD-classes associated to historical ancestors (with small segments </= 200 kb) accounted for 21.6% of the genome length (71.4% of the total length of the genome in HBD segments), whereas classes associated to more recent ancestors accounted for only 22.6% of the total length of the genome in HBD segments. However, these recent classes presented more individual variation than more ancient classes. Although inbreeding coefficients obtained with low SNP densities (7 and 32 K) were much lower (0.060 and 0.093), they were highly correlated with those obtained at higher density (r = 0.934 and 0.975, respectively), indicating that they captured most of the individual variation. At higher SNP density, smaller HBD segments are identified and, thus, more past generations can be explored. We observed very high correlations between our estimates and those based on homozygosity (r = 0.95) or on runs-of-homozygosity (r = 0.95). As expected, pedigree-based estimates were mainly correlated with recent HBD-classes (r = 0.56). CONCLUSIONS: Although we observed high levels of autozygosity associated with small HBD segments in BBB cattle, recent inbreeding accounted for most of the individual variation. Recent autozygosity can be captured efficiently with low-density SNP arrays and relatively simple models (e.g., two HBD classes). The HMM framework provides local HBD probabilities that are still useful at lower SNP densities. [less ▲]

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See detailFixed-length haplotypes can improve genomic prediction accuracy in an admixed dairy cattle population
Hess, Melanie; Druet, Tom ULiege; Hess, Andrew et al

in Genetics, Selection, Evolution (2017), 49(1), 54

Fitting covariates representing the number of haplotype alleles rather than single nucleotide polymorphism (SNP) alleles may increase genomic prediction accuracy if linkage disequilibrium between ... [more ▼]

Fitting covariates representing the number of haplotype alleles rather than single nucleotide polymorphism (SNP) alleles may increase genomic prediction accuracy if linkage disequilibrium between quantitative trait loci and SNPs is inadequate. The objectives of this study were to evaluate the accuracy, bias and computation time of Bayesian genomic prediction methods that fit fixed-length haplotypes or SNPs. Genotypes at 37,740 SNPs that were common to Illumina BovineSNP50 and high-density panels were phased for ~58,000 New Zealand dairy cattle. Females born before 1 June 2008 were used for training, and genomic predictions for milk fat yield (n = 24,823), liveweight (n = 13,283) and somatic cell score (n = 24,864) were validated within breed (predominantly Holstein–Friesian, predominantly Jersey, or admixed KiwiCross) in later-born females. Covariates for haplotype alleles of five lengths (125, 250, 500 kb, 1 or 2 Mb) were generated and rare haplotypes were removed at four thresholds (1, 2, 5 or 10%), resulting in 20 scenarios tested. Genomic predictions fitting covariates for either SNPs or haplotypes were calculated by using BayesA, BayesB or BayesN. This is the first study to quantify the accuracy of genomic prediction using haplotypes across the whole genome in an admixed population. [less ▲]

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See detailA strategy to improve phasing of whole-genome sequenced individuals through integration of familial information from dense genotype panels.
Faux, Pierre; Druet, Tom ULiege

in Genetics, Selection, Evolution (2017), 49(1), 46

BACKGROUND: Haplotype reconstruction (phasing) is an essential step in many applications, including imputation and genomic selection. The best phasing methods rely on both familial and linkage ... [more ▼]

BACKGROUND: Haplotype reconstruction (phasing) is an essential step in many applications, including imputation and genomic selection. The best phasing methods rely on both familial and linkage disequilibrium (LD) information. With whole-genome sequence (WGS) data, relatively small samples of reference individuals are generally sequenced due to prohibitive sequencing costs, thus only a limited amount of familial information is available. However, reference individuals have many relatives that have been genotyped (at lower density). The goal of our study was to improve phasing of WGS data by integrating familial information from haplotypes that were obtained from a larger genotyped dataset and to quantify its impact on imputation accuracy. RESULTS: Aligning a pre-phased WGS panel [~5 million single nucleotide polymorphisms (SNPs)], which is based on LD information only, to a 50k SNP array that is phased with both LD and familial information (called scaffold) resulted in correctly assigning parental origin for 99.62% of the WGS SNPs, their phase being determined unambiguously based on parental genotypes. Without using the 50k haplotypes as scaffold, that value dropped as expected to 50%. Correctly phased segments were on average longer after alignment to the genotype phase while the number of switches decreased slightly. Most of the incorrectly assigned segments, and subsequent switches, were due to singleton errors. Imputation from 50k SNP array to WGS data with improved phasing had a marginal impact on imputation accuracy (measured as r 2), i.e. on average, 90.47% with traditional techniques versus 90.65% with pre-phasing integrating familial information. Differences were larger for SNPs located in chromosome ends and rare variants. Using a denser WGS panel (~13 millions SNPs) that was obtained with traditional variant filtering rules, we found similar results although performances of both phasing and imputation accuracy were lower. CONCLUSIONS: We present a phasing strategy for WGS data, which indirectly integrates familial information by aligning WGS haplotypes that are pre-phased with LD information only on haplotypes obtained with genotyping data, with both LD and familial information and on a much larger population. This strategy results in very few mismatches with the phase obtained by Mendelian segregation rules. Finally, we propose a strategy to further improve phasing accuracy based on haplotype clusters obtained with genotyping data. [less ▲]

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See detailNGS- based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.
Charlier, Carole ULiege; Li, Wanbo; Harland, Chad ULiege et al

in Genome Research (2016), 26:1-9

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See detailA hidden Markov model to estimate inbreeding from whole genome sequence data
Druet, Tom ULiege; Gautier, Mathieu

