Christophe Hitte

Publications of Christophe Hitte

• Annotation of the domestic dog genome sequence: finding the missing genes.

  Authors: Thomas Derrien, Amaury Vaysse, Catherine André, Christophe Hitte

  Mammalian genome : official journal of the International Mammalian Genome Society. 11/2011; 23(1-2):124-31.

  There are over 350 genetically distinct breeds of domestic dog that present considerable variation in morphology, physiology, and disease susceptibility. The genome sequence of the domestic dog wasThere are over 350 genetically distinct breeds of domestic dog that present considerable variation in morphology, physiology, and disease susceptibility. The genome sequence of the domestic dog was assembled and released in 2005, providing an estimated 20,000 protein-coding genes that are a great asset to the scientific community that uses the dog system as a genetic biomedical model and for comparative and evolutionary studies. Although the canine gene set had been predicted using a combination of ab initio methods, homology studies, motif analysis, and similarity-based programs, it still requires a deep annotation of noncoding genes, alternative splicing, pseudogenes, regulatory regions, and gain and loss events. Such analyses could benefit from new sequencing technologies (RNA-Seq) to better exploit the advantages of the canine genetic system in tracking disease genes. Here, we review the catalog of canine protein-coding genes and the search for missing genes, and we propose rationales for an accurate identification of noncoding genes though next-generation sequencing.

• Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

  Authors: Amaury Vaysse, Abhirami Ratnakumar, Thomas Derrien, Erik Axelsson, Gerli Rosengren Pielberg, Snaevar Sigurdsson, Tove Fall, Eija H Seppälä, Mark S T Hansen, Cindy T Lawley [......] Carles Vilà, Hannes Lohi, Francis Galibert, Merete Fredholm, Jens Häggström, Ake Hedhammar, Catherine André, Kerstin Lindblad-Toh, Christophe Hitte, Matthew T Webster

  PLoS genetics. 10/2011; 7(10):e1002316.

  The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysisThe extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

• LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs.

  Authors: Anne-Sophie Lequarré, Leif Andersson, Catherine André, Merete Fredholm, Christophe Hitte, Tosso Leeb, Hannes Lohi, Kerstin Lindblad-Toh, Michel Georges

  Veterinary journal (London, England : 1997). 08/2011; 189(2):155-9.

  The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal modelThe domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.

• Toward understanding dog evolutionary and domestication history.

  Authors: Francis Galibert, Pascale Quignon, Christophe Hitte, Catherine André

  Comptes rendus biologies. 03/2011; 334(3):190-6.

  Dog domestication was probably started very early during the Upper paleolithic period (~35,000 BP), thus well before any other animal or plant domestication. This early process, probably unconscious,Dog domestication was probably started very early during the Upper paleolithic period (~35,000 BP), thus well before any other animal or plant domestication. This early process, probably unconscious, is called proto-domestication to distinguish it from the real domestication process that has been dated around 14,000 BC. Genomic DNA analyses have shown recently that domestication started in the Middle East and rapidly expanded into all human populations. Nowadays, the dog population is fragmented in several hundreds of breeds well characterized by their phenotypes that offer a unique spectrum of polymorphism. More recent studies detect genetic signatures that will be useful to highlight breed history as well as the impact of domestication at the DNA level.

• A radiation hybrid map of the European sea bass (Dicentrarchus labrax) based on 1581 markers: Synteny analysis with model fish genomes.

  Authors: Richard Guyon, Fabrice Senger, Michaelle Rakotomanga, Naoual Sadequi, Filip A M Volckaert, Christophe Hitte, Francis Galibert

  Genomics. 10/2010; 96(4):228-38.

