Publications by authors named "Tom Druet"

39 Publications

On the estimation of inbreeding depression using different measures of inbreeding from molecular markers.

Evol Appl 2021 Feb 23;14(2):416-428. Epub 2020 Oct 23.

Unit of Animal Genomics GIGA-R & Faculty of Veterinary Medicine University of Liège Liège Belgium.

The inbreeding coefficient () of individuals can be estimated from molecular marker data, such as SNPs, using measures of homozygosity of individual markers or runs of homozygosity (ROH) across the genome. These different measures of can then be used to estimate the rate of inbreeding depression (ID) for quantitative traits. Some recent simulation studies have investigated the accuracy of this estimation with contradictory results. Whereas some studies suggest that estimates of inbreeding from ROH account more accurately for ID, others suggest that inbreeding measures from SNP-by-SNP homozygosity giving a large weight to rare alleles are more accurate. Here, we try to give more light on this issue by carrying out a set of computer simulations considering a range of population genetic parameters and population sizes. Our results show that the previous studies are indeed not contradictory. In populations with low effective size, where relationships are more tight and selection is relatively less intense, measures based on ROH provide very accurate estimates of ID whereas SNP-by-SNP-based measures with high weight to rare alleles can show substantial upwardly biased estimates of ID. However, in populations of large effective size, with more intense selection and trait allele frequencies expected to be low if they are deleterious for fitness because of purifying selection, average estimates of ID from SNP-by-SNP-based values become unbiased or slightly downwardly biased and those from ROH-based values become slightly downwardly biased. The noise attached to all these estimates, nevertheless, can be very high in large-sized populations. We also investigate the relationship between the different measures and the homozygous mutation load, which has been suggested as a proxy of inbreeding depression.
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http://dx.doi.org/10.1111/eva.13126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896712PMC
February 2021

An evaluation of inbreeding measures using a whole-genome sequenced cattle pedigree.

Heredity (Edinb) 2021 Mar 6;126(3):410-423. Epub 2020 Nov 6.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

The estimation of the inbreeding coefficient (F) is essential for the study of inbreeding depression (ID) or for the management of populations under conservation. Several methods have been proposed to estimate the realized F using genetic markers, but it remains unclear which one should be used. Here we used whole-genome sequence data for 245 individuals from a Holstein cattle pedigree to empirically evaluate which estimators best capture homozygosity at variants causing ID, such as rare deleterious alleles or loci presenting heterozygote advantage and segregating at intermediate frequency. Estimators relying on the correlation between uniting gametes (F) or on the genomic relationships (F) presented the highest correlations with these variants. However, homozygosity at rare alleles remained poorly captured. A second group of estimators relying on excess homozygosity (F), homozygous-by-descent segments (F), runs-of-homozygosity (F) or on the known genealogy (F) was better at capturing whole-genome homozygosity, reflecting the consequences of inbreeding on all variants, and for young alleles with low to moderate frequencies (0.10 < . < 0.25). The results indicate that F and F might present a stronger association with ID. However, the situation might be different when recessive deleterious alleles reach higher frequencies, such as in populations with a small effective population size. For locus-specific inbreeding measures or at low marker density, the ranking of the methods can also change as F makes better use of the information from neighboring markers. Finally, we confirmed that genomic measures are in general superior to pedigree-based estimates. In particular, F was uncorrelated with locus-specific homozygosity.
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http://dx.doi.org/10.1038/s41437-020-00383-9DOI Listing
March 2021

Theoretical and empirical comparisons of expected and realized relationships for the X-chromosome.

Genet Sel Evol 2020 Aug 20;52(1):50. Epub 2020 Aug 20.

GenPhySE, INPT, INRAE, ENVT, 31326, Castanet Tolosan, France.

Background: X-chromosomal loci present different inheritance patterns compared to autosomal loci and must be modeled accordingly. Sexual chromosomes are not systematically considered in whole-genome relationship matrices although rules based on genealogical or marker information have been derived. Loci on the X-chromosome could have a significant contribution to the additive genetic variance, in particular for some traits such as those related to reproduction. Thus, accounting for the X-chromosome relationship matrix might be informative to better understand the architecture of complex traits (e.g., by estimating the variance associated to this chromosome) and to improve their genomic prediction. For such applications, previous studies have shown the benefits of combining information from genotyped and ungenotyped individuals.

