Publications by authors named "Andre Eggen"

32 Publications

Whole-genome analysis of introgressive hybridization and characterization of the bovine legacy of Mongolian yaks.

Nat Genet 2017 Mar 30;49(3):470-475. Epub 2017 Jan 30.

GABI, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.

The yak is remarkable for its adaptation to high altitude and occupies a central place in the economies of the mountainous regions of Asia. At lower elevations, it is common to hybridize yaks with cattle to combine the yak's hardiness with the productivity of cattle. Hybrid males are sterile, however, preventing the establishment of stable hybrid populations, but not a limited introgression after backcrossing several generations of female hybrids to male yaks. Here we inferred bovine haplotypes in the genomes of 76 Mongolian yaks using high-density SNP genotyping and whole-genome sequencing. These yaks inherited ∼1.3% of their genome from bovine ancestors after nearly continuous admixture over at least the last 1,500 years. The introgressed regions are enriched in genes involved in nervous system development and function, and particularly in glutamate metabolism and neurotransmission. We also identified a novel mutation associated with a polled (hornless) phenotype originating from Mongolian Turano cattle. Our results suggest that introgressive hybridization contributed to the improvement of yak management and breeding.
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http://dx.doi.org/10.1038/ng.3775DOI Listing
March 2017

WIDDE: a Web-Interfaced next generation database for genetic diversity exploration, with a first application in cattle.

BMC Genomics 2015 Nov 14;16:940. Epub 2015 Nov 14.

CIRAD, UMR INTERTRYP, F34398, Montpellier, France.

Background: The advent and democratization of next generation sequencing and genotyping technologies lead to a huge amount of data for the characterization of population genetic diversity in model and non model-species. However, efficient storage, management, cross-analyzing and exploration of such dense genotyping datasets remain challenging. This is particularly true for the bovine species where many SNP datasets have been generated in various cattle populations with different genotyping tools.

Description: We developed WIDDE, a Web-Interfaced Next Generation Database that stands as a generic tool applicable to a wide range of species and marker types ( http://widde.toulouse.inra.fr). As a first illustration, we hereby describe its first version dedicated to cattle biodiversity, which includes a large and evolving cattle genotyping dataset for over 750,000 SNPs available on 129 (89 public) different cattle populations representative of the world-wide bovine genetic diversity and on 7 outgroup bovid species. This version proposes an optional marker and individual filtering step, an export of genotyping data in different popular formats, and an exploration of genetic diversity through a principal component analysis. Users can also explore their own genotyping data together with data from WIDDE, assign their samples to WIDDE populations based on distance assignment method and supervised clustering, and estimate their ancestry composition relative to the populations represented in the database.

Conclusion: The cattle version of WIDDE represents to our knowledge the first database dedicated to cattle biodiversity and SNP genotyping data that will be very useful for researchers interested in this field. As a generic tool applicable to a wide range of marker types, WIDDE is overall intended to the genetic diversity exploration of any species and will be extended to other species shortly. The structure makes it easy to include additional output formats and new tools dedicated to genetic diversity exploration.
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http://dx.doi.org/10.1186/s12864-015-2181-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647285PMC
November 2015

C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle.

Nat Commun 2015 Apr 23;6:6894. Epub 2015 Apr 23.

1] Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche 1313-Génétique Animale et Biologie Intégrative (UMR1313-GABI), F-78352 Jouy-en-Josas, France [2] Allice, Département R&D, F-75595 Paris, France.

Caprine-like Generalized Hypoplasia Syndrome (SHGC) is an autosomal-recessive disorder in Montbéliarde cattle. Affected animals present a wide range of clinical features that include the following: delayed development with low birth weight, hind limb muscular hypoplasia, caprine-like thin head and partial coat depigmentation. Here we show that SHGC is caused by a truncating mutation in the CEP250 gene that encodes the centrosomal protein C-Nap1. This mutation results in centrosome splitting, which neither affects centriole ultrastructure and duplication in dividing cells nor centriole function in cilium assembly and mitotic spindle organization. Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype. This discovery extends the range of loci that constitute the spectrum of autosomal primary recessive microcephaly (MCPH) and Seckel-like syndromes.
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http://dx.doi.org/10.1038/ncomms7894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423223PMC
April 2015

Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle.

Nat Genet 2014 Aug 13;46(8):858-65. Epub 2014 Jul 13.

1] Biosciences Research Division, Department of Environment and Primary Industries, Bundoora, Victoria, Australia. [2] School of Applied Systems Biology, La Trobe University, Bundoora, Victoria, Australia. [3] Dairy Futures Cooperative Research Centre, Bundoora, Victoria, Australia.

The 1000 bull genomes project supports the goal of accelerating the rates of genetic gain in domestic cattle while at the same time considering animal health and welfare by providing the annotated sequence variants and genotypes of key ancestor bulls. In the first phase of the 1000 bull genomes project, we sequenced the whole genomes of 234 cattle to an average of 8.3-fold coverage. This sequencing includes data for 129 individuals from the global Holstein-Friesian population, 43 individuals from the Fleckvieh breed and 15 individuals from the Jersey breed. We identified a total of 28.3 million variants, with an average of 1.44 heterozygous sites per kilobase for each individual. We demonstrate the use of this database in identifying a recessive mutation underlying embryonic death and a dominant mutation underlying lethal chrondrodysplasia. We also performed genome-wide association studies for milk production and curly coat, using imputed sequence variants, and identified variants associated with these traits in cattle.
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http://dx.doi.org/10.1038/ng.3034DOI Listing
August 2014

Design and characterization of a 52K SNP chip for goats.