  The selective breeding of fish for aquaculture purposes requires the understanding of the genetic basis of traits such as growth, behaviour, resistance to pathogens and sex determinism. Access toThe selective breeding of fish for aquaculture purposes requires the understanding of the genetic basis of traits such as growth, behaviour, resistance to pathogens and sex determinism. Access to well-developed genomic resources is a prerequisite to improve the knowledge of these traits. Having this aim in mind, a radiation hybrid (RH) panel of European sea bass (Dicentrarchus labrax) was constructed from splenocytes irradiated at 3000 rad, allowing the construction of a 1581 marker RH map. A total of 1440 gene markers providing ~4400 anchors with the genomes of three-spined stickleback, medaka, pufferfish and zebrafish, helped establish synteny relationships with these model species. The identification of Conserved Segments Ordered (CSO) between sea bass and model species allows the anticipation of the position of any sea bass gene from its location in model genomes. Synteny relationships between sea bass and gilthead seabream were addressed by mapping 37 orthologous markers. The sea bass genetic linkage map was integrated in the RH map through the mapping of 141 microsatellites. We are thus able to present the first complete gene map of sea bass. It will facilitate linkage studies and the identification of candidate genes and Quantitative Trait Loci (QTL). The RH map further positions sea bass as a genetic and evolutionary model of Perciformes and supports their ongoing aquaculture expansion.

• MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.

  Authors: Alan H Beggs, Johann Böhm, Elizabeth Snead, Marek Kozlowski, Marie Maurer, Katie Minor, Martin K Childers, Susan M Taylor, Christophe Hitte, James R Mickelson, Ling T Guo, Andrew P Mizisin, Anna Buj-Bello, Laurent Tiret, Jocelyn Laporte, G Diane Shelton

  Proceedings of the National Academy of Sciences of the United States of America. 08/2010; 107(33):14697-702.

  Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14-26 wk, wereMutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14-26 wk, were clinically evaluated for generalized weakness and muscle atrophy. Muscle biopsies showed variability in fiber size, centrally placed nuclei resembling fetal myotubes, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions. Ultrastructural studies confirmed the centrally located nuclei, abnormal perinuclear structure, and mitochondrial accumulations. Wild-type triads were infrequent, with most exhibiting an abnormal orientation of T tubules. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. Analysis of a worldwide panel of 237 unaffected Labrador Retrievers and 59 additional control dogs from 25 other breeds failed to identify this variant, supporting it as the pathogenic mutation. Myotubularin protein levels and localization were abnormal in muscles from affected dogs, and expression of GFP-MTM1 p.N155K in COS-1 cells showed that the mutant protein was sequestered in proteasomes, where it was presumably misfolded and prematurely degraded. These data demonstrate that XLMTM in Labrador Retrievers is a faithful genetic model of the human condition.

• A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.

  Authors: Marie Abitbol, Jean-Laurent Thibaud, Natasha J Olby, Christophe Hitte, Jean-Philippe Puech, Marie Maurer, Fanny Pilot-Storck, Benoit Hédan, Stéphane Dréano, Sandra Brahimi, Delphine Delattre, Catherine André, Françoise Gray, Françoise Delisle, Catherine Caillaud, Florence Bernex, Jean-Jacques Panthier, Geneviève Aubin-Houzelstein, Stéphane Blot, Laurent Tiret

  Proceedings of the National Academy of Sciences of the United States of America. 08/2010; 107(33):14775-80.

  Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motorNeuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

• Revisiting the missing protein-coding gene catalog of the domestic dog.

  Authors: Thomas Derrien, Julien Theze, Amaury Vaysse, Catherine Andre, Elaine Ostrander, Francis Galibert, Christophe Hitte

  BMC genomics. 03/2009; 10(1):62.

