Meiotic recombination and flanking marker exchange at the highly unstable human minisatellite CEB1 (D2S90)
Meiotic recombination and flanking marker exchange at the highly unstable human minisatellite CEB1 (D2S90)
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DOI：
10.1086/303015
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发表时间：
2000-08-01
影响因子：
9.8
通讯作者：
Jeffreys, AJ
中科院分区：
文献类型：
--
作者：
Buard, J;Shone, AC;Jeffreys, AJ
长期以来，不平等交换一直被怀疑在串联重复DNA的种系特异性不稳定中起作用，但关于不平等交换的动力学和过程的信息很少。因此，我们表征了与高度不稳定的人类小卫星CEB1的侧翼标记交换相关的新的长度等位基因，该基因在男性生殖系中通过一个复杂的过程发生突变，通常导致等位基因之间重复序列的基因转换。CEB1两侧的DNA富含单核苷酸多态(SNPs)，并显示出广泛的单倍型多样性，这与小卫星附近重组活性的升高一致。这些SNPs被用来直接从精子DNA中回收与侧翼标记交换相关的突变CEB1分子。同时具有近端和远端侧翼标记交换的突变体被证明对CEB1的周转有显著的贡献，并表明阵列的5‘端在减数分裂不等交换中非常活跃。涉及重复序列的等位基因间转移和紧邻侧翼DNA的共转化也很常见，在CEB1的5‘端也是极化的，似乎定义了从重复序列延伸到相邻DNA的转换梯度。虽然许多与完全交换相关的突变导致了简单的重组重复阵列，显示出互惠，但共转化高度偏向于增益，平均而言，更复杂，等位基因重排类似于在大多数精子突变中看到的。这表明，不同的重组加工路径一方面产生CEB1中的简单交叉，另一方面产生复杂的转换，有时延伸到DNA侧翼。
Unequal crossover has long been suspected to play a role in the germline-specific instability of tandem-repeat DNA, but little information exists on the dynamics and processes of unequal exchange. We have therefore characterized new length alleles associated with flanking-marker exchange at the highly unstable human minisatellite CEB1, which mutates in the male germline by a complex process often resulting in the gene conversion-like transfer of repeats between alleles. DNA flanking CEB1 is rich in single-nucleotide polymorphisms (SNPs) and shows extensive haplotype diversity, consistent with elevated recombinational activity near the minisatellite. These SNPs were used to recover mutant CEB1 molecules associated with flanking-marker exchange, directly from sperm DNA. Mutants with both proximal and distal flanking-marker exchange were shown to contribute significantly to CEB1 turnover and suggest that the 5' end of the array is very active in meiotic unequal crossover. Coconversions involving the interallelic transfer of repeats plus immediate flanking DNA were also common, were also polarized at the 5' end of CEB1, and appeared to define a conversion gradient extending from the repeat array into adjacent DNA. Whereas many mutants associated with complete exchange resulted in simple recombinant-repeat arrays that show reciprocity, coconversions were highly gain-biassed and were, on average, more complex, with allele rearrangements similar to those seen in the bulk of sperm mutants. This suggests distinct recombination-processing pathways producing, on the one hand, simple crossovers in CEB1 and, on the other hand, complex conversions that sometimes extend into flanking DNA.