Sereth H, Shoshani T, Bashan N, Kerem B S
Genetics Department, Hebrew University of Jerusalem, Israel.
Hum Genet. 1993 Oct 1;92(3):289-95. doi: 10.1007/BF00244474.
The major cystic fibrosis (CF) mutation, delta F508, is associated with one haplotype (B) determined by the two polymorphic markers, XV2C and KM19. This haplotype is rare (15%) among non-CF chromosomes. Its frequency among non-delta F508 CF chromosomes is 50% with variation between populations. One hypothesis for the high frequency of CF haplotype B chromosomes suggests that there was a selective advantage for CF mutations on this specific "background" as a result of epistatic selection at other closely linked loci. Since the XV2C and KM19 markers are located 200 kb 5' to the CF gene and span only 60 kb, an extended haplotype analysis was needed to test this hypothesis. Haplotypes were determined for 183 CF and 120 non-CF Israeli chromosomes at the XV2C and KM19 loci and at three intragenic polymorphic sites (GATT in intron 6A, TUB18 in intron 19, and 24M in exon 24). Among the studied chromosomes the frequency of non-delta F508 CF chromosomes associated with haplotype B was 70% (88% among Ashkenazi CF chromosomes). Nine mutations (delta F508, W1282X, G542X, N1303K, 3849 + 10 kb C-->T, Q359K/T360K, S549I, S549R, and 1717-1G-->A) were identified among the studied chromosomes. These mutations accounted for 96% of CF chromosomes of Ashkenazi origin. Haplotype B was associated with seven of these (delta F508, W1282X, G542X, N1303K, Q359K/T360K, S549R, and 1717-1G-->A). The extended haplotype analysis revealed that in five of the seven mutations associated with the haplotype B, 97% of the chromosomes shared the same intragenic haplotype, 212. The variation found in 3% of the chromosomes was only in the GATT repeat. Two mutations, W1282X and 1717-1G-->A, were associated with a completely different intragenic haplotype, 121. The results of this study indicate that grouping of CF chromosome by haplotype analysis spanning a small extragenic region might not be sufficient. In addition, the results of the extended haplotype analysis indicate that all the studied CF chromosomes that carry the same mutation derived from the same origin. Furthermore, the results indicate that the majority of the CF mutations are associated with the same extended haplotype, supporting the selective advantage hypothesis.
囊性纤维化（CF）的主要突变，即ΔF508，与由两个多态性标记XV2C和KM19确定的一种单倍型（B）相关。这种单倍型在非CF染色体中很罕见（15%）。其在非ΔF508 CF染色体中的频率为50%，不同人群之间存在差异。关于CF单倍型B染色体高频率的一种假说认为，由于其他紧密连锁位点上的上位性选择作用，在这个特定的“背景”上CF突变具有选择优势。由于XV2C和KM19标记位于CF基因5'端200 kb处，跨度仅60 kb，因此需要进行扩展单倍型分析来检验这一假说。在XV2C和KM19位点以及三个基因内多态性位点（内含子6A中的GATT、内含子19中的TUB18和外显子24中的24M）确定了183条CF以色列染色体和120条非CF以色列染色体的单倍型。在所研究的染色体中，与单倍型B相关的非ΔF508 CF染色体的频率为70%（在德系犹太裔CF染色体中为88%）。在所研究的染色体中鉴定出9种突变（ΔF508、W1282X、G542X、N1303K、3849 + 10 kb C→T、Q359K/T360K、S549I、S549R和1717 - 1G→A）。这些突变占德系犹太裔起源CF染色体的96%。单倍型B与其中7种突变相关（ΔF508、W1282X、G542X、N1303K、Q359K/T360K、S549R和1717 - 1G→A）。扩展单倍型分析显示，在与单倍型B相关的7种突变中的5种中，97%的染色体共享相同的基因内单倍型212。在3%的染色体中发现的变异仅存在于GATT重复序列中。两种突变W1282X和1717 - 1G→A与完全不同的基因内单倍型121相关。本研究结果表明，通过跨越一个小的基因外区域的单倍型分析对CF染色体进行分组可能并不充分。此外，扩展单倍型分析结果表明，所有携带相同突变的所研究CF染色体都源自同一来源。而且，结果表明大多数CF突变与相同的扩展单倍型相关，支持了选择优势假说。
