Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot
Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot
复制标题
DOI：
10.1038/ng910
复制
发表时间：
2002-07-01
期刊：
影响因子：
30.8
通讯作者：
Neumann, R
中科院分区：
文献类型：
--
作者：
Jeffreys, AJ;Neumann, R
人类DNA多样性最终产生于生殖系突变，这种突变产生了新的单倍型，可以通过减数分裂重组重新洗牌。正反交叉产生重组单倍型，但不应影响种群中等位基因的频率。我们在主要组织相容性复合体(1)的重组热点上展示了交叉不对称性，由此精子中的相互交换映射到热点中的不同位置。我们在热点中心发现了一个单核苷酸多态，并表明，当杂合时，它似乎足以导致这种不对称，显然是通过影响高度定位的交叉启动的效率。因此，杂合子的交叉伴随着有偏见的基因转换，最有可能发生的是缺口修复，这也可以通过修复延长的缺口来影响附近的多态。其结果是大量过度传递重组抑制等位基因和邻近标记到交叉产品。计算机模拟表明，这种减数分裂驱动，尽管在种群水平上很弱，但足以有利于重组抑制变体的最终固定。这些发现为人类交叉热点相对均匀的宽度提供了解释，并表明热点可能通常容易因减数分裂驱动而灭绝(3)。
Human DNA diversity arises ultimately from germline mutation that creates new haplotypes that can be reshuffled by meiotic recombination. Reciprocal crossover generates recombinant haplotypes but should not influence the frequencies of alleles in a population. We demonstrate crossover asymmetry at a recombination hot spot in the major histocompatibility complex(1), whereby reciprocal exchanges in sperm map to different locations in the hot spot. We identify a single-nucleotide polymorphism at the center of the hot spot and show that, when heterozygous, it seems sufficient to cause this asymmetry, apparently by influencing the efficiency of highly localized crossover initiation. As a consequence, crossovers in heterozygotes are accompanied by biased gene conversion, most likely occurring by gap repair(2), that can also affect nearby polymorphisms through repair of an extended gap. The result is substantial over-transmission of the recombination-suppressing allele and neighboring markers to crossover products. Computer simulations show that this meiotic drive, although weak at the population level, is sufficient to favor eventual fixation of the recombination-suppressing variant. These findings provide an explanation for the relatively uniform widths of human crossover hot spots and suggest that hot spots may be generally prone to extinction by meiotic drive(3).