PLoS One 2014 22;9(1):e86227. Epub 2014 Jan 22.

Kunming Institute of Zoology, Chinese Academy of Sciences, State Key Laboratory of Genetic Resources and Evolution, Kunming, China ; Inner Mongolia Agricultural University, Inner Mongolia Key Laboratory of Animal Genetics, Breeding and Reproduction, Hohhot, Inner Mongolia, China.

The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50-60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086227PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899236PMC
November 2014

Novel insights into the bovine polled phenotype and horn ontogenesis in Bovidae.

PLoS One 2013 22;8(5):e63512. Epub 2013 May 22.

Institut National de la Recherche Agronomique, UMR 1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France.

Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661542PMC
April 2014

Fine mapping of copy number variations on two cattle genome assemblies using high density SNP array.

BMC Genomics 2012 Aug 6;13:376. Epub 2012 Aug 6.

Bovine Functional Genomics Laboratory, ANRI, USDA-ARS, BARC-East, Beltsville, MD 20705, USA.

Background: Btau_4.0 and UMD3.1 are two distinct cattle reference genome assemblies. In our previous study using the low density BovineSNP50 array, we reported a copy number variation (CNV) analysis on Btau_4.0 with 521 animals of 21 cattle breeds, yielding 682 CNV regions with a total length of 139.8 megabases.

Results: In this study using the high density BovineHD SNP array, we performed high resolution CNV analyses on both Btau_4.0 and UMD3.1 with 674 animals of 27 cattle breeds. We first compared CNV results derived from these two different SNP array platforms on Btau_4.0. With two thirds of the animals shared between studies, on Btau_4.0 we identified 3,346 candidate CNV regions representing 142.7 megabases (~4.70%) of the genome. With a similar total length but 5 times more event counts, the average CNVR length of current Btau_4.0 dataset is significantly shorter than the previous one (42.7 kb vs. 205 kb). Although subsets of these two results overlapped, 64% (91.6 megabases) of current dataset was not present in the previous study. We also performed similar analyses on UMD3.1 using these BovineHD SNP array results. Approximately 50% more and 20% longer CNVs were called on UMD3.1 as compared to those on Btau_4.0. However, a comparable result of CNVRs (3,438 regions with a total length 146.9 megabases) was obtained. We suspect that these results are due to the UMD3.1 assembly's efforts of placing unplaced contigs and removing unmerged alleles. Selected CNVs were further experimentally validated, achieving a 73% PCR validation rate, which is considerably higher than the previous validation rate. About 20-45% of CNV regions overlapped with cattle RefSeq genes and Ensembl genes. Panther and IPA analyses indicated that these genes provide a wide spectrum of biological processes involving immune system, lipid metabolism, cell, organism and system development.

Conclusion: We present a comprehensive result of cattle CNVs at a higher resolution and sensitivity. We identified over 3,000 candidate CNV regions on both Btau_4.0 and UMD3.1, further compared current datasets with previous results, and examined the impacts of genome assemblies on CNV calling.
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http://dx.doi.org/10.1186/1471-2164-13-376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583728PMC
August 2012

Design of a bovine low-density SNP array optimized for imputation.

PLoS One 2012 28;7(3):e34130. Epub 2012 Mar 28.

UMR1313 Animal Genetics and Integrative Biology, National Institute for Agricultural Research (INRA), Jouy-en-Josas, France.

The Illumina BovineLD BeadChip was designed to support imputation to higher density genotypes in dairy and beef breeds by including single-nucleotide polymorphisms (SNPs) that had a high minor allele frequency as well as uniform spacing across the genome except at the ends of the chromosome where densities were increased. The chip also includes SNPs on the Y chromosome and mitochondrial DNA loci that are useful for determining subspecies classification and certain paternal and maternal breed lineages. The total number of SNPs was 6,909. Accuracy of imputation to Illumina BovineSNP50 genotypes using the BovineLD chip was over 97% for most dairy and beef populations. The BovineLD imputations were about 3 percentage points more accurate than those from the Illumina GoldenGate Bovine3K BeadChip across multiple populations. The improvement was greatest when neither parent was genotyped. The minor allele frequencies were similar across taurine beef and dairy breeds as was the proportion of SNPs that were polymorphic. The new BovineLD chip should facilitate low-cost genomic selection in taurine beef and dairy cattle.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034130PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314603PMC
August 2012

A newly described bovine type 2 scurs syndrome segregates with a frame-shift mutation in TWIST1.

PLoS One 2011 21;6(7):e22242. Epub 2011 Jul 21.

Unité Mixte de Recherche 1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.