Results: In this paper, we start by presenting rules to compute a genomic relationship matrix (GRM) for the X-chromosome (G) without making any assumption on dosage compensation, and based on coding of gene content with 0/1 for males and 0/1/2 for females. This coding adjusts naturally to previously derived pedigree-based relationships (S) for the X-chromosome. When needed, we propose to accommodate and estimate dosage compensation and genetic heterogeneity across sexes via multiple trait models. Using a Holstein dairy cattle dataset, including males and females, we then empirically illustrate that realized relationships (G) matches expectations (S). However, G presents high deviations from S. G has also a lower dimensionality compared to the autosomal GRM. In particular, individuals are frequently identical along the entire chromosome. Finally, we confirm that the heritability of gene content for markers on the X-chromosome that are estimated by using S is 1, further demonstrating that S and G can be combined. For the pseudo-autosomal region, we demonstrate that the expected relationships vary according to position because of the sex-gradient. We end by presenting the rules to construct the 'H matrix' by combining both relationship matrices.

Conclusions: This work shows theoretically and empirically that a pedigree-based relationship matrix built with rules specifically developed for the X-chromosome (S) matches the realized GRM for the X-chromosome. Therefore, applications that combine expected relationships and genotypes for markers on the X-chromosome should use S and G.
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http://dx.doi.org/10.1186/s12711-020-00570-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441635PMC
August 2020

Performances of Adaptive MultiBLUP, Bayesian regressions, and weighted-GBLUP approaches for genomic predictions in Belgian Blue beef cattle.

BMC Genomics 2020 Aug 6;21(1):545. Epub 2020 Aug 6.

Unit of Animal Genomics, GIGA-R, 11 Avenue de l'Hôpital (B34), University of Liège, 4000, Liège, Belgium.

Background: Genomic selection has been successfully implemented in many livestock and crop species. The genomic best linear unbiased predictor (GBLUP) approach, assigning equal variance to all SNP effects, is one of the reference methods. When large-effect variants contribute to complex traits, it has been shown that genomic prediction methods that assign a higher variance to subsets of SNP effects can achieve higher prediction accuracy. We herein compared the efficiency of several such approaches, including the Adaptive MultiBLUP (AM-BLUP) that uses local genomic relationship matrices (GRM) to automatically identify and weight genomic regions with large effects, to predict genetic merit in Belgian Blue beef cattle.

Results: We used a population of approximately 10,000 genotyped cows and their phenotypes for 14 traits, mostly related to muscular development and body dimensions. According to the trait, we found that 4 to 25% of the genetic variance could be associated with 2 to 12 genomic regions harbouring large-effect variants. Noteworthy, three previously identified recessive deleterious variants presented heterozygote advantage and were among the most significant SNPs for several traits. The AM-BLUP resulted in increased reliability of genomic predictions compared to GBLUP (+ 2%), but Bayesian methods proved more efficient (+ 3%). Overall, the reliability gains remained thus limited although higher gains were observed for skin thickness, a trait affected by two genomic regions having particularly large effects. Higher accuracies than those from the original AM-BLUP were achieved when applying the Bayesian Sparse Linear Mixed Model to pre-select groups of SNPs with large effects and subsequently use their estimated variance to build a weighted GRM. Finally, the single-step GBLUP performed best and could be further improved (+ 3% prediction accuracy) by using these weighted GRM.

Conclusions: The AM-BLUP is an attractive method to automatically identify and weight genomic regions with large effects on complex traits. However, the method was less accurate than Bayesian methods. Overall, weighted methods achieved modest accuracy gains compared to GBLUP. Nevertheless, the computational efficiency of the AM-BLUP might be valuable at higher marker density, including with whole-genome sequencing data. Furthermore, weighted GRM are particularly useful to account for large variance loci in the single-step GBLUP.
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http://dx.doi.org/10.1186/s12864-020-06921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430838PMC
August 2020

Genetic architecture of individual variation in recombination rate on the X chromosome in cattle.

Heredity (Edinb) 2020 Nov 10;125(5):304-316. Epub 2020 Jul 10.

Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

Meiotic recombination is an essential biological process that ensures proper chromosome segregation and creates genetic diversity. Individual variation in global recombination rates has been shown to be heritable in several species, and variants significantly associated with this trait have been identified. Recombination on the sex chromosome has often been ignored in these studies although this trait may be particularly interesting as it may correspond to a biological process distinct from that on autosomes. For instance, recombination in males is restricted to the pseudo-autosomal region (PAR). We herein used a large cattle pedigree with more than 100,000 genotyped animals to improve the genetic map of the X chromosome and to study the genetic architecture of individual variation in recombination rate on the sex chromosome (XRR). The length of the genetic map was 46.4 and 121.2 cM in males and females, respectively, but the recombination rate in the PAR was six times higher in males. The heritability of CO counts on the X chromosome was comparable to that of autosomes in males (0.011) but larger than that of autosomes in females (0.024). XRR was highly correlated (0.76) with global recombination rate (GRR) in females, suggesting that both traits might be governed by shared variants. In agreement, a set of eleven previously identified variants associated with GRR had correlated effects on female XRR (0.86). In males, XRR and GRR appeared to be distinct traits, although more accurate CO counts on the PAR would be valuable to confirm these results.
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http://dx.doi.org/10.1038/s41437-020-0341-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553937PMC
November 2020

Guided wave imaging of composite plates using passive acquisitions by fiber Bragg gratings.

J Acoust Soc Am 2020 05;147(5):3565

Safran Tech, Magny-Les-Hameaux, France.

In this paper, imaging results of defects in composite plates using guided wave-based algorithms, such as delay and sum and Excitelet, are presented. Those algorithms are applied to passive data for which the signal corresponding to each emitter-receiver couple is recovered as a result of the cross correlation of the ambient noise measured simultaneously by the two sensors. The transition to passive imaging allows the use of lighter sensors that are unable to emit ultrasonic waves, such as fiber Bragg gratings (FBGs) sensors on optical fibers, which are used in this study. The imaging results presented here show the feasibility of active and passive imaging in composite plates using FBGs as receivers, reducing the impact of the acquisition system on the structure in the context of structural health monitoring.
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http://dx.doi.org/10.1121/10.0001300DOI Listing
May 2020

Genomic Footprints of Recovery in the European Bison.

J Hered 2020 04;111(2):194-203

INRAE, UMR CBGP (INRAE-IRD-Cirad-Montpellier SupAgro), Montferrier-sur-Lez, France.

After extinction in the wild in the beginning of the 20th century, the European bison has been successfully recovered in 2 distinct genetic lines from only 12 and 7 captive founders. We here aimed at characterizing the levels of realized inbreeding in these 2 restored lines to provide empirical insights into the genomic footprints left by population recovery from a small number of founders. To that end, we genotyped 183 European bison born over the last 40 years with the Illumina BovineHD beadchip that contained 22 602 informative autosomal single-nucleotide polymorphisms after data filtering. We then identified homozygous-by-descent (HBD) segments and classified them into different age-related classes relying on a model-based approach. As expected, we observed that the strong and recent founder effect experienced by the 2 lines resulted in very high levels of recent inbreeding and in the presence of long HBD tracks (up to 120 Mb). These long HBD tracks were associated with ancestors living approximately from 4 to 32 generations in the past, suggesting that inbreeding accumulated over multiple generations after the bottleneck. The contribution to inbreeding of the most recent groups of ancestors was however found to be decreasing in both lines. In addition, comparison of Lowland individuals born at different time periods showed that the levels of inbreeding tended to stabilize, HBD segments being shorter in animals born more recently which indicates efficient control of inbreeding. Monitoring HBD segment lengths over generations may thus be viewed as a valuable genomic diagnostic tool for populations in conservation or recovery programs.
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http://dx.doi.org/10.1093/jhered/esaa002DOI Listing
April 2020

Passive guided wave tomography for structural health monitoring.

J Acoust Soc Am 2019 10;146(4):2395

IEMN UMR CNRS 8520, Université Polytechnique Hauts-de-France, F-59313 Valenciennes cedex 9, France.

