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E A Ostrander

Publications and source records attributed to E A Ostrander.

At least 55 records · Page 3Linked to original sources
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

Construction and characterization of an eightfold redundant dog genomic bacterial artificial chromosome library.

A large insert canine genomic bacterial artificial chromosome (BAC) library was built from a Doberman pinscher. Approximately 166,000 clones were gridded on nine high-density hybridization filters. Insert analysis of randomly selected clones indicated a mean insert size of 155 kb and predicted 8.1 coverage of the canine genome. Two percent of the clones were nonrecombinant. Chromosomal fluorescence in situ hybridization studies of 60 BAC clones indicated no chimerism. The library was hybridized with dog PCR products representing eight genes (ADA, TNFA, GCA, MYB, HOXA, GUSB, THY1, and TOP1). The resulting positive clones were characterized and shown to be compatible with an eightfold redundant library.

Animals↗
PubMed1999

Origin, genetic diversity, and genome structure of the domestic dog.

Comparative analysis of mammalian genomes provides important insight into the structure and function of genes. However, the comparative analysis of gene sequences from individuals of the same and different species also provides insight into the evolution of genes, populations, and species. We exemplify these two uses of genomic information. First, we document the evolutionary relationships of the domestic dog to other carnivores by using a variety of DNA-based information. A phylogenetic comparison of mitochondrial DNA sequences in dogs and gray wolves shows that dogs may have originated from multiple wolf populations at a time much earlier than suggested by the archaeologic record. We discuss previous theories about dog development and evolution in light of the new genetic data. Second, we review recent progress in dog genetic mapping due to the development of hypervariable markers and specific chromosome paints. Extensive genetic homology in gene order and function between humans and dogs has been discovered. The dog promises to be a valuable model for identifying genes that control morphologic differences between mammals as well as understanding genetically based disease.

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

Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36.

Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region.

Aged↗
PubMed1999

Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer.

One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data.

Age Factors↗
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↗
PubMed1999

Confirmation of prostate cancer susceptibility genes using high-risk families.

Data from many types of studies support the hypothesis that strong familial components are involved in the etiology of prostate cancer. One way to access such genes is through the study of families with multiple affected family members and, in particular, families with individuals affected comparatively early in life. Several prostate cancer susceptibility loci have been described to date. Confirmation of the linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of susceptibility genes. We explore the methodology used to perform such studies and the factors that can limit the ability to confirm linkage results. We report specifically the example of the HPC1 gene on 1q24-25.

Chromosome Mapping↗
PubMed1999

Evaluation of the APOH gene as a positional candidate for prcd in dogs.

PURPOSE: Progressive rod-cone degeneration (prcd) is an autosomal recessive retinal degeneration of dogs characterized by abnormalities in lipid metabolism. It has recently been mapped to the centromeric region of canine chromosome 9, homologous to human 17q, which contains the apolipoprotein H (apoH, protein; APOH, gene) gene involved in lipid metabolism and regulation of triglycerides. The present study was undertaken to evaluate APOH as a positional candidate for prcd. METHODS: Expression of APOH in the retina was examined by reverse transcription-polymerase chain reaction (RT-PCR) and by immunocytochemistry in normal and prcd-affected dogs. The level of apoH in the plasma was determined by western blot analysis. Intragenic polymorphic markers were identified and typed in the prcd pedigree. Canine-rodent hybrid cell lines were analyzed to detect canine APOH. RESULTS: ApoH has been localized to the photoreceptor outer segment layer by immunocytochemistry. Its expression in the retina of normal and prcd-affected dogs was confirmed by RT-PCR. The levels of antihuman apoH cross-reacting material in plasma were similar in all dogs, regardless of disease status. Finally, linkage analysis of the APOH gene with the disease locus in the prcd pedigree detected 3 recombinants among 70 informative offsprings (lod score 15.09 at 0 = 4.3 centimorgan [cM]). CONCLUSIONS: APOH is expressed in the retina and tightly linked to the prcd locus. However, despite its potential role in phenotypes of abnormal lipid metabolism associated with prcd, the gene has been excluded as a primary candidate for prcd by linkage analysis.

Animals↗
PubMed1998

BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history.

