Publications by authors named "Latifa Karim"

22 Publications

  • Page 1 of 1

SNP-based quantitative deconvolution of biological mixtures: application to the detection of cows with subclinical mastitis by whole-genome sequencing of tank milk.

Genome Res 2020 08 26;30(8):1201-1207. Epub 2020 Jun 26.

Unit of Animal Genomics, GIGA Institute & Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium.

Biological products of importance in food (e.g., milk) and medical (e.g., donor blood-derived products) sciences often correspond to mixtures of samples contributed by multiple individuals. Identifying which individuals contributed to the mixture and in what proportions may be of interest in several circumstances. We herein present a method that allows to do this by shallow whole-genome sequencing of the DNA in mixed samples from hundreds of donors. We show the efficacy of the approach for the detection of cows with subclinical mastitis by analysis of farms' tank mixtures containing milk from as many as 500 cows.
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http://dx.doi.org/10.1101/gr.256172.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462076PMC
August 2020

Detection and identification of transgenic events by next generation sequencing combined with enrichment technologies.

Sci Rep 2019 10 30;9(1):15595. Epub 2019 Oct 30.

Walloon Agricultural Research Center (CRA-W), Unit Traceability and Authentication, chaussée de Namur 24, 5030, Gembloux, Belgium.

Next generation sequencing (NGS) is a promising tool for analysing the quality and safety of food and feed products. The detection and identification of genetically modified organisms (GMOs) is complex, as the diversity of transgenic events and types of structural elements introduced in plants continue to increase. In this paper, we show how a strategy that combines enrichment technologies with NGS can be used to detect a large panel of structural elements and partially or completely reconstruct the new sequence inserted into the plant genome in a single analysis, even at low GMO percentages. The strategy of enriching sequences of interest makes the approach applicable even to mixed products, which was not possible before due to insufficient coverage of the different genomes present. This approach is also the first step towards a more complete characterisation of agrifood products in a single analysis.
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http://dx.doi.org/10.1038/s41598-019-51668-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821802PMC
October 2019

Codon-specific translation reprogramming promotes resistance to targeted therapy.

Nature 2018 06 20;558(7711):605-609. Epub 2018 Jun 20.

Laboratory of Cancer Signaling, University of Liège, Liège, Belgium.

Reprogramming of mRNA translation has a key role in cancer development and drug resistance . However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U) tRNA (U enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF oncogene and by resistance to targeted therapy in melanoma. We show that BRAF -expressing melanoma cells are dependent on U enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U enzymes. Mechanistically, U enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U enzymes and HIF1α. Together, these results demonstrate that U enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
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http://dx.doi.org/10.1038/s41586-018-0243-7DOI Listing
June 2018

Complete Genome Sequence of Streptomyces lunaelactis MM109, Isolated from Cave Moonmilk Deposits.

Genome Announc 2018 May 24;6(21). Epub 2018 May 24.

InBioS-Centre for Protein Engineering, Institut de Chimie, University of Liège, Liège, Belgium

MM109 is a ferroverdin A (anticholesterol) producer isolated from cave moonmilk deposits. The complete genome sequence of MM109 was obtained by combining Oxford Nanopore MinION and Illumina HiSeq and MiSeq technologies, revealing an 8.4-Mb linear chromosome and two plasmids, pSLUN1 (127,264 bp, linear) and pSLUN2 (46,827 bp, circular).
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http://dx.doi.org/10.1128/genomeA.00435-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968722PMC
May 2018

Isolation, Characterization, and Antibacterial Activity of Hard-to-Culture Actinobacteria from Cave Moonmilk Deposits.

Antibiotics (Basel) 2018 Mar 22;7(2). Epub 2018 Mar 22.

Integrative Biological Sciences (InBioS), Center for Protein Engineering, Liège University, B-4000 Liège, Belgium.

Cave moonmilk deposits host an abundant and diverse actinobacterial population that has a great potential for producing novel natural bioactive compounds. In our previous attempt to isolate culturable moonmilk-dwelling Actinobacteria, only species were recovered, whereas a metagenetic study of the same deposits revealed a complex actinobacterial community including 46 actinobacterial genera in addition to streptomycetes. In this work, we applied the rehydration-centrifugation method to lessen the occurrence of filamentous species and tested a series of strategies to achieve the isolation of hard-to-culture and rare Actinobacteria from the moonmilk deposits of the cave "Grotte des Collemboles". From the "tips and tricks" that were tested, separate autoclaving of the components of the International Streptomyces Project (ISP) medium number 5 (ISP5) medium, prolonged incubation time, and dilution of the moonmilk suspension were found to most effectively improve colony forming units. Taxonomic analyses of the 40 isolates revealed new representatives of the , , , , , , and species, as well as additional new streptomycetes. The applied methodologies allowed the isolation of strains associated with both the least and most abundant moonmilk-dwelling actinobacterial operational taxonomic units. Finally, bioactivity screenings revealed that some isolates displayed high antibacterial activities, and genome mining uncovered a strong potential for the production of natural compounds.
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http://dx.doi.org/10.3390/antibiotics7020028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023089PMC
March 2018

Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

Gastroenterology 2018 06 6;154(8):2165-2177. Epub 2018 Mar 6.