In this paper the authors present a baseline-free quantitative method for imaging corrosion flaws in thin plates. It only requires an embedded guided wave sensor network used in a fully passive way, i.e., without active emission of waves. This method is called passive guided wave tomography. The aim of this development is the use of this method for the structural health monitoring of critical structures with heavy limitations on both sensor's intrusiveness and diagnostic's reliability because it allows the use of sensors that cannot emit elastic waves such as fiber Bragg gratings, which are less intrusive than piezoelectric transducers. The idea consists in using passive methods in order to retrieve the impulse response from elastic diffuse fields-naturally present in structures-measured simultaneously between the sensors. In this paper, two passive methods are studied: the ambient noise cross-correlation and the passive inverse filter. Once all the impulse responses between the sensors are retrieved, they are used as input data to perform guided wave tomography.
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http://dx.doi.org/10.1121/1.5128332DOI Listing
October 2019

A Random Forests Framework for Modeling Haplotypes as Mosaics of Reference Haplotypes.

Front Genet 2019 27;10:562. Epub 2019 Jun 27.

Unit of Animal Genomics, GIGA-R, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

Many genomic data analyses such as phasing, genotype imputation, or local ancestry inference share a common core task: matching pairs of haplotypes at any position along the chromosome, thereby inferring a target haplotype as a succession of pieces from reference haplotypes, commonly called a mosaic of reference haplotypes. For that purpose, these analyses combine information provided by linkage disequilibrium, linkage and/or genealogy through a set of heuristic rules or, most often, by a hidden Markov model. Here, we develop an extremely randomized trees framework to address the issue of local haplotype matching. In our approach, a supervised classifier using extra-trees (a particular type of random forests) learns how to identify the best local matches between haplotypes using a collection of observed examples. For each example, various features related to the different sources of information are observed, such as the length of a segment shared between haplotypes, or estimates of relationships between individuals, gametes, and haplotypes. The random forests framework was fed with 30 relevant features for local haplotype matching. Repeated cross-validations allowed ranking these features in regard to their importance for local haplotype matching. The distance to the edge of a segment shared by both haplotypes being matched was found to be the most important feature. Similarity comparisons between predicted and true whole-genome sequence haplotypes showed that the random forests framework was more efficient than a hidden Markov model in reconstructing a target haplotype as a mosaic of reference haplotypes. To further evaluate its efficiency, the random forests framework was applied to imputation of whole-genome sequence from 50k genotypes and it yielded average reliabilities similar or slightly better than IMPUTE2. Through this exploratory study, we lay the foundations of a new framework to automatically learn local haplotype matching and we show that extra-trees are a promising approach for such purposes. The use of this new technique also reveals some useful lessons on the relevant features for the purpose of haplotype matching. We also discuss potential improvements for routine implementation.
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http://dx.doi.org/10.3389/fgene.2019.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610336PMC
June 2019

Passive guided waves measurements using fiber Bragg gratings sensors.

J Acoust Soc Am 2018 Sep;144(3):1198

IEMN UMR CNRS 8520, Université de Valenciennes et du Hainaut-Cambrésis, F-59313 Valenciennes cedex 9, France.

Guided elastic waves are often studied as an effective solution for Structural Health Monitoring (SHM) systems of plate-like structures thanks to the capacity to propagate on large distances. In typical applications such as monitoring delaminations in aircraft fuselage, a network made of piezoelectric transducer (PZT) is used to emit and receive such waves in the structure. Fiber Bragg grating (FBG) sensors on optical fibers are a promising alternative to PZT for guided waves measurements in practical applications due to the capacity for dense multiplexing and robustness with respect to the environment. However, unlike conventional PZT transducers, FBG sensors cannot emit waves. It is demonstrated here that FBG sensors can be used in combination with a passive diffuse noise cross-correlation technique in order to extract the coherent guided waves propagating between two sensors. This could lead to a system using only FBG sensors in the near future. The reconstructed signals can then be analyzed with usual guided waves algorithms, like in active SHM systems, keeping all the advantages of this kind of monitoring in terms of fine diagnosis. The experimental demonstration shown in this paper is performed at ultrasonic frequencies (20-100 kHz) typically used in guided waves based SHM systems showing the potential of the approach.
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http://dx.doi.org/10.1121/1.5054015DOI Listing
September 2018

Age-based partitioning of individual genomic inbreeding levels in Belgian Blue cattle.

