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C S Mellersh

Publications and source records attributed to C S Mellersh.

At least 19 recordsLinked to original sources
PubMed2001

Characterization of a minimal screening set of 172 microsatellite markers for genome-wide screens of the canine genome.

We have characterized a subset of 172 microsatellite markers from the canine map, termed 'Minimal Screening Set 1' (Canine MSS-1), which we propose be used for initial genome-wide genetic linkage studies. Three hierarchical criteria were used to select markers from the current meiotic linkage and radiation hybrid maps for MSS-1. Markers were selected that (1) provided as complete coverage as possible of the canine genome, (2) were highly informative, and (3) have been ordered in linkage groups with a high degree of statistical support. This resulting screening set spans all reported meiotic linkage and RH groups, leaving only 10 known gaps > or = 20 cM. The average polymorphic information content (PIC) value of markers tested is 0.74. Coverage estimates suggest 42% of the genome is within 5 cM of at least one marker in the minimal screening set, 77% of the genome is within 10 cM. This minimal mapping set therefore provides an efficient and cost effective way to begin screening pedigrees of interest for genetic linkage.

Animals↗
PubMed2001

Meiotic linkage mapping of 52 genes onto the canine map does not identify significant levels of microrearrangement.

In an effort to extend our understanding of the evolutionary relationship between the canine and human genomes, we have developed and positioned 52 new gene-associated polymorphic markers on the canine meiotic linkage map. Canine-specific PCR primers were developed from the consensus of published sequences of several mammalian genomes and were designed to span intronic regions, thus optimizing the probability that a polymorphic site was included. The resulting markers were analyzed on a panel of three-generation canine reference families and the data were incorporated into the current meiotic linkage map. The data were compared with those generated by three chromosome paint studies in an effort to understand the distribution and frequency of microrearrangements within the canine genome. Forty-eight of 52 genes map to a chromosomal region predicted to contain genes from the corresponding region of the human genome according to all published reciprocal chromosome paint studies. Meiotic linkage mapping data for three genes can be used to resolve discrepancies between the published reciprocal chromosome paint studies, and for an additional two genes, meiotic mapping data allow evolutionary breakpoints to be more precisely defined. We conclude that microrearrangements of evolutionarily conserved segments between the canine and human genomes are rare, occurring for less than 0.5% of gene data reported to date. In addition, we have found that the placement of genes on the meiotic linkage map is a useful mechanism for resolving discrepancies between existing data sets.

Animals↗
PubMed2001

Chromosome-specific single-locus FISH probes allow anchorage of an 1800-marker integrated radiation-hybrid/linkage map of the domestic dog genome to all chromosomes.

We present here the first fully integrated, comprehensive map of the canine genome, incorporating detailed cytogenetic, radiation hybrid (RH), and meiotic information. We have mapped a collection of 266 chromosome-specific cosmid clones, each containing a microsatellite marker, to all 38 canine autosomes by fluorescence in situ hybridization (FISH). A 1500-marker RH map, comprising 1078 microsatellites, 320 dog gene markers, and 102 chromosome-specific markers, has been constructed using the RHDF5000-2 whole-genome radiation hybrid panel. Meiotic linkage analysis was performed, with at least one microsatellite marker from each dog autosome on a panel of reference families, allowing one meiotic linkage group to be anchored to all 38 dog autosomes. We present a karyotype in which each chromosome is identified by one meiotic linkage group and one or more RH groups. This updated integrated map, containing a total of 1800 markers, covers >90% of the dog genome. Positional selection of anchor clones enabled us, for the first time, to orientate nearly all of the integrated groups on each chromosome and to evaluate the extent of individual chromosome coverage in the integrated genome map. Finally, the inclusion of 320 dog genes into this integrated map enhances existing comparative mapping data between human and dog, and the 1000 mapped microsatellite markers constitute an invaluable tool with which to perform genome scanning studies on pedigrees of interest.

Animals↗
PubMed2000

Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs.

Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs. Genetic linkage analysis of an RCND-informative pedigree has identified a linkage group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05. 771-[RCND-CPH18]-C02608-GLUT4-TP53-ZuBe Ca6-AHT141-FH2140-FH2594) thus localizing the disease to a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (theta) of 0.016, supported by a logarithm of odds score of 16.7. C02608 and the adjacent linked markers map to a region of the canine genome corresponding to portions of human chromosomes 1p and 17p. A combination of linkage analysis and direct sequencing eliminate several likely candidate genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor suppressor gene TP53. These data suggest that RCND may be caused by a previously unidentified tumor suppressor gene and highlight the potential for canine genetics in the study of human disease predisposition.

Animals↗
PubMed2000

An integrated linkage-radiation hybrid map of the canine genome.

