Antonarakis S E, Orkin S H, Kazazian H H, Goff S C, Boehm C D, Waber P G, Sexton J P, Ostrer H, Fairbanks V F, Chakravarti A
Proc Natl Acad Sci U S A. 1982 Nov;79(21):6608-11. doi: 10.1073/pnas.79.21.6608.
To investigate whether recurrent mutation has contributed to the high frequency of the beta E-globin gene in Southeast Asia, we used the haplotypes at three polymorphic restriction sites within and to the 3' side of the beta-globin gene to predict the framework of 23 beta E-globin genes. These haplotypes suggested that beta E-globin genes are present in two different beta-globin gene frameworks. DNA sequence determination of one gene representing each framework demonstrated that the same mutation (GAG leads to AAG at codon 26) was present in both frameworks. Moreover, the frameworks differed at three nucleotide positions known to be polymorphic in Mediterraneans. These polymorphic sites are located 70 nucleotides to the 5' side of the beta E mutation and 382 and 1032 nucleotides to the 3' side of it. The existence of the beta E mutation in these two beta-globin gene frameworks can be explained by (i) recurrent mutation giving rise to beta E-globin, (ii) a double crossing-over event, or (iii) two single crossing-over events. Mathematical analysis suggests that the first alternative, recurrent mutation of G leads to A at the first nucleotide of codon 26, is most likely.
为了研究反复突变是否导致了东南亚β珠蛋白基因的高频率出现，我们利用β珠蛋白基因内部及3'端三个多态性限制位点的单倍型来预测23个βE珠蛋白基因的框架。这些单倍型表明βE珠蛋白基因存在于两种不同的β珠蛋白基因框架中。对代表每种框架的一个基因进行DNA序列测定表明，两种框架中都存在相同的突变（密码子26处的GAG突变为AAG）。此外，这两种框架在已知地中海人群中具有多态性的三个核苷酸位置上存在差异。这些多态性位点位于βE突变位点5'端70个核苷酸处以及其3'端382和1032个核苷酸处。这两种β珠蛋白基因框架中βE突变的存在可以通过以下方式解释：（i）反复突变产生βE珠蛋白；（ii）双交换事件；或（iii）两个单交换事件。数学分析表明，第一种可能性，即密码子26第一个核苷酸处的G反复突变为A，最有可能。