Genet Sel Evol 2017 12 22;49(1):92. Epub 2017 Dec 22.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, B34 (+1) Avenue de l'Hôpital 1, 4000, Liège, Belgium.

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.
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http://dx.doi.org/10.1186/s12711-017-0370-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741860PMC
December 2017

Fixed-length haplotypes can improve genomic prediction accuracy in an admixed dairy cattle population.

Genet Sel Evol 2017 07 3;49(1):54. Epub 2017 Jul 3.

Iowa State University, Ames, IA, USA.

Background: 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.

Results: A correlation of 0.349 ± 0.016 between yield deviation and genomic breeding values was obtained for milk fat yield in Holstein-Friesians using BayesA fitting covariates. Genomic predictions were more accurate with short haplotypes than with SNPs but less accurate with longer haplotypes than with SNPs. Fitting only the most frequent haplotype alleles reduced computation time with little decrease in prediction accuracy for short haplotypes. Trends were similar for all traits and breeds and there was little difference between Bayesian methods.

Conclusions: Fitting covariates for haplotype alleles rather than SNPs can increase prediction accuracy, although it decreased drastically for long (>500 kb) haplotypes. In this population, fitting 250 kb haplotypes with a 1% frequency threshold resulted in the highest genomic prediction accuracy and fitting 125 kb haplotypes with a 10% frequency threshold improved genomic prediction accuracy with comparable computation time to fitting SNPs. This increased accuracy is likely to increase genetic gain by changing the ranking of selection candidates.
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http://dx.doi.org/10.1186/s12711-017-0329-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494768PMC
July 2017

A strategy to improve phasing of whole-genome sequenced individuals through integration of familial information from dense genotype panels.

Genet Sel Evol 2017 05 16;49(1):46. Epub 2017 May 16.

Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, 4000, Liège, Belgium.

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 ), 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.
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http://dx.doi.org/10.1186/s12711-017-0321-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434521PMC
May 2017

NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock.

Genome Res 2016 10 19;26(10):1333-1341. Epub 2016 Sep 19.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 4000-Liège, Belgium.

We herein report the result of a large-scale, next generation sequencing (NGS)-based screen for embryonic lethal (EL) mutations in Belgian beef and New Zealand dairy cattle. We estimated by simulation that cattle might carry, on average, ∼0.5 recessive EL mutations. We mined exome sequence data from >600 animals, and identified 1377 stop-gain, 3139 frame-shift, 1341 splice-site, 22,939 disruptive missense, 62,399 benign missense, and 92,163 synonymous variants. We show that cattle have a comparable load of loss-of-function (LoF) variants (defined as stop-gain, frame-shift, or splice-site variants) as humans despite having a more variable exome. We genotyped >40,000 animals for up to 296 LoF and 3483 disruptive missense, breed-specific variants. We identified candidate EL mutations based on the observation of a significant depletion in homozygotes. We estimated the proportion of EL mutations at 15% of tested LoF and 6% of tested disruptive missense variants. We confirmed the EL nature of nine candidate variants by genotyping 200 carrier × carrier trios, and demonstrating the absence of homozygous offspring. The nine identified EL mutations segregate at frequencies ranging from 1.2% to 6.6% in the studied populations and collectively account for the mortality of ∼0.6% of conceptuses. We show that EL mutations preferentially affect gene products fulfilling basic cellular functions. The resulting information will be useful to avoid at-risk matings, thereby improving fertility.
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http://dx.doi.org/10.1101/gr.207076.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052051PMC
October 2016

Coding and noncoding variants in HFM1, MLH3, MSH4, MSH5, RNF212, and RNF212B affect recombination rate in cattle.

Genome Res 2016 10 11;26(10):1323-1332. Epub 2016 Aug 11.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 4000 Liège, Belgium.

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 ∼10% of the genetic variance in males.
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http://dx.doi.org/10.1101/gr.204214.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052053PMC
October 2016

An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture.

G3 (Bethesda) 2016 09 8;6(9):2963-70. Epub 2016 Sep 8.

Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Switzerland Dermfocus, Vetsuisse Faculty, University of Bern, 3001 Switzerland

We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses, the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semidominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of four BR1 and 60 nonbrindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBTPS2 transcripts in skin, and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect cosegregation with the brindle phenotype in the investigated family, and was absent from 457 control horses of diverse breeds. Altogether, our genetic data, and previous knowledge on MBTPS2 function in the skin, suggest that the identified MBTPS2 intronic variant leads to partial exon skipping, and causes the BR1 phenotype in horses.
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http://dx.doi.org/10.1534/g3.116.032433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015953PMC
September 2016

Genome-wide next-generation DNA and RNA sequencing reveals a mutation that perturbs splicing of the phosphatidylinositol glycan anchor biosynthesis class H gene (PIGH) and causes arthrogryposis in Belgian Blue cattle.

BMC Genomics 2015 Apr 18;16:316. Epub 2015 Apr 18.

GIGA-R & Department of Animal Sciences, Unit of Animal Genomics, Faculty of Veterinary Medicine, University of Liège, Avenue de l'Hôpital 1, 4000, Liège, Belgium.

Background: Cattle populations are characterized by regular outburst of genetic defects as a result of the extensive use of elite sires. The causative genes and mutations can nowadays be rapidly identified by means of genome-wide association studies combined with next generation DNA sequencing, provided that the causative mutations are conventional loss-of-function variants. We show in this work how the combined use of next generation DNA and RNA sequencing allows for the rapid identification of otherwise difficult to identify splice-site variants.

Results: We report the use of haplotype-based association mapping to identify a locus on bovine chromosome 10 that underlies autosomal recessive arthrogryposis in Belgian Blue Cattle. We identify 31 candidate mutations by resequencing the genome of four cases and 15 controls at ~10-fold depth. By analyzing RNA-Seq data from a carrier fetus, we observe skipping of the second exon of the PIGH gene, which we confirm by RT-PCR to be fully penetrant in tissues from affected calves. We identify - amongst the 31 candidate variants - a C-to-G transversion in the first intron of the PIGH gene (c211-10C > G) that is predicted to affect its acceptor splice-site. The resulting PIGH protein is likely to be non-functional as it lacks essential domains, and hence to cause arthrogryposis.

Conclusions: This work illustrates how the growing arsenal of genome exploration tools continues to accelerate the identification of an even broader range of disease causing mutations, therefore improving the management and control of genetic defects in livestock.
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http://dx.doi.org/10.1186/s12864-015-1528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404575PMC
April 2015

LINKPHASE3: an improved pedigree-based phasing algorithm robust to genotyping and map errors.

Bioinformatics 2015 May 7;31(10):1677-9. Epub 2015 Jan 7.

Unit of Animal Genomics, GIGA-R, University of Liège (B34), 1 avenue de l'Hôpital, B-4000, Liège, Belgium.

Many applications in genetics require haplotype reconstruction. We present a phasing program designed for large half-sibs families (as observed in plant and animals) that is robust to genotyping and map errors. We demonstrate that it is more efficient than previous versions and other programs, particularly in the presence of genotyping errors.
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http://dx.doi.org/10.1093/bioinformatics/btu859DOI Listing
May 2015

Selection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle.

BMC Genomics 2014 Sep 17;15:796. Epub 2014 Sep 17.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège - B34 (+1), Avenue de l'Hôpital 1, Liège B-4000, Belgium.

Background: Belgian Blue cattle are famous for their exceptional muscular development or "double-muscling". This defining feature emerged following the fixation of a loss-of-function variant in the myostatin gene in the eighties. Since then, sustained selection has further increased muscle mass of Belgian Blue animals to a comparable extent. In the present paper, we study the genetic determinants of this second wave of muscle growth.

Results: A scan for selective sweeps did not reveal the recent fixation of another allele with major effect on muscularity. However, a genome-wide association study identified two genome-wide significant and three suggestive quantitative trait loci (QTL) affecting specific muscle groups and jointly explaining 8-21% of the heritability. The top two QTL are caused by presumably recent mutations on unique haplotypes that have rapidly risen in frequency in the population. While one appears on its way to fixation, the ascent of the other is compromised as the likely underlying MRC2 mutation causes crooked tail syndrome in homozygotes. Genomic prediction models indicate that the residual additive variance is largely polygenic.