Purebred dogs are a unique resource for dissecting the molecular basis of simple and complex genetic diseases and traits. As a result of strong selection for physical and behavioral characteristics among the 300 established breeds, modern dogs are characterized by high levels of interbreed variation, complemented by significant intrabreed homogeneity. A high-resolution map of the canine genome is necessary to exploit the mapping power of this unusual resource. We describe here the integration of an expanded canine radiation hybrid map, comprised of 600 markers, with the latest linkage map of 341 markers, to generate a map of 724 markers-the densest map of the canine genome described to date. Through the inclusion of 217 markers on both the linkage and RH maps, the 77 RH groups are reduced to 44 syntenic groups, thus providing comprehensive coverage of most of the canine genome.

Animals↗
PubMed2000

Chromosomal assignment of canine TSC2, PKD1 and CLN3 genes by radiation hybrid- and linkage analyses.

The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).

Animals↗
PubMed1999

A novel retinal degeneration locus identified by linkage and comparative mapping of canine early retinal degeneration.

Early retinal degeneration (erd) is an early onset progressive retinal atrophy, a hereditary canine retinal disease phenotypically similar to human retinitis pigmentosa (RP). In previous efforts to identify the erd locus, canine homologs of genes causally associated with RP in humans, such as opsin (RHO), the beta-subunit gene for cyclic GMP phosphodiesterase (PDE6B), and RDS/peripherin, were excluded. A genome-wide screen was undertaken on canine families segregating the erd disease. Analysis of over 150 canine-specific markers has localized erd to a single linkage group comprising two previously identified canine linkage groups, 20 and 26, corresponding to canine radiation hybrid groups RH.34-a and RH.40-a. Multipoint analysis places erd in the interval between marker FH2289 (distance 23.6 cM) and FH2407 (5.9 cM) with a lod score of 12.23. Although the erd linkage group has not been assigned to an identified canine chromosome, conserved synteny of this linkage group with human 12p13-q13 suggests several candidates for erd and identifies a novel retinal degeneration locus. The rapid progress now occurring in canine genetics will expedite identification of the genes and molecular mechanisms underlying the inherited traits and diseases that make the dog a unique asset for study of mammalian traits.

Animals↗
PubMed1999

Anchoring of canine linkage groups with chromosome-specific markers.

A high-resolution genetic map with polymorphic markers spaced frequently throughout the genome is a key resource for identifying genes that control specific traits or diseases. The lack of rigorous selection against genetic disorders has resulted in many breeds of dog suffering from a very high frequency of genetic diseases, which tend to be breed-specific and usually inherited as autosomal recessive or apparently complex genetic traits. Many of these closely resemble human genetic disorders in their clinical and pathologic features and are likely to be caused by mutations in homologous genes. To identify loci important in canine disease genes, as well as traits associated with morphological and behavioral variation, we are developing a genetic map of the canine genome. Here we report on an updated version of the canine linkage map, which includes 341 mapped markers distributed over the X and 37 autosomal linkage groups. The average distance between markers on the map is 9.0 cM, and the linkage groups provide estimated coverage of over 95% of the genome. Fourteen linkage groups contain either gene-associated or anonymous markers localized to cosmids that have been assigned to specific canine chromosomes by FISH. These 14 linkage groups contain 150 microsatellite markers and allow us to assign 40% of the linkage groups to specific canine chromosomes. This new version of the map is of sufficient density and characterization to initiate mapping of traits of interest.

Animals↗
PubMed1999

A second-generation genetic linkage map of the domestic dog, Canis familiaris.

Purebred strains, pronounced phenotypic variation, and a high incidence of heritable disease make the domestic dog uniquely suited to complement genetic analyses in humans and mice. A comprehensive genetic linkage map would afford many opportunities in dogs, ranging from the positional cloning of disease genes to the dissection of quantitative differences in size, shape, and behavior. Here we report a canine linkage map with the number of mapped loci expanded to 276 and 10-cM coverage extended to 75-90% of the genome. Most of the 38 canine autosomes are likely represented in the collection of 39 autosomal linkage groups. Eight markers were sufficiently informative to detect linkage at distances of 10-13 cM, yet remained unlinked to any other marker. Taken together, the results suggested a genome size of about 27 M. As in other species, the genetic length varied between sexes, with the female autosomal distance being approximately 1.4-fold greater than that of male meioses. Fifteen markers anchored well-described genes on the map, thereby serving as landmarks for comparative mapping in dogs. We discuss the utility of the current map and outline steps necessary for future map improvement.

Animals↗
PubMed1998

Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans.

