Genetic Epidemiology of Telomere Maintenance

端粒由长TTAGGG核苷酸重复序列和染色体末端的相关蛋白组成，对维持染色体完整性至关重要。我们已经证明，与其他类型的基因相比，端粒维持途径中编码关键蛋白质的基因的核苷酸多样性是有限的。它们在物种之间也是高度保守的。由于这些基因似乎受到严格的遗传约束，这些基因的种系遗传变异（即单核苷酸多态性，snp）可能是癌症或其他疾病的一个重要危险因素。对端粒维持的12个关键基因的群体遗传学和遗传变异的进一步研究已经开始。这些研究基于CGF的SNP 500和SNP多样性面板产生的数据，并将进一步定义世界范围内的遗传多样性和端粒生物学中重要基因的连锁不平衡程度。方法学研究正在进行评估端粒长度在不同的目标组织，由不同的实验室方法确定。这些将构成对端粒生物学至关重要的基因的种系遗传变异研究的基础，作为健康个体和癌症个体端粒长度的潜在遗传标记。端粒长度和癌症风险的病例对照研究已经开始，目标人群是乳腺癌和前列腺癌。我们对这些基因正常遗传变异的理解将用于鉴定在先天性角化不良症（一种遗传性骨髓衰竭综合征，IBMFS）中重要的新基因，这种疾病的特征是指甲异常、网状色素沉着、口腔白斑、端粒短和再生障碍性贫血的显著风险。通过NCIs的IBMFS研究，评估DC家族已知基因（DKC1、TERC和TERT）的突变，并进一步研究那些没有已知突变的家族，使用各种旨在寻找新基因的实验室策略。

Telomeres consist of long TTAGGG nucleotide repeats and associated proteins at the ends of chromosomes that are essential to maintaining chromosomal integrity. We have shown that nucleotide diversity in genes coding for critical proteins in the telomere maintenance pathway is limited when compared with other types of genes. They are also highly conserved between species. Because these genes appear to be under tight genetic constraint, it is possible that germ-line genetic variation (i.e. single nucleotide polymorphisms, SNPs) in these genes could be a significant risk factor for cancer or other diseases.Further investigation into the population genetics and genetic variation of twelve genes critical in telomere maintenance has begun. These studies are based upon data generated in CGF's SNP 500 and SNP Diversity Panels, and will further define the world-wide genetic diversity and the extent of linkage disequilibrium of genes important in telomere biology. Methodological studies are underway to evaluate telomere length in diverse target tissues as determined by differing laboratory methods. These will form the basis for studies of germ-line genetic variants in genes critical in telomere biology as potential genetic markers for telomere length in healthy individuals and in individuals with cancer. Case-control studies of telomere length and cancer risk have been initiated, targeting populations with breast and prostate cancer. Our understanding of normal genetic variation in these genes will be used to identify new genes important in dyskeratosis congenita, an inherited bone marrow failure syndrome (IBMFS) characterized by abnormal nails, lacey reticular pigmentation, oral leukoplakia, short telomeres and significant risk of aplastic anemia. Through the NCIs IBMFS study, families with DC are evaluated for mutations known genes (DKC1, TERC and TERT) and those without a known mutation are studied further, using a variety of laboratory strategies aimed at finding new genes.