  ABSTRACT: BACKGROUND: Among mammals for which there is a high sequence coverage, the whole genome assembly of the dog is unique in that it predicts a low number of protein-coding genes, ~19,000,ABSTRACT: BACKGROUND: Among mammals for which there is a high sequence coverage, the whole genome assembly of the dog is unique in that it predicts a low number of protein-coding genes, ~19,000, compared to over 20,000 reported for other mammalian species. Of particular interest are the ~400 genes annotated in primates and rodent genomes which are missing in the dog. RESULTS: Using over 14,000 orthologous genes between human, chimpanzee, mouse, rat and dog, we built multiple pairwise synteny maps to infer short orthologous intervals that were targeted for characterizing the canine missing genes. Based on gene prediction and a functionality test using the ratio of silent to replacement nucleotide substitution rates (dN/dS), we provide compelling structural and functional evidence for the identification of 232 new protein-coding genes in the canine genome and 69 gene losses, characterized as undetected gene or pseudogenes. Gene loss phyletic pattern analysis using ten species from chicken to human allowed us to characterize 28 canine-specific gene losses that have functional orthologs continuously from chicken or marsupials through human, and 10 genes that arose specifically in the evolutionary lineage leading to rodent and human. In addition, we identified a set of 10 genes that have been independently lost in canine as well as other lineages. CONCLUSIONS: This study demonstrates the central role of comparative genomics for refining gene catalogs and exploring the evolutionary history of gene repertoires, particularly as applied for the characterization of species-specific gene gains and losses.

• Genetic diversity of canine olfactory receptors.

  Authors: Stephanie Robin, Sandrine Tacher, Maud Rimbault, Amaury Vaysse, Stephane Dreano, Catherine Andre, Christophe Hitte, Francis Galibert

  BMC genomics. 02/2009; 10(1):21.

  ABSTRACT: BACKGROUND: Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity ofABSTRACT: BACKGROUND: Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations. RESULTS: We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently. CONCLUSIONS: Our demonstration of a high overall level of polymorphism likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why in a context in which most OR genes are highly polymorphic a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.

• Survey sequencing and radiation hybrid mapping to construct comparative maps.

  Authors: Christophe Hitte, Ewen F Kirkness, Elaine A Ostrander, Francis Galibert

  Methods in molecular biology (Clifton, N.J.). 01/2008; 422:65-77.

  Radiation hybrid (RH) mapping has become one of the most well-established techniques for economically and efficiently navigating genomes of interest. The success of the technique relies on randomRadiation hybrid (RH) mapping has become one of the most well-established techniques for economically and efficiently navigating genomes of interest. The success of the technique relies on random chromosome breakage of a target genome, which is then captured by recipient cells missing a preselected marker. Selection for hybrid cells that have DNA fragments bearing the marker of choice, plus a random set of DNA fragments from the initial irradiation, generates a set of cell lines that recapitulates the genome of the target organism several-fold. Markers or genes of interest are analyzed by PCR using DNA isolated from each cell line. Statistical tools are applied to determine both the linear order of markers on each chromosome, and the confidence of each placement. The resolution of the resulting map relies on many factors, most notably the degree of breakage from the initial radiation as well as the number of hybrid clones and mean retention value.A high-resolution RH map of a genome derived from low pass or survey sequencing (coverage from 1 to 2 times) can provide essentially the same comparative data on gene order that is derived from high-coverage (greater than x7) genome sequencing. When combined with fluorescence in situ hybridization, RH maps are complete and ordered blueprints for each chromosome. They give information about the relative order and spacing of genes and markers, and allow investigators to move between target and reference genomes, such as those of mouse or human, with ease although the approach is not limited to mammal genomes.

• AutoGRAPH: an interactive web server for automating and visualizing comparative genome maps.

  Authors: Thomas Derrien, Catherine André, Francis Galibert, Christophe Hitte

  Bioinformatics (Oxford, England). 03/2007; 23(4):498-9.

  AutoGRAPH is an interactive web server for automatic multi-species comparative genomics analyses based on personal datasets or pre-inserted public datasets. This program automatically identifiesAutoGRAPH is an interactive web server for automatic multi-species comparative genomics analyses based on personal datasets or pre-inserted public datasets. This program automatically identifies conserved segments (CS) and breakpoint regions, assesses the conservation of marker/gene order between organisms, constructs synteny maps for two to three species and generates high-quality, interactive displays facilitating the identification of chromosomal rearrangements. AutoGRAPH can also be used for the integration and comparison of several types of genomic resources (meiotic maps, radiation hybrid maps and genome sequences) for a single species, making AutoGRAPH a versatile tool for comparative genomics analysis. AVAILABILITY: http://genoweb.univ-rennes1.fr/tom_dog/AutoGRAPH/. SUPPLEMENTARY INFORMATION: A description of the algorithm and additional information are available at http://genoweb.univ-rennes1.fr/tom_dog/AutoGRAPH/Tutorial.php.