The developmental pathways involved in horn development are complex and still poorly understood. Here we report the description of a new dominant inherited syndrome in the bovine Charolais breed that we have named type 2 scurs. Clinical examination revealed that, despite a strong phenotypic variability, all affected individuals show both horn abnormalities similar to classical scurs phenotype and skull interfrontal suture synostosis. Based on a genome-wide linkage analysis using Illumina BovineSNP50 BeadChip genotyping data from 57 half-sib and full-sib progeny, this locus was mapped to a 1.7 Mb interval on bovine chromosome 4. Within this region, the TWIST1 gene encoding a transcription factor was considered as a strong candidate gene since its haploinsufficiency is responsible for the human Saethre-Chotzen syndrome, characterized by skull coronal suture synostosis. Sequencing of the TWIST1 gene identified a c.148_157dup (p.A56RfsX87) frame-shift mutation predicted to completely inactivate this gene. Genotyping 17 scurred and 20 horned founders of our pedigree as well as 48 unrelated horned controls revealed a perfect association between this mutation and the type 2 scurs phenotype. Subsequent genotyping of 32 individuals born from heterozygous parents showed that homozygous mutated progeny are completely absent, which is consistent with the embryonic lethality reported in Drosophila and mouse suffering from TWIST1 complete insufficiency. Finally, data from previous studies on model species and a fine description of type 2 scurs symptoms allowed us to propose different mechanisms to explain the features of this syndrome. In conclusion, this first report on the identification of a potential causal mutation affecting horn development in cattle offers a unique opportunity to better understand horn ontogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022242PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141036PMC
December 2011

The scurs inheritance: new insights from the French Charolais breed.

BMC Genet 2009 Jul 6;10:33. Epub 2009 Jul 6.

INRA, UMR 1313 Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France.

Background: Polled animals are valued in cattle industry because the absence of horns has a significant economic impact. However, some cattle are neither polled nor horned but have so-called scurs on their heads, which are corneous growths loosely attached to the skull. A better understanding of the genetic determinism of the scurs phenotype would help to fine map the polled locus. To date, only one study has attempted to map the scurs locus in cattle. Here, we have investigated the inheritance of the scurs phenotype in the French Charolais breed and examined whether the previously proposed localisation of the scurs locus on bovine chromosome 19 could be confirmed or not.

Results: Our results indicate that the inheritance pattern of the scurs phenotype in the French Charolais breed is autosomal recessive with complete penetrance in both sexes, which is different from what is reported for other breeds. The frequency of the scurs allele (Sc) reaches 69.9% in the French Charolais population. Eleven microsatellite markers on bovine chromosome 19 were genotyped in 267 offspring (33 half-sib and full-sib families). Both non-parametric and parametric linkage analyses suggest that in the French Charolais population the scurs locus may not map to the previously identified region. A new analysis of an Angus-Hereford and Hereford-Hereford pedigree published in 1978 enabled us to calculate the frequency of the Sc allele in the Hereford breed (89.4%) and to study the penetrance of this allele in males heterozygous for both polled and scurs loci (40%). This led us to revise the inheritance pattern of the scurs phenotype proposed for the Hereford breed and to suggest that allele Sc is not fully but partially dominant in double heterozygous males while it is always recessive in females. Crossbreeding involving the Charolais breed and other breeds gave results similar to those reported in the Hereford breed.

Conclusion: Our results suggest the existence of unknown genetics factors modifying the expression of the scurs locus in double heterozygous Hereford and Angus males. The specific inheritance pattern of the scurs locus in the French Charolais breed represents an opportunity to map this gene and to identify the molecular mechanisms regulating the growth of horns in cattle.
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http://dx.doi.org/10.1186/1471-2156-10-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719667PMC
July 2009

Chromosomal homology between the human and the bovine DMRT1 genes.

Folia Biol (Krakow) 2009 ;57(1-2):29-32

Department of Immuno- and Cytogenetics of Animals, National Research Institute of Animal Production, Krakowska 1, 32-083 Balice n. Kraków, Poland.

Doublesex and mab-3 related transcription factor 1 (DMRT1) is considered to be the most conserved gene among loci involved in the molecular pathways of animal sexual development. In the majority of the extensively examined vertebrates, its function is limited to the upstream or downstream testis regulators acting during embryogenesis. Our present study demonstrated the structural homology between DMRT1 orthologos in human and cattle. A BAC clone with a specific bovine sequence of the gene was used in the FISH mapping experiments. The physical localization of DMRT1 in cattle (BTA 8q17) was determined and its homology to the human locus was shown (HSA 9p24.3). Furthermore, another BAC probe, containing the sequence of the human homologue (pBACe3.6), generated hybridisation signals on bovine metaphase chromosomes and indicated the physical location of the autosomal bovine DMRT1 locus. Further investigations of the gene in domestic animals might provide more support for its conservative status and may help in understanding the molecular mechanisms involved in the occurrence of sexual abnormalities often diagnosed in livestock.
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June 2009

The genome sequence of taurine cattle: a window to ruminant biology and evolution.

Science 2009 Apr;324(5926):522-8

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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http://dx.doi.org/10.1126/science.1169588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943200PMC
April 2009

The bovine dilated cardiomyopathy locus maps to a 1.0-Mb interval on chromosome 18.

Mamm Genome 2009 Mar 14;20(3):187-92. Epub 2009 Feb 14.

Institute of Genetics, Vetsuisse Faculty, University of Berne, Bremgartenstrasse 109a, 3001, Berne, Switzerland.

