Dr. Ostranders research interests are in the area of genetic mapping and genomics. We have two main areas of study. First, we are mapping and identifying genetic variants that increase susceptibility to breast and prostate cancer in humans. Both family and population-based studies are underway. Second, we are interested in the development of the canine system for understanding the role of genetic variation in complex traits. Traits of interest include those related to both disease susceptibility and morphology. ? ? Recently, we completed a genome wide scan of 255 human prostate cancer families and identified several loci of interest. Stratification of our now complete dataset by clinical features of disease and family history data suggests multiple loci of interest that are currently the focus of extensive follow-up and fine mapping studies. Particular emphasis this year has been on chromosomes 11, 8 and 20. In addition, we have completed genotyping of approximately 750 single nucleotide polymorphisms (SNPs) that interrogate over 100 candidate genes for association with prostate cancer risk and progression in a large population-based, case control study of middle aged men. Analysis of these data is ongoing and will highlight variants for more detailed study. We have also participated in several meta analysis with the International Consortium of Prostate Cancer Genetics (ICPCG) to identify loci most likely to be relevant for susceptibility to aggressive forms of disease. As our recent individual and joint publications in journals such as Human Molecular Genetics illustrate, loci on chromosome 20 and 8 form the major focus of our family mapping studies at this time. ? ? With regard to breast cancer we have focused on understanding the role of the breast cancer susceptibility genes BRCA1 and BRCA2 in women drawn from the general population. Our most recent collaborative study has focused on a large data set of nearly 3000 women, nearly 13 of whom are African American, to define profiles of women likely to be at increased risk for being a BRCA1 or BRCA2 carrier. The resulting paper, published in Cancer Research, examined the data set for family history profiles including number and type of relatives, age of diagnosis of cases and affected relatives, and occurrence of ovarian cancer in determining the profiles of women at risk from the general population for being BRCA12 carriers. We are also taking an evolutionary approach to understanding the role of missense changes in BRCA1BRCA2, with a long term goal of identifying subtle variants of low genetic penetrance that are associated with increased disease risk. Towards this end we are working on the development of a yeast based functional assay for assessing the significance of missense changes that may play a role in disease susceptibility. ? ? Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. With regard to morphology we have identified a gene, IGF-1, that plays a role in distinguishing body size in dogs. A single ancient allele has been under strong selection in small dog breeds and, as was described in a high profile paper in Science, plays a major role in controlling overall body size in dog breeds. Several other loci identified from the same initial scan are currently under study. ? ? In addition to body size we are interested in other aspects of canine morphology including leg length and width, head shape, and musculature. In a paper featured in PloS Genetics we recently showed that a mutation in the myostatin gene is responsible for increased musculature in the whippet dog. Dogs with one copy of the mutation show a modest increase in fast twitch muscles while those with two are very heavily muscled, the so called bully whippet. This study highlighted the need for extensive studies of population stratification in dogs, which if unchecked, may lead to erroneous conclusions and false positive results. ? ? With regard to disease gene mapping we have been interested in taking advantage of the population structure of modern dogs to improve power for whole genome association studies. We have completed an expanded study of nearly 135 dog breeds and used clustering algorithms to better understand the relationship of the breeds one to another. Our data suggests five major clusters dominate the modern domestic dog. This data is useful for grouping affected dogs of different breeds which may share a common ancient disease allele for fine mapping studies following initial findings of linkage. We demonstrated the utility of this approach in a recent paper in which we identified the mutation for collie eye anomaly, a disorder of herding breeds that as features reminiscent of human macular degeneration. ? ? We have also begun a series of whole genome association studies aimed at finding genes for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma of the bladder in the Scottish terrier and west highland white terrier, malignant histiocytosis in the Bernese mountain dog and squamous cell carcinoma of the digit in the poodle and the giant schnauzer. We have successfully mapped loci for Addisons disease and osteoarthritis in the Portuguese water dog. We have also had suggestive evidence for linkage for hip dysplasia in the same breed. ? ? In summary, our work is aimed at understanding the role of genetic variation in changing phenotypes related to both morphology and disease susceptibility. In humans our studies focus on two cancers, breast and prostate and rely on both family-based linkage studies and whole genome association studies. In the canine system we continue to explore the organization of the genome. We are applying our findings to studies of disease susceptibility, with an emphasis on cancer, and to understanding the portfolio of genes important in growth regulation.
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