Department of Gastroenterology, Hepatopancreatology and Digestive Oncology and Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address:

Background & Aims: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD.

Methods: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays.

Results: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation.

Conclusions: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.
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http://dx.doi.org/10.1053/j.gastro.2018.02.028DOI Listing
June 2018

Transcriptome-wide analysis of natural antisense transcripts shows their potential role in breast cancer.

Sci Rep 2017 12 12;7(1):17452. Epub 2017 Dec 12.

University of Liège, GIGA-Research, Laboratory of Human Genetics, Liege, Belgium.

Non-coding RNAs (ncRNA) represent 1/5 of the mammalian transcript number, and 90% of the genome length is transcribed. Many ncRNAs play a role in cancer. Among them, non-coding natural antisense transcripts (ncNAT) are RNA sequences that are complementary and overlapping to those of either protein-coding (PCT) or non-coding transcripts. Several ncNATs were described as regulating protein coding gene expression on the same loci, and they are expected to act more frequently in cis compared to other ncRNAs that commonly function in trans. In this work, 22 breast cancers expressing estrogen receptors and their paired adjacent non-malignant tissues were analyzed by strand-specific RNA sequencing. To highlight ncNATs potentially playing a role in protein coding gene regulations that occur in breast cancer, three different data analysis methods were used: differential expression analysis of ncNATs between tumor and non-malignant tissues, differential correlation analysis of paired ncNAT/PCT between tumor and non-malignant tissues, and ncNAT/PCT read count ratio variation between tumor and non-malignant tissues. Each of these methods yielded lists of ncNAT/PCT pairs that were enriched in survival-associated genes. This work highlights ncNAT lists that display potential to affect the expression of protein-coding genes involved in breast cancer pathology.
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http://dx.doi.org/10.1038/s41598-017-17811-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727077PMC
December 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

A stop-gain in the laminin, alpha 3 gene causes recessive junctional epidermolysis bullosa in Belgian Blue cattle.

Anim Genet 2015 Oct 15;46(5):566-70. Epub 2015 Sep 15.

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

Four newborn purebred Belgian Blue calves presenting a severe form of epidermolysis bullosa were recently referred to our heredo-surveillance platform. SNP array genotyping followed by autozygosity mapping located the causative gene in a 8.3-Mb interval on bovine chromosome 24. Combining information from (i) whole-genome sequencing of an affected calf, (ii) transcriptomic data from a panel of tissues and (iii) a list of functionally ranked positional candidates pinpointed a private G to A nucleotide substitution in the LAMA3 gene that creates a premature stop codon (p.Arg2609*) in exon 60, truncating 22% of the corresponding protein. The LAMA3 gene encodes the alpha 3 subunit of the heterotrimeric laminin-332, a key constituent of the lamina lucida that is part of the skin basement membrane connecting epidermis and dermis layers. Homozygous loss-of-function mutations in this gene are known to cause severe junctional epidermolysis bullosa in human, mice, horse, sheep and dog. Overall, our data strongly support the causality of the identified gene and mutation.
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http://dx.doi.org/10.1111/age.12342DOI Listing
October 2015

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

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 genome scan conducted in a multigenerational pedigree with convergent strabismus supports a complex genetic determinism.

PLoS One 2013 23;8(12):e83574. Epub 2013 Dec 23.

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

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083574PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871668PMC
March 2015

Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome.

Brain 2013 Mar 18;136(Pt 3):882-90. Epub 2013 Feb 18.

Department of Genetics and Cell Biology, P.O. Box 616, 6200 MD Maastricht, the Netherlands.

Leigh syndrome is an early onset, often fatal progressive neurodegenerative disorder caused by mutations in the mitochondrial or nuclear DNA. Until now, mutations in more than 35 genes have been reported to cause Leigh syndrome, indicating an extreme genetic heterogeneity for this disorder, but still only explaining part of the cases. The possibility of whole exome sequencing enables not only mutation detection in known candidate genes, but also the identification of new genes associated with Leigh syndrome in small families and isolated cases. Exome sequencing was combined with homozygosity mapping to identify the genetic defect in a Moroccan family with fatal Leigh syndrome in early childhood and specific magnetic resonance imaging abnormalities in the brain. We detected a homozygous nonsense mutation (c.20C>A; p.Ser7Ter) in the thiamine transporter SLC19A3. In vivo overexpression of wild-type SLC19A3 showed an increased thiamine uptake, whereas overexpression of mutant SLC19A3 did not, confirming that the mutation results in an absent or non-functional protein. Seventeen additional patients with Leigh syndrome were screened for mutations in SLC19A3 using conventional Sanger sequencing. Two unrelated patients, both from Moroccan origin and one from consanguineous parents, were homozygous for the same p.Ser7Ter mutation. One of these patients showed the same MRI abnormalities as the patients from the first family. Strikingly, patients receiving thiamine had an improved life-expectancy. One patient in the third family deteriorated upon interruption of the thiamine treatment and recovered after reinitiating. Although unrelated, all patients came from the province Al Hoceima in Northern Morocco. Based on the recombination events the mutation was estimated to have occurred 1250-1750 years ago. Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome, who might benefit from high doses of thiamine and/or biotin. Especially, Moroccan patients with Leigh syndrome should be tested for the c.20C>A founder mutation in SLC19A3.
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http://dx.doi.org/10.1093/brain/awt013DOI Listing
March 2013