Conclusions: Contrary to complex traits in humans which have a near-exclusive polygenic architecture, muscle mass in beef cattle (as other production traits under directional selection), appears to be controlled by (i) a handful of recent mutations with large effect that rapidly sweep through the population, and (ii) a large number of presumably older variants with very small effects that rise slowly in the population (polygenic adaptation).
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http://dx.doi.org/10.1186/1471-2164-15-796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190573PMC
September 2014

Error rate for imputation from the Illumina BovineSNP50 chip to the Illumina BovineHD chip.

Genet Sel Evol 2014 Feb 4;46:10. Epub 2014 Feb 4.

CRV BV, P,O, Box 454, 6800 AL Arnhem, The Netherlands.

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.
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http://dx.doi.org/10.1186/1297-9686-46-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929158PMC
February 2014

A 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.

PLoS Genet 2014 Jan 2;10(1):e1004049. Epub 2014 Jan 2.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium.

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.
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http://dx.doi.org/10.1371/journal.pgen.1004049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879169PMC
January 2014

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.

Dis Model Mech 2014 Jan 23;7(1):119-28. Epub 2013 Oct 23.

Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, 4000-Liège (Sart Tilman), Belgium.

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 perinatal 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.
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http://dx.doi.org/10.1242/dmm.012500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882054PMC
January 2014

Use of ancestral haplotypes in genome-wide association studies.

Methods Mol Biol 2013 ;1019:347-80

Fonds National de la Recherche Scientifique, Brussels, Belgium.

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.
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http://dx.doi.org/10.1007/978-1-62703-447-0_15DOI Listing
December 2013

Genetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle.

PLoS Genet 2012 26;8(7):e1002854. Epub 2012 Jul 26.

Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

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.
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http://dx.doi.org/10.1371/journal.pgen.1002854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406008PMC
January 2013

A splice site variant in the bovine RNF11 gene compromises growth and regulation of the inflammatory response.

PLoS Genet 2012 15;8(3):e1002581. Epub 2012 Mar 15.

Unit of Animal Genomics, GIGA-R, Department of Animal Sciences, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

We report association mapping of a locus on bovine chromosome 3 that underlies a Mendelian form of stunted growth in Belgian Blue Cattle (BBC). 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.
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http://dx.doi.org/10.1371/journal.pgen.1002581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305398PMC
September 2012

Serial translocation by means of circular intermediates underlies colour sidedness in cattle.

Nature 2012 Feb 1;482(7383):81-4. Epub 2012 Feb 1.

Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, 4000-Liège (Sart Tilman), Belgium.

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.
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http://dx.doi.org/10.1038/nature10757DOI Listing
February 2012

A common reference population from four European Holstein populations increases reliability of genomic predictions.

Genet Sel Evol 2011 Dec 12;43:43. Epub 2011 Dec 12.

Department of Molecular Biology and Genetics, Faculty of Science and Technology, Aarhus University, AU-Foulum, PO Box 50, DK-8830 Tjele, Denmark.

Background: Size of the reference population and reliability of phenotypes are crucial factors influencing the reliability of genomic predictions. It is therefore useful to combine closely related populations. Increased accuracies of genomic predictions depend on the number of individuals added to the reference population, the reliability of their phenotypes, and the relatedness of the populations that are combined.

Methods: This paper assesses the increase in reliability achieved when combining four Holstein reference populations of 4000 bulls each, from European breeding organizations, i.e. UNCEIA (France), VikingGenetics (Denmark, Sweden, Finland), DHV-VIT (Germany) and CRV (The Netherlands, Flanders). Each partner validated its own bulls using their national reference data and the combined data, respectively.

Results: Combining the data significantly increased the reliability of genomic predictions for bulls in all four populations. Reliabilities increased by 10%, compared to reliabilities obtained with national reference populations alone, when they were averaged over countries and the traits evaluated. For different traits and countries, the increase in reliability ranged from 2% to 19%.

Conclusions: Genomic selection programs benefit greatly from combining data from several closely related populations into a single large reference population.
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http://dx.doi.org/10.1186/1297-9686-43-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292506PMC
December 2011

Results of a haplotype-based GWAS for recurrent laryngeal neuropathy in the horse.

