Homology requirements for unequal crossing over in humans.
Homology requirements for unequal crossing over in humans.
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发表时间：
1991-05
期刊：
影响因子：
3.3
通讯作者：
A. Metzenberg;G. Wurzer;T. Huisman;O. Smithies
中科院分区：
文献类型：
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作者：
A. Metzenberg;G. Wurzer;T. Huisman;O. Smithies
为了深入了解体内不等同源重组的机制，通过核苷酸测序和杂交实验检查了人类β-珠蛋白基因簇中同源不等交换产生的基因。研究的天然存在的基因包括一个delta-beta Lepore-Baltimore融合基因，一个delta-beta Lepore-Hollandia融合基因，12个delta-beta Lepore-Boston基因，一个A gamma-beta融合Kenya基因，一个A gamma-G gamma融合基因（三重的中心基因）和一个G gamma-A gamma融合基因。三个Lepore-Boston基因的核苷酸序列的比较表明，它们来自至少两个独立的同源，但不平等的交叉事件，虽然发生在相同的58 bp区域内的交叉。通过与特定寡核苷酸探针杂交，显示了来自不同种族起源的个体的另外9个Lepore-Boston基因，这些基因是通过与测序基因相同区域的交叉产生的。仅在一种情况下发现了伴随同源不相等交换事件的基因转换的证据（尽管在本研究中在其他基因中观察到的一些单核苷酸差异可能以我们目前尚不了解的方式与交换事件相关）。因此，根据这一有限的样本判断，同时发生的基因转换通常与人类体内的同源但不相等的交换无关。重组染色体的多态性限制性位点的β-珠蛋白基因簇的分类表明，Lepore-Boston基因被发现在至少六个不同的单倍型背景。因此，本研究中独立样本的总数至少为6，最多为12。我们已经证明，在至少六个由同源但不相等的体内交换产生的基因中，每个事件都发生在亲本基因之间不间断的相对广泛的区域中。这种偏好不能用一种机制来解释，即在错位的相关但不相同的基因中随机发生交叉。一般来说，交叉发生在特定的一对错配基因的最大可用身份延伸区域中。我们的数据与其他类型的同源重组的研究是一致的，并支持序列同一性，而不是一般的同源性，是同源重组的关键因素的想法。
To gain insight into mechanisms of unequal homologous recombination in vivo, genes generated by homologous unequal crossovers in the human beta-globin gene cluster were examined by nucleotide sequencing and hybridization experiments. The naturally occurring genes studied included one delta-beta Lepore-Baltimore fusion gene, one delta-beta Lepore-Hollandia fusion gene, 12 delta-beta Lepore-Boston genes, one A gamma-beta fusion Kenya gene, one A gamma-G gamma fusion (the central gene of a triplication) and one G gamma-A gamma fusion. A comparison of the nucleotide sequences of three Lepore-Boston genes indicates that they were derived from at least two independent homologous but unequal crossover events, although the crossovers occurred within the same 58-bp region. Nine additional Lepore-Boston genes from individuals of various ethnic origins were shown, by hybridization to specific oligonucleotide probes, to have been generated by a crossover in the same region as the sequenced genes. Evidence for gene conversion accompanying a homologous unequal crossover event was found in only one case (although some of the single nucleotide differences observed in other genes in this study may be related to the crossover events in ways that we do not presently understand). Thus, as judged by this limited sample, concurrent gene conversions are not commonly associated with homologous but unequal exchange in humans in vivo. Classification of the recombinant chromosomes by their polymorphic restriction sites in the beta-globin gene cluster indicated that the Lepore-Boston genes are found in at least six different haplotype backgrounds. Therefore the total number of independent examples in this study is at least 6, and at most 12. We have shown that in at least six cases of genes that have arisen by homologous but unequal crossing over in vivo, each event occurred in a relatively extensive region of uninterrupted identity between the parental genes. This preference cannot be explained by a mechanism whereby crossovers occur at random within misaligned related but not identical genes. In general, crossovers occur in regions that are among the largest available stretches of identity for a particular pair of mismatched genes. Our data are in agreement with those of other types of studies of homologous recombination, and support the idea that sequence identity, rather than general homology, is a critical factor in homologous recombination.