Cardiomyopathies are myocardial diseases that lead to cardiac dysfunction, heart failure, arrhythmia, and sudden death. In human medicine, cardiomyopathies frequently warrant heart transplantation in children and adults. Bovine dilated cardiomyopathy (BDCMP) is a heart muscle disorder that has been observed during the last 30 years in cattle of Holstein-Friesian origin. In Switzerland BDCMP affects Swiss Fleckvieh and Red Holstein breeds. BDCMP is characterized by a cardiac enlargement with ventricular remodeling and chamber dilatation. The common symptoms in affected animals are subacute subcutaneous edema, congestion of the jugular veins, and tachycardia with gallop rhythm. A cardiomegaly with dilatation and hypertrophy of all heart chambers, myocardial degeneration, and fibrosis are typical postmortem findings. It was shown that all BDCMP cases reported worldwide traced back to a red factor-carrying Holstein-Friesian bull, ABC Reflection Sovereign. An autosomal recessive mode of inheritance was proposed for BDCMP. Recently, the disease locus was mapped to a 6.7-Mb interval MSBDCMP06-BMS2785 on bovine Chr 18 (BTA18). In the present study the BDCMP locus was fine mapped by using a combined strategy of homozygosity mapping and association study. A BAC contig of 2.9 Mb encompassing the crucial interval was constructed to establish the correct marker order on BTA18. We show that the disease locus is located in a gene-rich interval of 1.0 Mb and is flanked by the microsatellite markers DIK3006 and MSBDCMP51.
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http://dx.doi.org/10.1007/s00335-009-9171-zDOI Listing
March 2009

Fine mapping of quantitative trait loci affecting female fertility in dairy cattle on BTA03 using a dense single-nucleotide polymorphism map.

Genetics 2008 Apr;178(4):2227-35

INRA, UR337 Station de Génétique Quantitative et Appliquée, F-78350 Jouy-en-Josas, France.

Fertility quantitative trait loci (QTL) are of high interest in dairy cattle since insemination failure has dramatically increased in some breeds such as Holstein. High-throughput SNP analysis and SNP microarrays give the opportunity to genotype many animals for hundreds SNPs per chromosome. In this study, due to these techniques a dense SNP marker map was used to fine map a QTL underlying nonreturn rate measured 90 days after artificial insemination previously detected with a low-density microsatellite marker map. A granddaughter design with 17 Holstein half-sib families (926 offspring) was genotyped for a set of 437 SNPs mapping to BTA3. Linkage analysis was performed by both regression and variance components analysis. An additional analysis combining both linkage analysis and linkage-disequilibrium information was applied. This method first estimated identity-by-descent probabilities among base haplotypes. These probabilities were then used to group the base haplotypes in different clusters. A QTL explaining 14% of the genetic variance was found with high significance (P < 0.001) at position 19 cM with the linkage analysis and four sires were estimated to be heterozygous (P < 0.05). Addition of linkage-disequilibrium information refined the QTL position to a set of narrow peaks. The use of the haplotypes of heterozygous sires offered the possibility to give confidence in some peaks while others could be discarded. Two peaks with high likelihood-ratio test values in the region of which heterozygous sires shared a common haplotype appeared particularly interesting. Despite the fact that the analysis did not fine map the QTL in a unique narrow region, the method proved to be able to handle efficiently and automatically a large amount of information and to refine the QTL position to a small set of narrow intervals. In addition, the QTL identified was confirmed to have a large effect (explaining 13.8% of the genetic variance) on dairy cow fertility as estimated by nonreturn rate at 90 days.
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http://dx.doi.org/10.1534/genetics.107.085035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323811PMC
April 2008

Genetic and haplotypic structure in 14 European and African cattle breeds.

Genetics 2007 Oct 24;177(2):1059-70. Epub 2007 Aug 24.

INRA, UR339 Laboratoire de Génétique Biochimique et Cytogénétique, F-78350 Jouy-en-Josas, France.

To evaluate and compare the extent of LD in cattle, 1536 SNPs, mostly localized on BTA03, were detected in silico from available sequence data using two different methods and genotyped on samples from 14 distinct breeds originating from Europe and Africa. Only 696 SNPs could be validated, confirming the importance of trace-quality information for the in silico detection. Most of the validated SNPs were informative in several breeds and were used for a detailed description of their genetic structure and relationships. Results obtained were in agreement with previous studies performed on microsatellite markers and using larger samples. In addition, the majority of the validated SNPs could be mapped precisely, reaching an average density of one marker every 311 kb. This allowed us to analyze the extent of LD in the different breeds. Decrease of LD with physical distance across breeds revealed footprints of ancestral LD at short distances (<10 kb). As suggested by the haplotype block structure, these ancestral blocks are organized, within a breed, into larger blocks of a few hundred kilobases. In practice, such a structure similar to that already reported in dogs makes it possible to develop a chip of <300,000 SNPs, which should be efficient for mapping purposes in most cattle breeds.
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http://dx.doi.org/10.1534/genetics.107.075804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034613PMC
October 2007

A physical map of the bovine genome.

Genome Biol 2007 ;8(8):R165

USDA, ARS, US Meat Animal Research Center, Clay Center, NE 68933, USA.

