Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements
Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements
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DOI：
10.1086/319506
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发表时间：
2001-04-01
影响因子：
9.8
通讯作者：
Zuffardi, O
中科院分区：
文献类型：
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作者：
Giglio, S;Broman, KW;Zuffardi, O
嗅觉受体基因超家族是哺乳动物基因组中最大的家族。几个人类OR基因以大于或等于10个成员的簇出现在几乎所有人类染色体上，并且一些染色体包含多于一个簇。我们证明，通过实验和计算机数据，两个OR基因簇在8 p之间的不平等的交叉是负责形成三个经常性的染色体大重排和亚显微倒置多态性。前两个大重排是8 p的反向重复，inv dup（8 p），其与独特的表型相关，以及额外标记染色体，+der（8）（8p23.1pter），其也是一种复发性重排，与轻微异常相关。我们证明它是inv dup（8 p）的倒数。第三个宏报告是与心脏缺陷相关的复发性8 p23间质缺失。由于inv dup（8 p）始终起源于母体减数分裂，我们通过两个8 p-OR基因簇之间的探针，研究了8名inv dup（8 p）受试者母亲和1名+der（8）受试者母亲的母体8号染色体。所有的母亲都是杂合的8 p亚显微倒位，由8 p-OR基因簇界定，并存在于杂合状态，在26%的欧洲血统的人口。因此，倒位杂合性可能导致对不等重组的敏感性，导致形成inv dup（8 p）或其倒数产物+der（8 p）。Yp倒位多态性是XX男性和XY女性中PRKX/PRKY易位的优先背景，在Yp倒位多态性之后，OR-8 p倒位是第二个赋予形成常见染色体重排的易感性的基因组多态性。因此，有可能开发出具有染色体重排后代的个体风险的概况。
The olfactory receptor (OR)-gene superfamily is the largest in the mammalian genome. Several of the human OR genes appear in clusters with greater than or equal to 10 members located on almost all human chromosomes, and some chromosomes contain more than one cluster. We demonstrate, by experimental and in silico data, that unequal crossovers between two OR gene clusters in 8p are responsible for the formation of three recurrent chromosome macrorearrangements and a submicroscopic inversion polymorphism. The first two macrorearrangements are the inverted duplication of 8p, inv dup(8p), which is associated with a distinct phenotype, and a supernumerary marker chromosome, +der(8)(8p23.1pter), which is also a recurrent rearrangement and is associated with minor anomalies. We demonstrate that it is the reciprocal of the inv dup(8p). The third macrorearrangment is a recurrent 8p23 interstitial deletion associated with heart defect. Since inv dup(8p)s originate consistently in maternal meiosis, we investigated the maternal chromosomes 8 in eight mothers of subjects with inv dup(8p) and in the mother of one subject with +der(8), by means of probes included between the two 8p-OR gene clusters. All the mothers were heterozygous for an 8p submicroscopic inversion that was delimited by the 8p-OR gene clusters and was present, in heterozygous state, in 26% of a population of European descent. Thus, inversion heterozygosity may cause susceptibility to unequal recombination, leading to the formation of the inv dup(8p) or to its reciprocal product, the +der(8p). After the Yp inversion polymorphism, which is the preferential background for the PRKX/PRKY translocation in XX males and XY females, the OR-8p inversion is the second genomic polymorphism that confers susceptibility to the formation of common chromosome rearrangements. Accordingly, it may be possible to develop a profile of the individual risk of having progeny with chromosome rearrangements.