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See detailOn the use of the transmission disequilibrium test to detect pseudo-autosomal variants affecting traits with sex-limited expression
Elansary, Mahmoud ULg; Stinckens, Anneleen; Ahariz, Naïma ULg et al

in Animal Genetics (2015)

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission ... [more ▼]

We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission disequilibrium test to avoid spurious associations due to population stratification. By doing so, we obtained genome-wide significant signals for both diseases with SNPs located in the pseudo-autosomal region in the vicinity of the pseudo-autosomal boundary. By further analyzing these signals, we demonstrate that the observed transmission disequilibria are artifactual. We determine that transmission bias at pseudo-autosomal markers will occur (i) when analyzing traits with sex-limited expression and (ii) when the allelic frequencies at the marker locus differ between X and Y chromosomes. We show that the bias is due to the fact that (i) sires will preferentially transmit the allele enriched on the Y (respectively X) chromosome to affected sons (respectively daughters) and (ii) dams will appear to preferentially transmit the allele enriched on the Y (respectively X) to affected sons (respectively daughters), as offspring inheriting the other allele are more likely to be non-informative. We define the conditions to mitigate these issues, namely by (i) extracting information from maternal meiosis only and (ii) ignoring trios for which sire and dam have the same heterozygous genotype. We show that by applying these rules to scrotal hernia and cryptorchidism, the pseudo-autosomal signals disappear, confirming their spurious nature. [less ▲]

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See detailHigher male than female recombination rate in cattle is controlled by genetic variants effective in both sexes
Kadri, Naveen Kumar ULg; Harland, Chad ULg; Coppieters, Wouter ULg et al

Poster (2015, May 05)

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We apply a new phasing algorithm extracting familial information suited for large half ... [more ▼]

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We apply a new phasing algorithm extracting familial information suited for large half-sib families to reconstruct haplotypes and detect cross-overs (CO). The software is robust to genotyping and map errors. We identify more than 2,000,000 CO events in sperm cells transmitted by 3008 sires to 94,603 offspring, and more than 500,000 CO events in oocytes transmitted by 11,497 cows to 25,390 offspring. When measured in identical family structures, the average number of CO in males (24.0) was found to be larger than in females (21.8). In males, recombination rates were higher closer to telomeres whereas in females, recombination rates dropped at both centromeres and telomeres (probably as a result of lower informativity). The heritability of the global recombination rate (GRR) was close to 0.20 in males and to 0.08 in females. Genetic correlation ranged from 0.38 to 0.69 depending on the population, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed four genome-wide significant QTL, including two previously identified ones (involving REC8 and RNF212). For all QTLs, there was a positive correlation between haplotype effects across sexes, ranging from 0.35 to 0.68. We selected two reference panels of respectively 122 and 215 bulls sequenced at cover > 15x to impute variants in the New-Zealand and French populations. All variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed with Beagle in order to perform a sequence-based association study. For three QTLs, we identified missense mutations in genes known to be involved in meiosis among the most significantly associated variants. These variants were perfectly associated with the haplotypes underlying the QTL effects. The variant identified in RNF212 had already been reported, whereas missense mutations in MLH3 (N408S) and HFM1 (S1189L) are new findings. Surprisingly, variants previously identified in REC8 did not capture the QTL effect whereas variants in RNF212B, PPP1R3E, BCL2L2, HOMEZ and PABPN1 had much stronger association with the phenotype. The three missense mutations were significant in both genders with two of them accounting for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). 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 detailX-Linked acro-gigantism (X-LAG) due to microduplications of chromosome Xq26 : A new disorder and implications for acromegaly
Trivellin, G; Daly, AF; Faucz, FR et al

in Abstract book - ENDO 2015 (2015, March)

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See detailScanning the genome for QTL affecting the recombination process in the male and female cattle germline
Kadri, Naveen Kumar ULg; Harland, Chad ULg; Coppieters, Wouter ULg et al

Poster (2015, February)

We herein study genetic recombination in three dairy cattle population from France, New-Zealand and The Netherlands. We apply a new phasing algorithm extracting familial information suited for large half ... [more ▼]

We herein study genetic recombination in three dairy cattle population from France, New-Zealand and The Netherlands. We apply a new phasing algorithm extracting familial information suited for large half-sib families to reconstruct haplotypes and detect cross-overs. The software is robust to genotyping errors and map errors (genome builts still contain errors for non-model organisms). We identify more than 2,000,000 cross-over events in sperm cells transmitted by 2942 sires to 94,049 offspring, and more than 500,000 cross-over events in oocytes transmitted by 10,943 cows to 23,850 offspring. The estimated number of cross-overs per gamete and its accuracy were influenced by the family structure (number of offsprings, parents and grand-parents genotyped). The average number of cross-overs in males (24.0) was larger than in females (21.8), even after correction for family structure. In males, recombination rates were higher closer to telomeres whereas in females, recombination rates dropped at both centromeres and telomeres (probably as a result of lower informativity). The heritability of the global recombination rate was close to 0.20 in males and to 0.10 in females and the genetic correlation was ~0.70, indicating that common genes are influencing both traits. Genome-wide association studies clearly confirmed QTL located close to REC8 and RNF212 in males. The QTL associated to REC8 was also detected in females and there was a positive correlation between QTL effects in males and females. The QTL associated to REC8 accounted for ~10% of the genetic variance in both males and females. [less ▲]

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See detailLordose et/ou xyphose chez le porc : mise à l’épreuve de l’hypothèse héréditaire
Laitat, Martine ULg; Veillat, Emilie; Van Cauwenberge, Henry et al