Background: Cattle are important agriculturally and relevant as a model organism. Previously described genetic and radiation hybrid (RH) maps of the bovine genome have been used to identify genomic regions and genes affecting specific traits. Application of these maps to identify influential genetic polymorphisms will be enhanced by integration with each other and with bacterial artificial chromosome (BAC) libraries. The BAC libraries and clone maps are essential for the hybrid clone-by-clone/whole-genome shotgun sequencing approach taken by the bovine genome sequencing project.

Results: A bovine BAC map was constructed with HindIII restriction digest fragments of 290,797 BAC clones from animals of three different breeds. Comparative mapping of 422,522 BAC end sequences assisted with BAC map ordering and assembly. Genotypes and pedigree from two genetic maps and marker scores from three whole-genome RH panels were consolidated on a 17,254-marker composite map. Sequence similarity allowed integrating the BAC and composite maps with the bovine draft assembly (Btau3.1), establishing a comprehensive resource describing the bovine genome. Agreement between the marker and BAC maps and the draft assembly is high, although discrepancies exist. The composite and BAC maps are more similar than either is to the draft assembly.

Conclusion: Further refinement of the maps and greater integration into the genome assembly process may contribute to a high quality assembly. The maps provide resources to associate phenotypic variation with underlying genomic variation, and are crucial resources for understanding the biology underpinning this important ruminant species so closely associated with humans.
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http://dx.doi.org/10.1186/gb-2007-8-8-r165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374996PMC
February 2008

Position independent and copy-number-related expression of the bovine neonatal Fc receptor alpha-chain in transgenic mice carrying a 102 kb BAC genomic fragment.

Transgenic Res 2007 Oct 27;16(5):613-27. Epub 2007 Jun 27.

Agricultural Biotechnology Center, 2100, Szent-Györgyi A. st.4, Godollo, Hungary.

We generated and characterized transgenic mice carrying a 102 kb bovine genomic fragment, encoding the neonatal Fc receptor alpha-chain (bFcRn). FcRn plays a crucial role in the maternal IgG transport and it also regulates the IgG and albumin homeostasis. Some of its functions and transcriptional regulation show species specific differences. The FcRn heterodimer is composed of the alpha-chain and beta-2-microglobulin (beta2 m). A bacterial artificial chromosome containing the bovine FcRn alpha-chain gene (bFCGRT) with its 44 kb 5' and 50 kb long 3' flanking sequences was microinjected into fertilized mouse oocytes. Two of the transgenic lines generated, showed copy number related and integration site independent bFcRn expression. The bFcRn alpha-chain forms a functional receptor with the mouse beta2-microglobulin and extends the half-life of the mouse IgG in transgenic mice. Our results underline the feasibility of creating BAC transgenic mouse models of economically important bovine genes.
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http://dx.doi.org/10.1007/s11248-007-9108-9DOI Listing
October 2007

Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4).

BMC Genet 2007 Feb 23;8. Epub 2007 Feb 23.

Institute of Genetics, Vetsuisse Faculty, University of Berne, Bremgartenstrasse 109a, 3001 Berne, Switzerland.

Background: Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds.

Results: We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families.

Conclusion: We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly.
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http://dx.doi.org/10.1186/1471-2156-8-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810560PMC
February 2007

Cloning of the bovine prion-like Shadoo (SPRN) gene by comparative analysis of the predicted genomic locus.

Mamm Genome 2006 Nov 7;17(11):1130-9. Epub 2006 Nov 7.

Department of Genetics and Microbiology A. Buzzati-Traverso, University of Pavia, Pavia, Italy.

SPRN is a new prion-like gene coding for Sho, a protein with significant similarity to PrP. SPRN was initially described in zebrafish; however, the strong evolutionary conservation led to the hypothesis that SPRN might be the ancestral prion-like gene. We mapped SPRN in Bos taurus by comparative analysis of the locus and of the predicted flanking genes. BACs, spanning the whole SPRN genomic locus, were assigned to BTA26q23 by radiation hybrid mapping and fluorescent in situ hybridization (FISH). Sequencing of five genes flanking SPRN, namely, ECHS1, PAOX, MTG1, SPRN, and CYP2E1, high-resolution FISH on mechanically stretched chromosomes, and combed BAC DNA allowed us to establish their order and reciprocal orientation. The results confirmed that BTA26q23 corresponds to HSA10q24.3-26.3, which is the site where the human SPRN is located. The gene order in Bos taurus is the same as in man, cen-ECHS1-PAOX-MTG1-SPRN-CYP2E1-tel, but PAOX has a different orientation in the two species. SPRN has the typical two-exon PRNP arrangement, with the CDS fully contained within exon 2; furthermore, it codes for a 143-amino-acid protein with 74.8% identity and 84.7% similarity with the human PRNP. RT-PCR and Northern blot analysis showed that SPRN is expressed at high levels in brain and less in testis and lung.
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http://dx.doi.org/10.1007/s00335-006-0078-7DOI Listing
November 2006

A second generation radiation hybrid map to aid the assembly of the bovine genome sequence.

BMC Genomics 2006 Nov 6;7:283. Epub 2006 Nov 6.

