Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure
Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure
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DOI：
10.1086/342928
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发表时间：
2002-10-01
影响因子：
9.8
通讯作者：
Rozen, S
中科院分区：
文献类型：
--
作者：
Repping, S;Skaletsky, H;Rozen, S
人们普遍认为，人类Y染色体上至少有三个不重叠的区域--AZF α、AZF B和AZF Fc（“无精子因子”a、B和c）--对正常精子发生是必需的。这些间隔是由间质性Y染色体缺失所定义的，这些缺失会损害或消除精子发生。AZFa和AZFc缺失的缺失断点、机制和长度以及受影响基因的清单已经阐明，但A-ZFb或AZFb + AZFc缺失的缺失尚未阐明。我们研究了三个AZFb缺失和八个AZA加AZFc缺失，由STS定义这些间隔。在Y染色体序列的指导下，我们精确地定位了断裂点，并对9个缺失连接点进行了测序。同源重组可以解释这些缺失中的7个，但不能解释其余2个。这一事实和我们发现的断点热点表明，除了同源性的因素，这些缺失。以前认为定义AZFb的缺失被发现从回文P5延伸到回文P1的近端臂，AZZFc内1.5 Mb。因此，它们不定义与AZFc分开的基因组区域。我们还发现A-ZFb加上AZFc的缺失，如通过迄今可用的标准STS测定的，实际上从PS延伸到P1的远端臂和备用远端AZFc。这两类缺失都是大规模的：P5/近端P1缺失涵盖高达6.2 Mb，删除32个基因和转录本; P5/远端P1缺失涵盖高达7.7 Mb，删除42个基因和转录本。据我们所知，这些是所有人类间质缺失中最大的缺失连接和完整的间插序列。相关表型仅限于生精障碍，表明Y染色体受影响区域的功能显著特化。
It is widely believed that at least three nonoverlapping regions of the human Y chromosome-AZFa, AZFb, and AZFc ("azoospermia factors" a, b, and c)-are essential for normal spermatogenesis. These intervals are defined by interstitial Y-chromosome deletions that impair or extinguish spermatogenesis. Deletion breakpoints, mechanisms, and lengths, as well as inventories of affected genes, have been elucidated for deletions of AZFa and of AZFc but not for deletions of A-ZFb or of AZFb plus AZFc. We studied three deletions of AZFb and eight deletions of AZA plus AZFc, as assayed by the STSs defining these intervals. Guided by Y-chromosome sequence, we localized breakpoints precisely and were able to sequence nine of the deletion junctions. Homologous recombination can explain seven of these deletions but not the remaining two. This fact and our discovery of breakpoint hotspots suggest that factors in addition to homology underlie these deletions. The deletions previously thought to define AZFb were found to extend from palindrome P5 to the proximal arm of palindrome P1, 1.5 Mb within AZZFc. Thus, they do not define a genomic region separate from AZFc. We also found that the deletions of A-ZFb plus AZFc, as assayed by standard STSs heretofore available, in fact extend from PS to the distal arm of P1 and spare distal AZFc. Both classes of deletions are massive: P5/proximal-P1 deletions encompass up to 6.2 Mb and remove 32 genes and transcripts; P5/distal-P1 deletions encompass up to 7.7 Mb and remove 42 genes and transcripts. To our knowledge, these are the largest of all human interstitial deletions for which deletion junctions and complete intervening sequence are available. The restriction of the associated phenotype to spermatogenic failure indicates the remarkable functional specialization of the affected regions of the Y chromosome.