A deletion in the bovine FANCI gene compromises fertility by causing fetal death and brachyspina.

PLoS One 2012 29;7(8):e43085. Epub 2012 Aug 29.

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

Fertility is one of the most important traits in dairy cattle, and has been steadily declining over the last decades. We herein use state-of-the-art genomic tools, including high-throughput SNP genotyping and next-generation sequencing, to identify a 3.3 Kb deletion in the FANCI gene causing the brachyspina syndrome (BS), a rare recessive genetic defect in Holstein dairy cattle. We determine that despite the very low incidence of BS (<1/100,000), carrier frequency is as high as 7.4% in the Holstein breed. We demonstrate that this apparent discrepancy is likely due to the fact that a large proportion of homozygous mutant calves die during pregnancy. We postulate that several other embryonic lethals may segregate in livestock and significantly compromise fertility, and propose a genotype-driven screening strategy to detect the corresponding deleterious mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430679PMC
February 2013

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

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

Highly effective SNP-based association mapping and management of recessive defects in livestock.

Nat Genet 2008 Apr 16;40(4):449-54. Epub 2008 Mar 16.

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

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings.
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http://dx.doi.org/10.1038/ng.96DOI Listing
April 2008

Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition.

Proc Natl Acad Sci U S A 2004 Feb;101(8):2398-403

Department of Genetics, Faculty of Veterinary Medicine, University of Liège (B43), 20 Boulevard de Colonster, 4000 Liège (Sart Tilman), Belgium.

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher Vmax in producing triglycerides than the A allele.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC356962PMC
http://dx.doi.org/10.1073/pnas.0308518100DOI Listing
February 2004

Molecular dissection of a quantitative trait locus: a phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition.

Genetics 2003 Jan;163(1):253-66

Department of Genetics, Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium.

We herein report on our efforts to improve the mapping resolution of a QTL with major effect on milk yield and composition that was previously mapped to bovine chromosome 20. By using a denser chromosome 20 marker map and by exploiting linkage disequilibrium using two distinct approaches, we provide strong evidence that a chromosome segment including the gene coding for the growth hormone receptor accounts for at least part of the chromosome 20 QTL effect. By sequencing individuals with known QTL genotype, we identify an F to Y substitution in the transmembrane domain of the growth hormone receptor gene that is associated with a strong effect on milk yield and composition in the general population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1462408PMC
January 2003

Simultaneous mining of linkage and linkage disequilibrium to fine map quantitative trait loci in outbred half-sib pedigrees: revisiting the location of a quantitative trait locus with major effect on milk production on bovine chromosome 14.

Genetics 2002 May;161(1):275-87

Department of Genetics, Faculty of Veterinary Medicine, University of Liège (B43), 4000-Liège, Belgium.

A maximum-likelihood QTL mapping method that simultaneously exploits linkage and linkage disequilibrium and that is applicable in outbred half-sib pedigrees is described. The method is applied to fine map a QTL with major effect on milk fat content in a 3-cM marker interval on proximal BTA14. This proximal location is confirmed by applying a haplotype-based association method referred to as recombinant ancestral haplotype analysis. The origin of the discrepancy between the QTL position derived in this work and that of a previous analysis is examined and shown to be due to the existence of distinct marker haplotypes associated with QTL alleles having large substitution effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1462117PMC
May 2002

Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition.

Genome Res 2002 Feb;12(2):222-31

Department of Genetics, Faculty of Veterinary Medicine, University of Liège (B43), 4000-Liège, Belgium.

We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition--particularly fat content--to the centromeric end of bovine chromosome 14. We subsequently exploited linkage disequilibrium to refine the map position of this QTL to a 3-cM chromosome interval bounded by microsatellite markers BULGE13 and BULGE09. We herein report the positional candidate cloning of this QTL, involving (1) the construction of a BAC contig spanning the corresponding marker interval, (2) the demonstration that a very strong candidate gene, acylCoA:diacylglycerol acyltransferase (DGAT1), maps to that contig, and (3) the identification of a nonconservative K232A substitution in the DGAT1 gene with a major effect on milk fat content and other milk characteristics.
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http://dx.doi.org/10.1101/gr.224202DOI Listing
February 2002