Lange Julian, Skaletsky Helen, van Daalen Saskia K M, Embry Stephanie L, Korver Cindy M, Brown Laura G, Oates Robert D, Silber Sherman, Repping Sjoerd, Page David C
Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
Cell. 2009 Sep 4;138(5):855-69. doi: 10.1016/j.cell.2009.07.042.
Massive palindromes in the human Y chromosome harbor mirror-image gene pairs essential for spermatogenesis. During evolution, these gene pairs have been maintained by intrapalindrome, arm-to-arm recombination. The mechanism of intrapalindrome recombination and risk of harmful effects are unknown. We report 51 patients with isodicentric Y (idicY) chromosomes formed by homologous crossing over between opposing arms of palindromes on sister chromatids. These ectopic recombination events occur at nearly all Y-linked palindromes. Based on our findings, we propose that intrapalindrome sequence identity is maintained via noncrossover pathways of homologous recombination. DNA double-strand breaks that initiate these pathways can be alternatively resolved by crossing over between sister chromatids to form idicY chromosomes, with clinical consequences ranging from spermatogenic failure to sex reversal and Turner syndrome. Our observations imply that crossover and noncrossover pathways are active in nearly all Y-linked palindromes, exposing an Achilles' heel in the mechanism that preserves palindrome-borne genes.
人类Y染色体上的大量回文序列含有对精子发生至关重要的镜像基因对。在进化过程中，这些基因对通过回文序列内部、臂间重组得以保留。回文序列内部重组的机制以及有害影响的风险尚不清楚。我们报告了51例等臂双着丝粒Y染色体（idicY）患者，这些染色体是由姐妹染色单体上回文序列的相对臂之间的同源交叉形成的。这些异位重组事件几乎发生在所有Y连锁的回文序列上。基于我们的发现，我们提出回文序列内部的序列同一性是通过同源重组的非交叉途径维持的。启动这些途径的DNA双链断裂可通过姐妹染色单体之间的交叉来替代解决，从而形成idicY染色体，其临床后果从生精失败到性反转和特纳综合征不等。我们的观察结果表明，交叉和非交叉途径在几乎所有Y连锁的回文序列中都很活跃，这揭示了在保护回文序列携带基因的机制中的一个致命弱点。
