Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism
Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism
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DOI：
10.1136/jmg.37.10.752
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发表时间：
2000-10-01
影响因子：
4
通讯作者：
Hurles, ME
中科院分区：
文献类型：
--
作者：
Blanco, P;Shlumukova, M;Hurles, ME
Y 染色体为研究人类基因组内的突变过程提供了独特的机会，与染色体间重组的混杂效应脱钩。有人提出，Y 上某些分散重复的密度增加可以解释不育男性中相对于单核苷酸突变的致病性微缺失的高频率。此前，我们将 AZFa 微缺失的断点定位在两个高度同源的完整人内源逆转录病毒序列 (HERV) 附近，相距 700 kb。在这里，我们通过跨断点测序表明，微缺失发生在 HERV 之间高度同源的片段内。此外，我们发现 HERV 之间发生了反复的双交换，导致一个 HERV 的 1.5 kb 插入丢失，这是有史以来第一个 Y 染色体多态性（12f2 缺失）的基础事件。该事件产生明显更长的绝对同源片段，因此可能导致进一步染色体内重组的倾向增加。因此，这两个 HERV 序列之间的染色体内串扰可能导致均质序列转换或微缺失，从而导致男性不育。这代表了 AZFa 缺失的一个主要子类。
The Y chromosome provides a unique opportunity to study mutational processes within the human genome, decoupled from the confounding effects of interchromosomal recombination. It has been suggested that the increased density of certain dispersed repeats on the Y could account for the high frequency of causative microdeletions relative to single nucleotide mutations in infertile males. Previously we localised breakpoints of an AZFa microdeletion close to two highly homologous complete human endogenous retroviral sequences (HERV), separated by 700 kb. Here we show, by sequencing across the breakpoint, that the microdeletion occurs in register within a highly homologous segment between the HERVs. Furthermore, we show that recurrent double crossovers have occurred between the HERVs, resulting in the loss of a 1.5 kb insertion from one HERV, an event underlying the first ever Y chromosomal polymorphism described, the 12f2 deletion. This event produces a substantially longer segment of absolute homology and as such may result in increased predisposition to further intrachromosomal recombination. Intrachromosomal crosstalk between these two HERV sequences can thus result in either homogenising sequence conversion or a microdeletion causing male infertility. This represents a major subclass of AZFa deletions.