• Analysis of the unassembled part of the dog genome sequence: chromosomal localization of 115 genes inferred from multispecies comparative genomics.

  Authors: Thomas Derrien, Catherine André, Francis Galibert, Christophe Hitte

  The Journal of heredity. 02/2007; 98(5):461-7.

  The identification of dog genes and their accurate localization to chromosomes remain a major challenge in the postgenomics era. The 132 annotated canine genes with human orthologs remaining in theThe identification of dog genes and their accurate localization to chromosomes remain a major challenge in the postgenomics era. The 132 annotated canine genes with human orthologs remaining in the unassembled part (chrUnknown) of the dog sequence assembly (CanFam1) are of limited use for candidate gene approaches or comparative mapping studies. We used a two-step comparative analysis to infer a canine chromosomal interval for localization of the chrUn genes. We first constructed a human-dog synteny map, using 14,456 gene-based comparative anchors. We then mapped the 132 chrUn genes onto the reference (human) synteny map and identified the corresponding, orthologous segment on the canine map, based on conserved gene order. Our results show that 110 chrUn genes could be localized to short intervals on 18 dog chromosomes, whereas 22 genes remained assigned to 2 possible intervals. We extended this comparative analysis to multiple species, using the chimpanzee, mouse, and rat genome sequences. This made it possible to narrow down the intervals concerned and to increase the number of canine chrUn genes with an inferred chromosome location to 115. This study demonstrates that dog chromosomal intervals for chrUn genes can be rapidly inferred, using a reference species, and indicates that comparative strategies based on larger numbers of species may be even more effective.

• Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies.

  Authors: Pascale Quignon, Laetitia Herbin, Edouard Cadieu, Ewen F Kirkness, Benoit Hédan, Dana S Mosher, Francis Galibert, Catherine André, Elaine A Ostrander, Christophe Hitte

  PLoS ONE. 02/2007; 2(12):e1324.

  BACKGROUND: In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogsBACKGROUND: In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we address the magnitude and impact of genetic diversity among common breeds sampled in the U.S. and Europe. The breeds selected, including the Rottweiler, Bernese mountain dog, flat-coated retriever, and golden retriever, share susceptibility to a class of soft tissue cancers typified by malignant histiocytosis in the Bernese mountain dog. We genotyped 722 SNPs at four unlinked loci (between 95 and 271 per locus) on canine chromosome 1 (CFA1). We showed that each population is characterized by distinct genetic diversity that can be correlated with breed history. When the breed studied has a reduced intra-breed diversity, the combination of dogs from international locations does not increase the rate of false positives and potentially increases the power of association studies. However, over-sampling cases from one geographic location is more likely to lead to false positive results in breeds with significant genetic diversity. CONCLUSIONS: These data provide new guidelines for association studies using purebred dogs that take into account population structure.

• A comparative genome approach to marker ordering.

  Authors: Thomas Faraut, Simon de Givry, Patrick Chabrier, Thomas Derrien, Francis Galibert, Christophe Hitte, Thomas Schiex

  Bioinformatics. 01/2007; 23:50-56.

• The first radiation hybrid map of a perch-like fish: the gilthead seabream (Sparus aurata L).

  Authors: Fabrice Senger, Catherine Priat, Christophe Hitte, Elena Sarropoulou, Rafaella Franch, Robert Geisler, Luca Bargelloni, Deborah Power, Francis Galibert

  Genomics. 07/2006; 87(6):793-800.

