Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications.
Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications.
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对22q11.2中的减数分裂重组分析，该区域经常经历缺失和重复。
DOI：
10.1186/1471-2350-8-14
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发表时间：
2007-04-02
影响因子：
--
通讯作者：
Heine-Suner, Damia
中科院分区：
文献类型：
--
作者：
Torres-Juan, Laura;Rosell, Jordi;Sanchez-de-la-Torre, Manuel;Fibla, Joan;Heine-Suner, Damia
22q11.2缺失综合征是最常见的基因组疾病，估计发生率为1/4000活产。大多数患者（90%）具有相同的3 Mb缺失（通常为缺失区，TDR），其由减数分裂时区域特异性低拷贝重复序列（LCR）之间的异常重组引起。作为第一步的重组率和断点的表征在22q11.2区域内，我们已经构建了一个高分辨率的重组断点地图的基础上系谱分析和基于LD分析的人口为基础的历史重组地图。我们的谱系图允许以高分辨率定位重组断点（潜在的重组热点），并且这种方法已经导致鉴定出5个50 kb或更小（最小8.6 kb）的断点片段，其与历史热点一致。已经表明，导致缺失（和重复）的异常重组是由受影响区域内的等位基因同源异型性（AHR）的低比率引起的。然而，22q11.2区域的重组率估计显示，22q11.2区域或LCR 22 -2（涉及大多数缺失和重复的LCR）内的平均重组率均不显著低于22号染色体平均值。此外，LCR 22 -2，最常涉及重排的重复序列，也是AHR水平最高的LCR 22。此外，我们发现在22q11.2区域的重组事件集群内的家庭。在这种情况下，同一个染色体在一个家族中重组两次;第一次由AHR重组，下一代由NAHR重组，导致个体患del22q11.2综合征。我们在第一个高分辨率的22q11.2区域的系谱图的背景下显示，NAHR在LCR 22内导致重复和缺失，不能完全根据低AHR率的假设来解释。此外，我们发现，AHR重组事件集群内的家庭。如果正常和异常重组是机械相关的，事实上，LCR 22经历频繁的AHR，我们发现22q11.2区域内重组率的家族差异将有明显的健康相关的影响。
The 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs). As a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis. Our pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome. We show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications.
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