Poster (2015, February)

Lordosis and/or kyphosis, also called ”dipped shoulder” or ”humpy‐back” is sporadically observed in growing pigs. This condition is characterized by a thoracic and/or lumbar spinal deformity ... [more ▼]

Lordosis and/or kyphosis, also called ”dipped shoulder” or ”humpy‐back” is sporadically observed in growing pigs. This condition is characterized by a thoracic and/or lumbar spinal deformity. Pathomorphologically, it may be comparable with Scheuermann’s kyphosis in man and so constitutes a spontaneous model for this humane kyphosis of the thoracic or thoracolumbar spine. In pigs, this condition may decrease the value of carcasses, making deboning efforts challenging. Three major and non‐exclusive hypotheses formulated to explain these back deformations are nutrition, intrauterine viral infection and inherited predisposition. The objective of the present study was to test the latter and, if possible, to identify a locus (some loci) associated with the affection. Forty‐eight pigs were included in this case‐control study. Based on a clinical examination and/or on a measure of the degree of spinal deformity, 25 pigs classified as affected were compared to 23 pigs considered as normal. A whole genome Single Nucleotide Polymorphism (SNP) analysis was performed using a 50,000 SNP array. DNA from forty‐seven samples (tail tissue or blood) was extracted while one sample was eliminated because of its poor quality. After applying quality controls, 40 pigs and 57,838 SNPs (on a total of 62,163) remained for further analysis. One SNP (ASGA0090747) located on Sus scrofa chromosome SSC8 crossed the genome‐wide significant threshold and is thus suspected of being associated with the lordosis and/or kyphosis phenotype. These results seem to confirm the hereditary hypothesis. Further investigations are however needed to confirm the suspected association. [less ▲]

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See detailHigh-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot et al

in Nature Genetics (2015), 47(2), 172-9

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major ... [more ▼]

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. [less ▲]

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See detailLINKPHASE3: an improved pedigree-based phasing algorithm robust to genotyping and map errors.
Druet, Tom ULg; Georges, Michel ULg

in Bioinformatics (Oxford, England) (2015), 31(10), 1677-9

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 ... [more ▼]

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. AVAILABILITY AND IMPLEMENTATION: The software LINKPHASE3 is included in the PHASEBOOK package and can be freely downloaded from www.giga.ulg.ac.be/jcms/prod_381171/software. The package is written in FORTRAN and contains source codes. A manual is provided with the package. CONTACT: tom.druet@ulg.ac.be SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. [less ▲]

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See detailSelection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle
Druet, Tom ULg; Ahariz, Naïma ULg; Cambisano, Nadine ULg et al

Conference (2014, October 17)

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 ... [more ▼]

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. 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 QTLs 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 underlying MRC2 mutation causes crooked tail syndrome in homozygotes. Genomic prediction models indicate that the residual additive variance is largely polygenic. Contrary to complex traits in humans which have a near-exclusively 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). [less ▲]

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See detailPhenotyping Belgian Blue cattle for their susceptibility to psoroptic mange
Abos, Romain ULg; Coussé, Annelies; Sarre, Charlotte et al

Poster (2014, October 17)

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See detailPedigree-based haplotype reconstruction, identification of cross-overs and detection of map and genotyping errors using PHASEBOOK
Druet, Tom ULg; Georges, Michel ULg

Conference (2014, August 22)

Haplotype reconstruction is important in many applications in animal genomics. In livestock species, thanks to the availability of large half-sibs families and genotyped relatives, phasing methods can ... [more ▼]

Haplotype reconstruction is important in many applications in animal genomics. In livestock species, thanks to the availability of large half-sibs families and genotyped relatives, phasing methods can rely on strong familial information and results in families with more than 10 offspring are very accurate. However, most methods are sensitive to genotyping and map errors which will be more common with next generation sequencing data. Such problems are particularly important when studying recombination rate as we plan to do in the near future. We herein describe a novel algorithm which is robust to genotyping errors and which can identify errors in marker maps. Using a large dairy cattle data set genotyped with high-density genotyping arrays, we show that the novel algorithm strongly reduces the occurrence of spurious cross-overs due to different sources of errors, and identifies map errors for most of the bovine autosomes. The implemented version is still experimental and further research will be conducted to characterize the novel method (including simulations) and to fully describe the identified map errors. [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 detailLordosis in pigs: testing the hereditary hypothesis.
Laitat, Martine ULg; Van Cauwenberge, H; Harmegnies, Natacha ULg et al

Poster (2014)

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See detailGigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation.
Trivellin, Giampaolo; Daly, Adrian ULg; Faucz, Fabio R. et al

in The New England journal of medicine (2014)

Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed ... [more ▼]

Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. Results We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. Conclusions We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.). [less ▲]

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See detailSelection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle.
Druet, Tom ULg; Ahariz, Naima; Cambisano, Nadine et al

in BMC genomics (2014), 15(1), 796

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 ... [more ▼]

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). [less ▲]

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See detailA genome scan conducted in a multigenerational pedigree with convergent strabismus supports a complex genetic determinism.
GEORGES, Anouk ULg; Cambisano, Nadine ULg; Ahariz, Naïma ULg et al

in PloS one (2013), 8(12), 83574

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree ... [more ▼]

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree. [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 detailMethod for identifying cows with mastitis by bulk genotyping of tank milk.
Georges, Michel ULg; Coppieters, Wouter ULg; Blard, Grégoire

Patent (2013)

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