Finding Genes for Cancer Susceptibility and Growth Reg

Ostrander博士？S的研究兴趣在基因图谱和基因组学领域。我们有两个主要的研究领域。首先，我们正在绘制和识别增加人类乳腺癌和前列腺癌易感性的基因变异。以家庭和人口为基础的研究正在进行中。其次，我们对犬类系统的发展感兴趣，这两个系统都是为了理解遗传变异在复杂性状中的作用。 最近，我们完成了对255个前列腺癌家系的全基因组扫描，并确定了几个感兴趣的基因座。根据疾病的临床特征和家族史对我们现已完成的数据集进行分层，今年发表的报告显示，多个感兴趣的部位目前是广泛随访的重点。此外，我们已经完成了大约500个单核苷酸多态(SNPs)与前列腺癌风险和进展相关的测试。对这些数据的分析将突出变量，以进行更多和更详细的研究。我们还参与了与国际前列腺癌遗传学联合会(ICPCG)的几项荟萃分析，以确定最可能与侵袭性疾病易感性相关的基因座。正如我们最近联合发表的出版物所表明的那样，这些结果与我们自己的研究小组报告的结果很好地吻合。 关于乳腺癌，我们的重点是了解乳腺癌易感基因BRCA1和BRCA2在普通人群中的作用。我们最新的合作研究集中在近3000名女性的大型数据集上，其中三分之一是非裔美国人，以定义有可能成为BRCA1或BRCA2携带者风险增加的女性的概况。我们还在采用进化论的方法来理解BRCA1/BRCA2错义变化的作用，长期目标是识别与疾病风险增加相关的低遗传外显率的细微变异。最近在《癌症研究》杂志上发表的一篇论文中总结了这些数据的一个子集。 我们和我们的合作者还开发了资源，使我们能够利用人类、啮齿动物和犬的基因组序列来识别在家犬的疾病易感性、行为和形态变异中重要的变异。这些数据体现在最近发表在《自然》杂志上的犬类基因组序列报告中。我们和同事正在利用这些资源确定髋关节发育不良、癌症(膀胱癌、肉瘤、皮肤、淋巴瘤和血管肉瘤)、艾迪生？S病和骨关节炎的基因座。在过去的一年里，我们报告了髋关节发育不良、爱迪生病和骨性关节炎的基因座。我们还看到了这些工具在与保护生物学相关的问题上的应用，并报道了第一个针对狼的SNP分析。 其他犬类研究的重点是通过与犬主、饲养员和养犬俱乐部密切合作，寻找对生长调节重要的基因。我们特别感兴趣的是犬类系统发育的组织和连锁不平衡在定位感兴趣的复杂性状方面的作用。为此，我们已经确定了基因座和序列水平的变异，这些变异处于强大的选择之下，用于调节家犬的整体身体大小，以及从狼到狗的进化转变。我们和我们的合作者今年报告了调节性二型性的基因座。正在进行的研究集中于确定与腿长与腿宽、头骨形状和其他形态特征相关的变异。

Dr. Ostrander?s 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 both understanding the role of genetic variation in complex traits. Recently, we completed a genome wide scan of 255 prostate cancer families and identified several loci of interest. Stratification of our now complete dataset by clinical features of disease and family history, published this year, suggest multiple loci of interest that are currently the focus of extensive follow-up. In addition, we have completed testing of approximately 500 single nucleotide polymorphisms (SNPs) for association with prostate cancer risk and progression. Analysis of these data will highlight variants for additional and 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 joint publications illustrate, these results dovetail well with those reported by our own research group. 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, 1/3 of whom are African American, to define profiles of women likely to be at increased risk for being a BRCA1 or BRCA2 carrier. We are also taking an evolutionary approach to understanding the role of missense changes in BRCA1/BRCA2, with a long term goal of identifying subtle variants of low genetic penetrance that are associated with increased disease risk. A subset of these data were summarized in a recent paper in Cancer Research. We and our collaborators have also developed resources that allows us to utilize the human, rodent and canine genome sequence for identifying variants important in disease susceptibility, behavior, and morphologic variation in the domestic dog. These data are embodied in the recent canine genome sequence report, published in Nature. We and colleagues are using those resources to identify loci for hip dysplasia, cancer (bladder, sarcoma, skin, lymphoma, and hemangiosarcoma), Addison?s disease, and osteoarthritis. In the past year, we reported loci for hip dysplasia, Addison's disease, and osteoarthritis. We have also seen the application these tools to issues related to conservation biology, and reported the first SNP analysis on wolves. Additional canine studies focus on finding genes important in growth regulation by working closely with dog owners, breeders and kennel clubs. We are specifically interested in the organization of the canine phylogeny and the utility of linkage disequilibrium for mapping complex traits of interest. Towards that end we have identified both loci and sequence level variants that are under strong selection for regulating overall body size in the domestic dog and the evolutionary transition from wolf to dog. We and our collaborators reported this year on loci which regulate sexual dimorphism. Ongoing studies focus on identifying variants associated with leg length versus width, skull shape, and other morphologic features.