CONTEXT: Studies of high-risk families with multiple early-onset cases of breast cancer have been useful for assessing the type and spectrum of germline mutations on the BRCA1 gene, but do not provide guidance to women with modest family history profiles. Thus, studies of women from the general population are needed to determine the BRCA1 mutation frequency in women perceived to be at high risk, and to develop profiles of those most likely to be carriers. OBJECTIVE: To characterize frequency and spectrum of germline BRCA1 mutations in 2 categories of women identified via population-based studies hypothesized to be at increased risk of carrying such mutations: those diagnosed as having breast cancer before age 35 years and those diagnosed before age 45 years who have first-degree breast cancer family history. DESIGN: Study subjects were drawn from 2 population-based case-control studies of breast cancer in young women on the basis of their family history or their age of diagnosis. Cases were younger than 35 years or were younger than 45 years with first-degree family history at the time of breast cancer diagnosis and were ascertained via a population-based cancer registry, and controls (women without breast cancer) were identified via random-digit dialing. SETTING: Three counties in western Washington State. MAIN OUTCOME MEASURE: BRCA1 germline mutations in study subjects identified in DNA from peripheral blood lymphocytes by single-strand conformation polymorphism analysis using primer pairs that span the BRCA1 coding region and intron-exon boundaries. RESULTS: Of 193 women diagnosed as having breast cancer before age 35 years, none of whom were selected on the basis of family history status, 12 (6.2%, 95% confidence interval [CI], 3.2%-10.6%) had germline BRCA1 mutations. In 208 women diagnosed before age 45 years who had first-degree breast cancer family history, 15 (7.2%, 95% CI,4.1%-11.6%) had germline mutations in BRCA1. In both groups, there were variations in mutation frequency noted by age and by family history. Mutation frequency decreased with increasing age of diagnosis. Higher proportions of mutations were seen in cases with at least 1 relative diagnosed as having breast cancer before age 45 years, in cases with greater numbers of affected relatives, and those with ovarian cancer family history. Mutation frequency did not vary by bilateral breast cancer family history. No frameshift or nonsense mutations were observed in 71 control women with a first-degree family history, although missense changes of unknown significance were seen in cases and controls. CONCLUSIONS: Women with BRCA1 germline mutations lacked a common family history profile. Also, a large proportion of the women with a first-degree breast cancer family history and women diagnosed as having breast cancer before age 35 years did not carry germline BRCA1 mutations. Hence, while early-onset disease and a strong breast cancer family history may be useful guidelines for checking BRCA1 status, these findings on women drawn from the general population suggest that it may be difficult to develop BRCA1 mutation screening criteria among women with modest family history profiles.

Adult↗
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↗
PubMed1998

Identification of a RAPD marker linked to progressive rod-cone degeneration in dogs.

Random amplified polymorphic DNA (RAPD) analysis has been used widely in plant and fungi for identification of markers linked to genetic traits and mapping, but its use is limited to identification of intra- and inter-species difference in domestic mammals. We report here identification of a RAPD-derived marker linked to progressive rod-cone degeneration (prcd), an inherited autosomal recessive retinal disease of dogs. A total of 400 standard 10-mer primers were used for amplification by use of DNA samples from normal (+/+) and affected (prcd/prcd) dogs. A single primer was identified which amplified a 1.5-kb DNA fragment only from normal dogs. PCR with longer primers designed from the sequence-characterized amplified region of the 1.5-kb DNA fragment identified a co-dominant multi-allelic polymorphism in the prcd-informative pedigree. Three recombinants were identified among 34 informative offsprings, yielding a LOD score of 5.568 at theta = 0.091. This marker was mapped to two canine-rodent hybrid cell lines in which two genes (canine homologues of human breast cancer 1 susceptibility gene, and cGMP phosphodiesterase gamma-subunit gene), and three anonymous microsatellites have been identified. This is the first reported identification of a RAPD-derived marker with multiple alleles linked to a mammalian disease locus.

Alleles↗
PubMed1998

Polymorphism analysis of four canine MHC class I genes.

We have studied the variability of four structurally complete dog leukocyte antigen (DLA) class I genes, termed DLA-12, -88, -79 and -64, in a population of mixed breed, unrelated dogs. The human HLA and canine DLA loci share a high degree of similarity in terms of gene structure. This analysis focused on the first three exons of each of four complete canine genes. Exons two and three are the major source of polymorphism in the corresponding human genes. In this analysis, DLA-88 was found to be significantly more polymorphic than the other three genes, with 44 distinct alleles observed among 63 mixed breed, unrelated dogs. The remaining genes had between one and four alleles when examined in 25 dogs. This work was carried out as part of an effort to develop an MHC typing system for the dog, which is critical to the further development of preclinical studies of hematopoietic stem cell and solid organ transplantation in the canine model.

Amino Acid Sequence↗
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

Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk.

We analyzed the polymorphic (CAG)n and (GGN)n regions within the androgen receptor gene from participants in a population-based case-control study of prostate cancer in middle-aged (40-64 years) Caucasian men. The associations between repeat lengths and risk of prostate cancer and the effects of confounding and modifying factors, such as age, family history of prostate cancer, and body mass index, were evaluated. DNA was available for 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of (CAG) repeats as a continuous variable was 0.97 [95% confidence interval (CI), 0.92-1.03], suggesting a 3% decrease in risk of prostate cancer for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were men with less than the median number of CAG repeats (< 22) that were younger [< 60 years; relative odds (RO), 1.47; 95% CI, 0.96-2.25], had an affected first-degree relative (RO, 1.59; 95% CI, 0.62-4.14), or were relatively thin (Quetelet index < 24.4; RO, 2.21; 95% CI, 1.07-4.69). Although only the latter result was statistically significant, these results are provocative and support the hypothesis that (CAG)n array length is a predictor of risk for prostate cancer. Similar analyses of (GGN)n showed that with the exception of men with a family history of prostate cancer and those in the highest quartile of body mass index, men with < or = 16 repeats had higher risk estimates than did men with > 16 repeats. Overall, those men who had < or = 16 repeats had a significant elevation in risk (RO, 1.60; 95% CI, 1.07-2.41). When both repeat lengths were considered jointly, the subgroup with two short repeats (CAG, < 22; GGN, < or = 16) had a 2-fold elevation in odds (RO, 2.05; 95% CI, 1.09-3.84) relative to those with two long repeats (CAG, > or = 22; GGN, > 16). These data suggest that determination of both androgen receptor repeats within germ-line DNA may be useful in assessing an individual's risk of developing prostate cancer.

Adenocarcinoma↗