Campbell Catarina, Mitui Midori, Eng Laura, Coutinho Gabriela, Thorstenson Yvonne, Gatti Richard A
Department of Pathology, University of California Los Angeles, Los Angeles, California 90095-1732, USA.
Hum Mutat. 2003 Jan;21(1):80-5. doi: 10.1002/humu.10156.
Due to the large size (150 kb) of the ataxia-telangiectasia mutated (ATM) gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia (A-T) is labor intensive. We compared the SNP and STR haplotypes of A-T patients from varying ethnicities who were carrying common ATM mutations. We used SSCP to determine SNP haplotypes. To our surprise, all of the most common ATM mutations in our large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predated STR haplotypes but not SNP haplotypes. We conclude that these frequently observed ATM mutations are not hot spots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. We estimate this approach will identify approximately 30% of mutations in A-T patients across all ethnic groups.
由于共济失调毛细血管扩张症突变（ATM）基因规模较大（150 kb）且存在400多种突变，因此在共济失调毛细血管扩张症（A-T）患者中识别突变需要耗费大量人力。我们比较了携带常见ATM突变的不同种族A-T患者的单核苷酸多态性（SNP）和短串联重复序列（STR）单倍型。我们使用单链构象多态性（SSCP）来确定SNP单倍型。令我们惊讶的是，在我们这个多民族的大型队列中，所有最常见的ATM突变都与特定的SNP单倍型相关，而STR单倍型则各不相同，这表明ATM突变早于STR单倍型出现，但并非早于SNP单倍型。我们得出结论，这些经常观察到的ATM突变并非热点突变，而是仅发生过一次，并随着时间传播到了不同的种族群体。更一般地说，SNP和STR单倍型分型相结合可作为一种筛查策略，通过首先确定祖先SNP和STR单倍型来识别其他大基因中的突变，从而识别特定的奠基者突变。我们估计这种方法将识别出所有种族A-T患者中约30%的突变。
