QTL mapping for genes regulating apoptosis capacity

描述（申请人提供）：细胞凋亡是一个高度保守的、持续的非炎性细胞死亡的生理过程，细胞凋亡的失调已被证明有助于肿瘤发生过程的开始和进展。细胞凋亡能力的变化预计会影响个体癌症的风险和进展，更好地了解个体之间细胞凋亡能力的变化可能有助于各种疾病的预后和治疗。然而，细胞凋亡是一个复杂的过程，涉及数百种蛋白质，并由多个冗余水平组成，这使得通过体外实验和动物模型在分子水平上解剖决定细胞凋亡能力的主要参与者是困难和繁琐的。在这里，我们提出了一种替代方法，通过鉴定数量性状位点（QTL）来确定细胞凋亡的主要决定因素，QTL在一系列信息丰富的家族中使用连锁分析来确定细胞凋亡能力。这些细胞凋亡QTL随后将被定位候选基因方法跟踪，该方法只关注目标染色体区域的功能相关基因，从而迅速缩小搜索范围，以促进细胞凋亡能力的变化，并与一般人群中的人类疾病最直接相关。在这项拨款申请中，我们建议使用188个遗传性前列腺癌（HPC）家族的大量数据来研究细胞凋亡能力的遗传变异和决定因素。利用现有的全基因组扫描标记数据集，我们可以系统地识别可能包含决定个体凋亡能力的基因的染色体区域，而不是主观选择特定基因进行评估。此外，我们可以将细胞凋亡能力的全基因组筛查结果与我们之前对遗传性前列腺癌、临床显著性前列腺癌和所有类型癌症的全基因组筛查结果进行比较，以确定对癌症易感性影响最大的细胞凋亡基因。我们的建议描述了一种新的和有效的方法来鉴定在癌症易感性中起关键作用的细胞凋亡基因。

DESCRIPTION (provided by applicant): Apoptosis is a highly conserved, continuous physiological process for non-inflammatory cell death, and the dysregulation of apoptosis has been shown to contribute to the initiation and progression of the tumorigenesis process. Variations in apoptosis capacity are expected to influence an individual's risk and progression of cancers, and an improved understanding of the variation in apoptosis capacity between individuals is likely to be beneficial in the prognosis and treatment of various diseases. However, apoptosis is a complex process that involves hundreds of proteins and is composed of multiple levels of redundancy, which makes it is difficult and tedious to dissect the major players that determine apoptosis capacity at the molecular level by in vitro experiments and animal models. Here we propose an alternative approach to pinpoint the major determinants of apoptosis through the identification of quantitative trait loci (QTL) that determine apoptosis capacity using a linkage analysis in a collection of informative families. These apoptosis QTL will then be followed up by a positional candidate gene approach that focuses only on the functionally relevant genes in the target chromosomal regions, thus quickly narrowing down the search to genes that contribute to variations in apoptosis capacity and are most directly relevant to human diseases in the general population. In this grant application, we propose to investigate the genetic variations and determinants of apoptosis capacity, using a large collection of 188 hereditary prostate cancer (HPC) families. Using an existing genome-wide scan marker dataset, we can systematically identify chromosomal regions likely to contain genes responsible for determining individuals' apoptosis capacity, in contrast to subjective selection of specific genes for evaluation. Furthermore, we can compare the results from genome-wide screens for apoptosis capacity with the results from our previous genome-wide screens for hereditary prostate cancer, clinically significant prostate cancer, and all types of cancers to identify apoptosis genes that have the greatest impact on cancer susceptibility. Our proposal describes a novel and efficient approach to identify apoptosis genes that are critical in cancer susceptibility.