IBD MAPPING & PATTERN OF HUMAN MEIOTIC RECOMBINATION

描述(申请人提供)：本次续展申请的重点是DNA序列变异。我们的目标是继续开发一种称为直接IBD作图的作图方法，并研究人类减数分裂重组的模式。改变的重组与非分离有关，这是非整倍体的主要原因。 首先，直接IBD作图是一种允许识别相关个体之间共享的基因组区域的方法，而不需要逐个标记的基因分型。在相关个体之间共享相同序列的大DNA片段(可能代表IBD DNA片段)在一种称为基因组错配扫描的过程中被浓缩。然后通过杂交将选定的DNA片段映射到基因组DNA微阵列上。在过去的几年里，我们已经优化了步骤，并为直接绘制IBD图谱创建了必要的资源。接下来，我们将通过绘制CEPH家族中个体之间共享的IBD区域来验证该程序，并将简化各种步骤，使直接IBD映射可以成为高通量映射的工具。其次，在IBD直接定位工作的刺激下，我们已经开始描述人类减数分裂重组的模式。在这次更新申请中，我们将扩大该项目的范围，以表征人类重组率的变异，并绘制这种变异的遗传决定因素图。 这一建议的目的如下：1.开发直接IBD作图，一种不需要基因分型的高分辨率身份-血统作图方法。2.描述人类重组率的自然变异。3.绘制人类总重组率自然变异的遗传决定因素图。 我们期望这项研究的结果将提供一种比现有方法更有效的稳健映射方法。它还将使人们深入了解人类减数分裂重组的模式，这是导致遗传多样性和不分离风险的关键过程。

DESCRIPTION (provided by applicant): The focus of this renewal application is DNA sequence variation. Our goal is to continue to develop a mapping method known as direct IBD mapping and to study the pattern of meiotic recombination in humans. Altered recombination is associated with non-disjunction, the major cause of aneuploidy. First, direct IBD mapping is a method that allows identification of genomic regions shared between related individuals without marker-by-marker genotyping. Large DNA segments shared identical in sequence (likely representing IBD DNA fragments) between related individuals are enriched in a procedure known as genomic mismatch scanning. The selected DNA fragments are then mapped by hybridization onto a genomic DNA microarray. In the last several years, we have optimized the steps and created the necessary resources for direct IBD mapping. Next, we will validate the procedure by mapping the IBD regions shared between individuals in CEPH families and will streamline various steps so that direct IBD mapping can become a tool for high-throughput mapping. Second, stimulated by the work on direct IBD mapping, we have begun to characterize the pattern of meiotic recombination in humans. In this renewal application, we will expand the scope of the project to characterize the variation in human recombination rates and map the genetic determinants of this variation. This proposal has the following aims: 1. Develop direct IBD mapping, a high-resolution identity-by-descent mapping method that does not require genotyping. 2. Characterize natural variation in recombination rate in humans. 3. Map the genetic determinants of natural variation in total recombination rate in humans. We expect the results from this study will provide a robust mapping method that is more efficient than current methods. It will also give insights into the pattern of human meiotic recombination, a key process that contributes to genetic diversity and to risk of non-disjunction.