Progressive rod-cone degeneration (prcd) is the most widespread hereditary retinal disease leading to blindness in dogs and phenotypically is the canine counterpart of retinitis pigmentosa (RP) in humans. In previous efforts to identify the genetic locus for prcd, the canine homologs for many of the genes causally associated with RP in humans, such as RHO, PDE6B, and RDS/peripherin, have been excluded. In parallel with a recent undertaking to establish a framework map of the canine genome, multiple prcd-informative pedigrees have been typed with a panel of more than 100 anchor loci and microsatellite-based markers. Identification of a linkage group flanking prcd ([TK1, GALK1, prcd]-[MYL4, C09.173, C09.2263]-RARA-C09.250-C09.474-NF1) localizes prcd close to the centromeric end of canine chromosome 9 (CFA9), and excludes RARA as a candidate gene. The conserved synteny of this region of CFA9 and distal human chromosome 17q establishes the potential locus homology of prcd in the dog with RP17, a human retinitis pigmentosa locus for which no gene has yet been identified. Assignment of the prcd disease locus to an identified canine autosome represents a powerful application of the developing canine linkage map in medical genetics. The usefulness of this approach is further demonstrated by identification of the correspondence of the prcd interval to homologous human and mouse chromosomal regions. The rapid progress that is now occurring in the field of canine genetics will expedite the identification of the genes underlying many of the inherited traits and diseases that make the dog a unique asset for the study of mammalian traits.

Animals↗
PubMed1997

Construction of a panel of canine-rodent hybrid cell lines for use in partitioning of the canine genome.

We have constructed a collection of canine-rodent microcell hybrid cell lines by fusion of canine fibroblast microcell donors with immortalized rodent recipient cells. Characterization of the hybrid cell lines using a combination of fluorescence in situ hybridization and PCR analysis of canine microsatellite repeat sequences allowed selection of a panel of hybrids in which most canine chromosomes are represented. Approximately 90% of genetic markers and genes that were tested could be assigned to 1 of 31 anonymous canine chromosome groups, based on common patterns of retention in the hybrid set. Many of these putative chromosome groups have now been validated by linkage analysis. This panel of cell lines provides a tool for development of genetic, physical, and comparative maps of the canine genome.

Animals↗
PubMed1997

A linkage map of the canine genome.

A genetic linkage map of the canine genome has been developed by typing 150 microsatellite markers using 17 three-generation pedigrees, composed of 163 F2 individuals. One hundred and thirty-nine markers were linked to at least one other marker with a lod score > or = 3.0, identifying 30 linkage groups. The largest chromosome had 9 markers spanning 106.1 cM. The average distance between markers was 14.03 cM, and the map covers an estimated 2073 cM. Eleven markers were informative on the mapping panel, but were unlinked to any other marker. These likely represent single markers located on small, distinct canine chromosomes. This map will be the initial resource for mapping canine traits of interest and serve as a foundation for development of a comprehensive canine genetic map.

Animals↗
PubMed1997

Variability of canine microsatellites within and between different dog breeds.

Polymorphic animal microsatellites have proved valuable genetic markers. For this project, the variability of 19 canine microsatellite loci was examined within and between three pure breeds of dog: Greyhounds, Labradors, and German Shepherds. The number of alleles, absolute and relative frequencies, and the statistics that express polymorphism within a breed were determined. The evolutionary relationships among these closely related dog breeds were estimated by genetic distance measures developed for use with microsatellite loci. According to the pairwise genetic distances, Greyhounds and German Shepherds had longer diverse evolutionary histories than Greyhounds and Labradors or Labradors and German Shepherds. Although a few breed-specific alleles were observed, the significant differences between breeds are in their relative frequencies and distribution of the alleles across a locus. None of the three pure dog breeds corresponds to Hardy-Weinberg equilibrium. A considerable reduction in intrapopulation variation was observed within three pure breeds, compared with the population of individuals belonging to 15 dog breeds. This reduction was especially pronounced in the Greyhound breed, which expressed the lowest degree of variation. Intrapopulation variations of Labradors and German Shepherds did not differ significantly, that of Labradors being only slightly higher. The intra-species variation of dogs is lower than in humans, mouse, or rat, but similar to that in domestic animals, probably reflecting similarly high inbreeding coefficients. However, some highly informative loci were common to all dog breeds tested so far. Such population data are necessary for mapping studies and linkage analysis in dogs.

Alleles↗
PubMed1996

A class of highly polymorphic tetranucleotide repeats for canine genetic mapping.

We have identified and characterized a new class of polymorphic markers for the canine genome from a simple tetranucleotide repeat sequence, (GAAA)n. Genetic markers derived from this repeat are highly polymorphic compared with other canine microsatellites, yet are stable enough to be useful for following Mendelian inheritance in multigeneration pedigrees. We show further that (GAAA)n repeats are distributed throughout the canine genome and occur with sufficient frequency to be useful in the development of a framework map of the canine genome.

Animals↗
PubMed1993

Isolation and characterization of microsatellites from the canine genome.

Microsatellite sequences comprising (dC-dA)n.(dG-dT)n repeats have been isolated from canine libraries and sequenced. Oligonucleotide primers have been synthesized to the microsatellite flanking sequences and used in the polymerase chain reaction to amplify those loci from genomic DNA. The degree of polymorphism of each microsatellite was estimated in a set of unrelated dogs. It is concluded that of the 10 loci studied, nine are sufficiently polymorphic to be useful in genetic studies.

Animals↗