Division of Genetics & Genomics, Roslin Institute, Roslin, Midlothian, Edinburgh, EH25 9PS, UK.

Background: Several approaches can be used to determine the order of loci on chromosomes and hence develop maps of the genome. However, all mapping approaches are prone to errors either arising from technical deficiencies or lack of statistical support to distinguish between alternative orders of loci. The accuracy of the genome maps could be improved, in principle, if information from different sources was combined to produce integrated maps. The publicly available bovine genomic sequence assembly with 6x coverage (Btau_2.0) is based on whole genome shotgun sequence data and limited mapping data however, it is recognised that this assembly is a draft that contains errors. Correcting the sequence assembly requires extensive additional mapping information to improve the reliability of the ordering of sequence scaffolds on chromosomes. The radiation hybrid (RH) map described here has been contributed to the international sequencing project to aid this process.

Results: An RH map for the 30 bovine chromosomes is presented. The map was built using the Roslin 3000-rad RH panel (BovGen RH map) and contains 3966 markers including 2473 new loci in addition to 262 amplified fragment-length polymorphisms (AFLP) and 1231 markers previously published with the first generation RH map. Sequences of the mapped loci were aligned with published bovine genome maps to identify inconsistencies. In addition to differences in the order of loci, several cases were observed where the chromosomal assignment of loci differed between maps. All the chromosome maps were aligned with the current 6x bovine assembly (Btau_2.0) and 2898 loci were unambiguously located in the bovine sequence. The order of loci on the RH map for BTA 5, 7, 16, 22, 25 and 29 differed substantially from the assembled bovine sequence. From the 2898 loci unambiguously identified in the bovine sequence assembly, 131 mapped to different chromosomes in the BovGen RH map.

Conclusion: Alignment of the BovGen RH map with other published RH and genetic maps showed higher consistency in marker order and chromosome assignment than with the current 6x sequence assembly. This suggests that the bovine sequence assembly could be significantly improved by incorporating additional independent mapping information.
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http://dx.doi.org/10.1186/1471-2164-7-283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636650PMC
November 2006

Comparative genomic mapping of the bovine Fragile Histidine Triad (FHIT) tumour suppressor gene: characterization of a 2 Mb BAC contig covering the locus, complete annotation of the gene, analysis of cDNA and of physiological expression profiles.

BMC Genomics 2006 May 23;7:123. Epub 2006 May 23.

Department of Genetics and Microbiology A, Buzzati-Traverso, University of Pavia, Italy.

Background: The Fragile Histidine Triad gene (FHIT) is an oncosuppressor implicated in many human cancers, including vesical tumors. FHIT is frequently hit by deletions caused by fragility at FRA3B, the most active of human common fragile sites, where FHIT lays. Vesical tumors affect also cattle, including animals grazing in the wild on bracken fern; compounds released by the fern are known to induce chromosome fragility and may trigger cancer with the interplay of latent Papilloma virus.

Results: The bovine FHIT was characterized by assembling a contig of 78 BACs. Sequence tags were designed on human exons and introns and used directly to select bovine BACs, or compared with sequence data in the bovine genome database or in the trace archive of the bovine genome sequencing project, and adapted before use. FHIT is split in ten exons like in man, with exons 5 to 9 coding for a 149 amino acids protein. VISTA global alignments between bovine genomic contigs retrieved from the bovine genome database and the human FHIT region were performed. Conservation was extremely high over a 2 Mb region spanning the whole FHIT locus, including the size of introns. Thus, the bovine FHIT covers about 1.6 Mb compared to 1.5 Mb in man. Expression was analyzed by RT-PCR and Northern blot, and was found to be ubiquitous. Four cDNA isoforms were isolated and sequenced, that originate from an alternative usage of three variants of exon 4, revealing a size very close to the major human FHIT cDNAs.

Conclusion: A comparative genomic approach allowed to assemble a contig of 78 BACs and to completely annotate a 1.6 Mb region spanning the bovine FHIT gene. The findings confirmed the very high level of conservation between human and bovine genomes and the importance of comparative mapping to speed the annotation process of the recently sequenced bovine genome. The detailed knowledge of the genomic FHIT region will allow to study the role of FHIT in bovine cancerogenesis, especially of vesical papillomavirus-associated cancers of the urinary bladder, and will be the basis to define the molecular structure of the bovine homologue of FRA3B, the major common fragile site of the human genome.
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http://dx.doi.org/10.1186/1471-2164-7-123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513570PMC
May 2006

Ruminants genome no longer contains Whey Acidic Protein gene but only a pseudogene.

Gene 2006 Mar 17;370:104-12. Epub 2006 Feb 17.

Laboratoire de Biologie du Développement et de la Reproduction, Institut National de la Recherche Agronomique (INRA), 78352 Jouy-en-Josas Cedex, France.