Conference (2016, August 29)

Inbreeding results from the mating of related individuals and has negative consequence because it brings together deleterious variants in one individual. Inbreeding is associated with recessive diseases ... [more ▼]

Inbreeding results from the mating of related individuals and has negative consequence because it brings together deleterious variants in one individual. Inbreeding is associated with recessive diseases and reduced production or fitness. Until recently inbreeding was estimated with genealogical data, which have some limitations. Genomic estimates of inbreeding can now be obtained thanks to new technologies. Methods based on genomic relationships assume either that identical-by-state markers are identical-by-descent (IBD) or correct for the allele frequencies estimated in a « founder generation ». Similarly, with runs of homozygosity (ROH), the hypothesis is that stretches of homozygous markers longer than a determined threshold (measured in number of markers or in Mb) are IBD. Although sequencing data are more informative, most of the recent studies used genotyping data. Due to high genotyping errors rates with sequencing technologies, ROH are difficult to use on such data. We herein describe an original method to model inbreeding along chromosomes. It relies on a hidden Markov model that determines locally whether a segment is inbred and gives a measure of inbreeding's age. The method uses a function modeling the probability to observe a genotype in an inbred segments. It is well suited for sequencing data because the function incorporates genotyping errors and uncertainty associated with low or moderate coverage. We first determine the properties of our new method with different simulation scenarii. Then, we use it to estimate inbreeding in the Belgian Blue Beef cattle population with either genotyping arrays (of various densities) or whole genome sequencing data. The estimates will be compared to those obtained with other methods (pedigree, ROH, genomic relationship). Latest results will be presented. [less ▲]

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See detailSequence-based association analysis identifies coding and non-coding variants in HFM1, MLH3, MSH4, MSH5, RNF212 and RNF212B with large effects on male and female recombination rate in cattle
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

Poster (2016, June 15)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires to 94,516 offspring, and 579,996 CO events in oocytes transmitted by 11,461 cows to 25,332 offspring. When measured in identical family structures, the average number of CO in males (23.3) was found to be larger than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females. The genetic correlation was equal to 0.66, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed seven genome-wide significant QTL. Variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed in order to perform a sequence-based association analysis. For four QTLs, we identified missense mutations in genes known to be involved in meiotic recombination among the most significantly associated variants. Most of the identified mutations had significant effects in both genders with three of them accounting each for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Thus, a large fraction of the genetic variance is associated with missense mutations in genes known to be involved in meiotic recombination. Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females, and the genetic correlation is close to 0, whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes. [less ▲]

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See detailHIGHER MALE THAN FEMALE RECOMBINATION RATE LARGELY CONTROLLED BY MISSENSE VARIANTS IN RNF212, MLH3, HFM1, MSH5 AND MSH4 IN CATTLE
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

Poster (2016, May 11)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires to 94,516 offspring, and 579,996 CO events in oocytes transmitted by 11,461 cows to 25,332 offspring. When measured in identical family structures, the average number of CO in males (23.3) was found to be larger than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females. The genetic correlation was equal to 0.66, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed seven genome-wide significant QTL. Variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed in order to perform a sequence-based association analysis. For four QTLs, we identified missense mutations in genes known to be involved in meiotic recombination among the most significantly associated variants. The P259S variant identified in RNF212 had already been reported, whereas missense mutations in MLH3 (N408S), HFM1 (S1189L), MSH5 (R631Q), MSH4 (C342Y) and a second in RNF212 (A77T) are new. Surprisingly, variants previously identified in REC8 were not associated with a QTL detected on BTA10 whereas variants in RNF212B, a paralog of RNF212, showed much stronger association with the phenotype in this region. This suggests that RNF212B might be involved in the recombination process. Most of the identified mutations had significant effects in both genders with three of them accounting each for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Thus, a large fraction of the genetic variance is associated with missense mutations in genes known to be involved in meiotic recombination. Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females, and the genetic correlation is close to 0, whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes. [less ▲]

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See detailGenetic architecture of male and female recombination rate in cattle
Druet, Tom ULiege

Conference (2016, March 30)

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See detailCoding and noncoding variants in HFM1, MLH3, MSH4, MSH5, RNF212, and RNF212B affect recombination rate in cattle.
Kadri, Naveen Kumar ULiege; Harland, Chad ULiege; Faux, Pierre ULiege et al

in Genome Research (2016)

We herein study genetic recombination in three cattle populations from France, New Zealand, and the Netherlands. We identify 2,395,177 crossover (CO) events in 94,516 male gametes, and 579,996 CO events ... [more ▼]

We herein study genetic recombination in three cattle populations from France, New Zealand, and the Netherlands. We identify 2,395,177 crossover (CO) events in 94,516 male gametes, and 579,996 CO events in 25,332 female gametes. The average number of COs was found to be larger in males (23.3) than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females, with a genetic correlation of 0.66 indicating that shared variants are influencing GRR in both sexes. A genome-wide association study identified seven quantitative trait loci (QTL) for GRR. Fine-mapping following sequence-based imputation in 14,401 animals pinpointed likely causative coding (5) and noncoding (1) variants in genes known to be involved in meiotic recombination (HFM1, MSH4, RNF212, MLH3, MSH5) for 5/7 QTL, and noncoding variants (3) in RNF212B for 1/7 QTL. This suggests that this RNF212 paralog might also be involved in recombination. Most of the identified mutations had significant effects in both sexes, with three of them each accounting for approximately 10% of the genetic variance in males. [less ▲]

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