Mamm Genome 2011 Oct 23;22(9-10):613-20. Epub 2011 Jun 23.

Unit of Animal Genetics, GIGA-Research, Faculty of Veterinary Medicine, University of Liège, 1 avenue de l'hôpital, B-4000 Liège, Belgium.

Recurrent laryngeal neuropathy (RLN) is a major upper-airway disease of horses that causes abnormal respiratory noise during exercise and can impair performance. Etiopathogenesis remains unclear but genetic factors have been suspected for many decades. The objective of this study was to identify risk loci associated with RLN. To that end we genotyped 234 cases (196 Warmbloods, 20 Trotters, 14 Thoroughbreds, and 4 Draft horses), 228 breed-matched controls, and 69 parents with the Illumina Equine SNP50 BeadChip. Using these data, we quantified population structure and performed single-marker and haplotype-based association studies, as well as family-based linkage analyses. We accounted for population stratification by modeling a random polygenic background effect with covariance structure estimated from genome-wide SNP data. Using the haplotype-based approach, we identified two genome-wide suggestive loci in Warmbloods, respectively on chromosomes 21 (p = 1.62 × 10(-6)) and 31 (p = 1.69 × 10(-5)). The two signals were driven by the enrichment of a "protective" haplotype in controls compared to cases.
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http://dx.doi.org/10.1007/s00335-011-9337-3DOI Listing
October 2011

Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature.

Nat Genet 2011 May 24;43(5):405-13. Epub 2011 Apr 24.

Unit of Animal Genomics, Interdisciplinary Institute of Applied Genomics (GIGA-R) and Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium.

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a ∼780-kb interval using a Hidden Markov Model-based approach that simultaneously exploits linkage and linkage disequilibrium. We re-sequenced the interval in six sires with known QTL genotype and identified 13 clustered candidate quantitative trait nucleotides (QTNs) out of >9,572 discovered variants. We eliminated five candidate QTNs by studying the phenotypic effect of a recombinant haplotype identified in a breed diversity panel. We show that the QTL influences fetal expression of seven of the nine genes mapping to the ∼780-kb interval. We further show that two of the eight candidate QTNs, mapping to the PLAG1-CHCHD7 intergenic region, influence bidirectional promoter strength and affect binding of nuclear factors. By performing expression QTL analyses, we identified a splice site variant in CHCHD7 and exploited this naturally occurring null allele to exclude CHCHD7 as single causative gene.
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http://dx.doi.org/10.1038/ng.814DOI Listing
May 2011

Modeling of identity-by-descent processes along a chromosome between haplotypes and their genotyped ancestors.

Genetics 2011 Jun 24;188(2):409-19. Epub 2011 Mar 24.

Unit of Animal Genomics, Faculty of Veterinary Medicine and Centre for Biomedical Integrative Genoproteomics, University of Liège, Liège, Belgium.

Identity-by-descent probabilities are important for many applications in genetics. Here we propose a method for modeling the transmission of the haplotypes from the closest genotyped relatives along an entire chromosome. The method relies on a hidden Markov model where hidden states correspond to the set of all possible origins of a haplotype within a given pedigree. Initial state probabilities are estimated from average genetic contribution of each origin to the modeled haplotype while transition probabilities are computed from recombination probabilities and pedigree relationships between the modeled haplotype and the various possible origins. The method was tested on three simulated scenarios based on real data sets from dairy cattle, Arabidopsis thaliana, and maize. The mean identity-by-descent probabilities estimated for the truly inherited parental chromosome ranged from 0.94 to 0.98 according to the design and the marker density. The lowest values were observed in regions close to crossing over or where the method was not able to discriminate between several origins due to their similarity. It is shown that the estimated probabilities were correctly calibrated. For marker imputation (or QTL allele prediction for fine mapping or genomic selection), the method was efficient, with 3.75% allelic imputation error rates on a dairy cattle data set with a low marker density map (1 SNP/Mb). The method should prove useful for situations we are facing now in experimental designs and in plant and animal breeding, where founders are genotyped with relatively high markers densities and last generation(s) genotyped with a lower-density panel.
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http://dx.doi.org/10.1534/genetics.111.127720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122309PMC
June 2011