Whey Acidic Protein (WAP) has been identified in the milk of only a few species, including mouse, rat, rabbit, camel, pig, tammar wallaby, brushtail possum, echidna and platypus. Despite intensive studies, it has not yet been found in the milk of Ruminants. We have isolated and characterized genomic WAP clones from ewe, goat and cow, identified their chromosomal localization and examined the expression of the endogenous WAP sequence in the mammary glands of all three species. The WAP sequences were localized on chromosome 4 (4q26) as expected from comparative mapping data. The three ruminant WAP sequences reveal the same deletion of a nucleotide at the end of the first exon when compared with the pig sequence. Due to this frameshift mutation, the putative proteins encoded by these sequences do not harbor the features of a usual WAP protein with two four-disulfide core domains. Moreover, RT-PCR experiments have shown that these sequences are not transcribed and are, thus, pseudogenes. This loss of functionality of the gene in Ruminants raises the question of the biological role of the WAP. Some putative roles previously suggested for WAP are discussed.
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http://dx.doi.org/10.1016/j.gene.2005.11.025DOI Listing
March 2006

Fine mapping and physical characterization of two linked quantitative trait loci affecting milk fat yield in dairy cattle on BTA26.

Genetics 2006 Jan 19;172(1):425-36. Epub 2005 Sep 19.

Laboratoire de Génétique Biochimique et Cytogénétique, INRA 78352 Jouy-en-Josas, France.

Previously, a highly significant QTL affecting fat yield and protein yield and mapped to the bovine BTA26 chromosome has been reported to segregate in the French Holstein cattle population. To confirm and refine the location of this QTL, the original detection experiment was extended by adding 12 new families and genotyping 25 additional microsatellite markers (including 11 newly developed markers). Data were then analyzed by an approach combining both linkage and linkage disequilibrium information, making it possible to identify two linked QTL separated by 20 cM corresponding to approximately 29 Mb. The presence of a QTL affecting protein yield was confirmed but its position was found to be more telomeric than the two QTLunderlying fat yield. Each identified QTL affecting milk fat yield was physically mapped within a segment estimated to be <500 kb. Two strong functional candidate genes involved, respectively, in fatty acid metabolism and membrane permeability were found to be localized within this segment while other functional candidate genes were discarded. A haplotype comprising the favorable allele at each QTL position appears to be overrepresented in the artificial insemination bull population.
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http://dx.doi.org/10.1534/genetics.105.046169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456170PMC
January 2006

Integrating linkage and radiation hybrid mapping data for bovine chromosome 15.

BMC Genomics 2004 Oct 8;5:77. Epub 2004 Oct 8.

USDA, ARS, U,S, Meat Animal Research Center, Spur 18D, Clay Center, Nebraska 68933-0166, USA.

Background: Bovine chromosome (BTA) 15 contains a quantitative trait loci (QTL) for meat tenderness, as well as several breaks in synteny with human chromosome (HSA) 11. Both linkage and radiation hybrid (RH) maps of BTA 15 are available, but the linkage map lacks gene-specific markers needed to identify genes underlying the QTL, and the gene-rich RH map lacks associations with marker genotypes needed to define the QTL. Integrating the maps will provide information to further explore the QTL as well as refine the comparative map between BTA 15 and HSA 11. A recently developed approach to integrating linkage and RH maps uses both linkage and RH data to resolve a consensus marker order, rather than aligning independently constructed maps. Automated map construction procedures employing this maximum-likelihood approach were developed to integrate BTA RH and linkage data, and establish comparative positions of BTA 15 markers with HSA 11 homologs.

Results: The integrated BTA 15 map represents 145 markers; 42 shared by both data sets, 36 unique to the linkage data and 67 unique to RH data. Sequence alignment yielded comparative positions for 77 bovine markers with homologs on HSA 11. The map covers approximately 32% of HSA 11 sequence in five segments of conserved synteny, another 15% of HSA 11 is shared with BTA 29. Bovine and human order are consistent in portions of the syntenic segments, but some rearrangement is apparent. Comparative positions of gene markers near the meat tenderness QTL indicate the region includes separate segments of HSA 11. The two microsatellite markers flanking the QTL peak are between defined syntenic segments.

Conclusions: Combining data to construct an integrated map not only consolidates information from different sources onto a single map, but information contributed from each data set increases the accuracy of the map. Comparison of bovine maps with well annotated human sequence can provide useful information about genes near mapped bovine markers, but bovine gene order may be different than human. Procedures to connect genetic and physical mapping data, build integrated maps for livestock species, and connect those maps to more fully annotated sequence can be automated, facilitating the maintenance of up-to-date maps, and providing a valuable tool to further explore genetic variation in livestock.
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http://dx.doi.org/10.1186/1471-2164-5-77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC526187PMC
October 2004

A first generation bovine BAC-based physical map.

Genet Sel Evol 2004 Jan-Feb;36(1):105-22

Laboratoire de génétique biochimique et de cytogénétique, Département de génétique animale, Institut national de la recherche agronomique, Centre de recherche de Jouy, 78352 Jouy-en-Josas, France.

A first generation clone-based physical map for the bovine genome was constructed combining, fluorescent double digestion fingerprinting and sequence tagged site (STS) marker screening. The BAC clones were selected from an Inra BAC library (105,984 clones) and a part of the CHORI-240 BAC library (26,500 clones). The contigs were anchored using the screening information for a total of 1303 markers (451 microsatellites, 471 genes, 127 EST, and 254 BAC ends). The final map, which consists of 6615 contigs assembled from 100,923 clones, will be a valuable tool for genomic research in ruminants, including targeted marker production, positional cloning or targeted sequencing of regions of specific interest.
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http://dx.doi.org/10.1186/1297-9686-36-1-105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697175PMC
September 2004

Genomic approaches to economic trait loci and tissue expression profiling: application to muscle biochemistry and beef quality.