  Among Teleosts, Perciformes are the largest order of fishes and include numerous species of commercial importance. Perciformes also comprise species of primary interest for evolutionary studies andAmong Teleosts, Perciformes are the largest order of fishes and include numerous species of commercial importance. Perciformes also comprise species of primary interest for evolutionary studies and analysis of the sex determination systems and sex chromosome plasticity. Unfortunately, genomics tools and resources for Perciformes remain to be developed. Here, we report the production of a seabream whole-genome radiation hybrid (RH) panel in which quality was ascertained by the construction of a 2-Mb-resolution RH map. The map encompasses 440 markers (288 microsatellites, 82 gene-based markers, and 70 STS) suitable for linkage analysis and comparative mapping studies. Achievement of a RH panel and a whole-genome RH map should contribute to establishing seabream as a fish model among the Perciformes and should be of importance in aquaculture for marker-assisted selection, improvement of growth performance, and disease management. Development of RH maps in a cost-effective manner for other fishes with the described methodology will offer a powerful approach in aquaculture and will provide extended capabilities for comparing vertebrate genome evolution.

• Coat colour in dogs: identification of the merle locus in the Australian shepherd breed.

  Authors: Benoit Hédan, Sébastien Corre, Christophe Hitte, Stéphane Dréano, Thierry Vilboux, Thomas Derrien, Bernard Denis, Francis Galibert, Marie-Dominique Galibert, Catherine André

  BMC veterinary research. 02/2006; 2:9.

  BACKGROUND: Coat colours in canines have many natural phenotypic variants. Some of the genes and alleles involved also cause genetic developmental defects, which are also observed in humans and mice.BACKGROUND: Coat colours in canines have many natural phenotypic variants. Some of the genes and alleles involved also cause genetic developmental defects, which are also observed in humans and mice. We studied the genetic bases of the merle phenotype in dogs to shed light on the pigmentation mechanisms and to identify genes involved in these complex pathways. The merle phenotype includes a lack of eumelanic pigmentation and developmental defects, hearing impairments and microphthalmia. It is similar to that observed in microphthalmia mouse mutants. RESULTS: Taking advantage of the dog as a powerful genetic model and using recently available genomic resources, we investigated the segregation of the merle phenotype in a five-generation pedigree, comprising 96 sampled Australian shepherd dogs. Genetic linkage analysis allowed us to identify a locus for the merle phenotype, spanning 5.5 megabases, at the centromeric tip of canine chromosome 10 (CFA10). This locus was supported by a Lod score of 15.65 at a recombination fraction theta = 0. Linkage analysis in three other breeds revealed that the same region is linked to the merle phenotype. This region, which is orthologous to human chromosome 12 (HSA12 q13-q14), belongs to a conserved ordered segment in the human and mouse genome and comprises several genes potentially involved in pigmentation and development. CONCLUSION: This study has identified the locus for the merle coat colour in dogs to be at the centromeric end of CFA10. Genetic studies on other breeds segregating the merle phenotype should allow the locus to be defined more accurately with the aim of identifying the gene. This work shows the power of the canine system to search for the genetic bases of mammalian pigmentation and developmental pathways.

• Genome sequence, comparative analysis and haplotype structure of the domestic dog.

  Authors: Kerstin Lindblad-Toh, Claire M Wade, Tarjei S Mikkelsen, Elinor K Karlsson, David B Jaffe, Michael Kamal, Michele Clamp, Jean L Chang, Edward J Kulbokas, Michael C Zody [......] Adam Wilson, Shailendra Yadav, Shuli Yang, Xiaoping Yang, Geneva Young, Qing Yu, Joanne Zainoun, Lisa Zembek, Andrew Zimmer, Eric S Lander

  Nature. 01/2006; 438(7069):803-19.

  Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particularHere we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.

• Construction of a 2-Mb resolution BAC microarray for CGH analysis of canine tumors.

  Authors: Rachael Thomas, Allyson Scott, Cordelia F Langford, Susan P Fosmire, Cristan M Jubala, Travis D Lorentzen, Christophe Hitte, Elinor K Karlsson, Ewen Kirkness, Elaine A Ostrander, Francis Galibert, Kerstin Lindblad-Toh, Jaime F Modiano, Matthew Breen

  Genome research. 01/2006; 15(12):1831-7.

