Zhong N, Ye L, Dobkin C, Brown W T
Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
Am J Med Genet. 1994 Jul 15;51(4):405-11. doi: 10.1002/ajmg.1320510421.
Previous studies of founder chromosome effects in fragile X have been based on linkage disequilibrium with either FRAXAC1 or DXS548 alone or combined with FRAXAC2. Recently, we found no linkage disequilibrium of FMR-1 with FRAXAC2, but rather, found FRAXAC2 was complex and highly mutable. Therefore, we have now analyzed FRAXAC1 and DXS548 together for haplotypes, two markers which have not been jointly analyzed previously, to test for disequilibrium. We typed 315 fragile X (FX) chromosomes and controls, further subdivided into large controls (LC) and small controls (SC) with < or = 35 repeats and identified 26 different haplotypes. Two were more frequent and one less frequent in FX than SCs, thus confirming apparent linkage disequilibrium in fragile X. However, we noted increased FX microsatellite heterozygosity, either individually (results quite similar to previous studies) or as haplotypes. This heterozygosity covaried with FX > LC > SC, which may indicate alternative explanation exists for the apparent disequilibrium. We hypothesize that large FMR-1 CGG repeat allele genes may be associated with the generation of new microsatellite mutations. Possible mechanisms include gene conversions between CGG repeats and flanking microsatellites involving unequal double cross-overs, the expansion of small control CGGs to larger sizes associated with episodic generalized microsatellite instability or as a direct result of mutant FMR-1 gene function. We conclude that the founder effects observed with the use of these CA repeats is likely to reflect both linkage disequilibrium and increased microsatellite instability of fragile X chromosomes.
以往关于脆性X综合征中奠基者染色体效应的研究，是基于单独与FRAXAC1或DXS548的连锁不平衡，或者是与FRAXAC2联合的连锁不平衡。最近，我们发现FMR - 1与FRAXAC2之间不存在连锁不平衡，相反，发现FRAXAC2复杂且高度可变。因此，我们现在一起分析了FRAXAC1和DXS548的单倍型，这两个标记此前未被联合分析过，以检测不平衡情况。我们对315条脆性X（FX）染色体及对照进行了分型，对照进一步细分为重复次数≤35次的大对照（LC）和小对照（SC），并鉴定出26种不同的单倍型。其中两种在FX中比在SCs中更常见，一种在FX中比在SCs中更少见，从而证实了脆性X中明显的连锁不平衡。然而，我们注意到FX微卫星杂合性增加，无论是单个（结果与以往研究非常相似）还是作为单倍型。这种杂合性与FX > LC > SC相关，这可能表明对明显的不平衡存在其他解释。我们假设大的FMR - 1 CGG重复等位基因可能与新的微卫星突变的产生有关。可能的机制包括CGG重复序列与侧翼微卫星之间涉及不等双交换的基因转换、小对照CGG向更大尺寸的扩展，这与偶发性全身性微卫星不稳定性相关，或者是突变FMR - 1基因功能的直接结果。我们得出结论，使用这些CA重复序列观察到的奠基者效应可能既反映了脆性X染色体的连锁不平衡，也反映了微卫星不稳定性的增加。