Meat Sci 2004 Jan;66(1):1-9

Biochemical Genetics and Cytogenetics Unit, Department of Animal Genetics, INRA, 78350 Jouy-en-Josas, France.

Genetic and environmental factors profoundly alter the phenotypes of animals. Nowadays, genomics allows large-scale analysis of gene characteristics (structural genomics) and expression (functional genomics). Genome mapping, comparative genomics and identification of quantitative trait loci and polymorphisms are the subject of active investigation to gain a better knowledge of the structure and function of genes. Gene expression profiling using DNA microarrays and proteomics holds great promise for the study of regulatory events which control the final biological functions. Combined with classical genetics and muscle biochemistry to form an integrative biology, these new approaches will bring a better understanding of complex traits and physiological processes. Major applications in meat science could be, for cattle, (1) the identification of new predictors of quality traits (for instance, tenderness), (2) the monitoring of beef quality (including traceability) through the production systems (nutrition level, growth path, grass-feeding), and (3) the improvement of animal selection (markers and gene assisted selection) which may also include quality traits.
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http://dx.doi.org/10.1016/S0309-1740(03)00020-2DOI Listing
January 2004

A comprehensive radiation hybrid map of bovine Chromosome 26 (BTA26): comparative chromosomal organization between HSA10q and BTA26 and BTA28.

Mamm Genome 2003 Oct;14(10):711-21

Laboratoire de Génétique biochimique et de Cytogénétique, Département de Génétique Animale, INRA-CRJ, 78350 Jouy-en-Josas, France.

In this study, we present a comprehensive 3000-rad radiation hybrid (RH) map of bovine Chromosome (Chr) 26 (BTA26) with 80 markers including 50 genes or ESTs: 44 have an ortholog mapping to human Chr 10 (HSA10) and 29 to mouse Chr (MMU) 7, 10, and 19. Moreover, 12 other HSA10 genes were integrated in a newly developed RH map of BTA28 (seven represent new assignments). The available draft of the mouse genome allowed us to present a detailed picture of the distribution of conserved synteny segments among the three species (human, cattle, and mouse) and to propose a simple model of the comparative chromosomal organization between the long arm of HSA10 and BTA26 and 28. Finally, the INRA bovine BAC library was screened for most of the BTA26 markers considered in this study to provide anchors for the bovine physical map.
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http://dx.doi.org/10.1007/s00335-003-3014-0DOI Listing
October 2003

A bovine whole-genome radiation hybrid panel and outline map.

Mamm Genome 2002 Aug;13(8):469-74

Roslin Institute (Edinburgh), Roslin, Midlothian, Scotland EH25 9PS, United Kingdom.

A 3000-rad radiation hybrid panel was constructed for cattle and used to build outline RH maps for all 29 autosomes and the X and Y chromosomes. These outline maps contain about 1200 markers, most of which are anonymous microsatellite loci. Comparisons between the RH chromosome maps, other published RH maps, and linkage maps allow regions of chromosomes that are poorly mapped or that have sparse marker coverage to be identified. In some cases, mapping ambiguities can be resolved. The RH maps presented here are the starting point for mapping additional loci, in particular genes and ESTs that will allow detailed comparative maps between cattle and other species to be constructed. Radiation hybrid cell panels allow high-density genetic maps to be constructed, with the advantage over linkage mapping that markers do not need to be polymorphic. A large quantity of DNA has been prepared from the cells forming the RH panel reported here and is publicly available for mapping large numbers of loci.
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http://dx.doi.org/10.1007/s00335-002-3001-xDOI Listing
August 2002

An extensive and comprehensive radiation hybrid map of bovine Chromosome 15: comparison with human Chromosome 11.

Mamm Genome 2002 Jun;13(6):316-9

Laboratoire de Génétique Biochimique et de Cytogénétique, Département de Génétique Animale, INRA-CRJ, 78350 Jouy-en-Josas, France.

An extensive and comprehensive radiation hybrid map of bovine Chromosome 15 (BTA15) was built with 42 anonymous markers, 3 ESTs, and 49 genes. This work allows us to refine the comparative map between human Chromosome (Chr) 11 (HSA11) and BTA15. Four blocks with a similar gene content and relatively good gene order conservation were identified. The discrepancies are concentrated on closely positioned genes for which discrimination is not possible between mapping resolution limits in either the human or the bovine maps and true local inversions. Using the gene order similarity and the human physical map as starting point, we estimated the overall physical length of BTA15 to be around 75.3 Mb. The INRA bovine BAC library was screened for all the markers ordered on the bovine map, which will provide anchors for future efforts in the construction of a physical map of the bovine genome.Finally, this map contains the majority of publicly available polymorphic markers described for BTA15 and integrates those with comparative mapping information. It should, therefore, constitute a powerful tool in the identification of relevant candidate genes in regions of BTA15 harboring economic trait loci.
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http://dx.doi.org/10.1007/s00335-001-3069-8DOI Listing
June 2002
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