  Recognition of the domestic dog as a model for the comparative study of human genetic traits has led to major advances in canine genomics. The pathophysiological similarities shared between manyRecognition of the domestic dog as a model for the comparative study of human genetic traits has led to major advances in canine genomics. The pathophysiological similarities shared between many human and dog diseases extend to a range of cancers. Human tumors frequently display recurrent chromosome aberrations, many of which are hallmarks of particular tumor subtypes. Using a range of molecular cytogenetic techniques we have generated evidence indicating that this is also true of canine tumors. Detailed knowledge of these genomic abnormalities has the potential to aid diagnosis, prognosis, and the selection of appropriate therapy in both species. We recently improved the efficiency and resolution of canine cancer cytogenetics studies by developing a small-scale genomic microarray comprising a panel of canine BAC clones representing subgenomic regions of particular interest. We have now extended these studies to generate a comprehensive canine comparative genomic hybridization (CGH) array that comprises 1158 canine BAC clones ordered throughout the genome with an average interval of 2 Mb. Most of the clones (84.3%) have been assigned to a precise cytogenetic location by fluorescence in situ hybridization (FISH), and 98.5% are also directly anchored within the current canine genome assembly, permitting direct translation from cytogenetic aberration to DNA sequence. We are now using this resource routinely for high-throughput array CGH and single-locus probe analysis of a range of canine cancers. Here we provide examples of the varied applications of this resource to tumor cytogenetics, in combination with other molecular cytogenetic techniques.

• Facilitating genome navigation: survey sequencing and dense radiation-hybrid gene mapping.

  Authors: Christophe Hitte, Jennifer Madeoy, Ewen F Kirkness, Catherine Priat, Travis D Lorentzen, Fabrice Senger, Dan Thomas, Thomas Derrien, Christina Ramirez, Carol Scott [......] David B Jaffe, Sandrine Tacher, Stéphane Dréano, Nadia Berkova, Catherine André, Panagiotis Deloukas, Claire Fraser, Kerstin Lindblad-Toh, Elaine A Ostrander, Francis Galibert

  Nature reviews. Genetics. 09/2005; 6(8):643-8.

  Accurate and comprehensive sequence coverage for large genomes has been restricted to only a few species of specific interest. Lower sequence coverage (survey sequencing) of related species can yieldAccurate and comprehensive sequence coverage for large genomes has been restricted to only a few species of specific interest. Lower sequence coverage (survey sequencing) of related species can yield a wealth of information about gene content and putative regulatory elements. But survey sequences lack long-range continuity and provide only a fragmented view of a genome. Here we show the usefulness of combining survey sequencing with dense radiation-hybrid (RH) maps for extracting maximum comparative genome information from model organisms. Based on results from the canine system, we propose that from now on all low-pass sequencing projects should be accompanied by a dense, gene-based RH map-construction effort to extract maximum information from the genome with a marginal extra cost.

• Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps.

  Authors: William J Murphy, Denis M Larkin, Annelie Everts-van der Wind, Guillaume Bourque, Glenn Tesler, Loretta Auvil, Jonathan E Beever, Bhanu P Chowdhary, Francis Galibert, Lisa Gatzke [......] Heidi G Parker, Terje Raudsepp, Margarita B Rogatcheva, Lawrence B Schook, Loren C Skow, Michael Welge, James E Womack, Stephen J O'Brien, Pavel A Pevzner, Harris A Lewin

  Science (New York, N.Y.). 08/2005; 309(5734):613-7.

  The genome organizations of eight phylogenetically distinct species from five mammalian orders were compared in order to address fundamental questions relating to mammalian chromosomal evolution.The genome organizations of eight phylogenetically distinct species from five mammalian orders were compared in order to address fundamental questions relating to mammalian chromosomal evolution. Rates of chromosome evolution within mammalian orders were found to increase since the Cretaceous-Tertiary boundary. Nearly 20% of chromosome breakpoint regions were reused during mammalian evolution; these reuse sites are also enriched for centromeres. Analysis of gene content in and around evolutionary breakpoint regions revealed increased gene density relative to the genome-wide average. We found that segmental duplications populate the majority of primate-specific breakpoints and often flank inverted chromosome segments, implicating their role in chromosomal rearrangement.