Sutherland G R, Richards R I
Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, Adelaide, Australia.
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3636-41. doi: 10.1073/pnas.92.9.3636.
The human genome contains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an increase in copy number by a process of dynamic mutation. Dynamic mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromosomes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most common familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of mental retardation. Similar mutations of AGC repeats give rise to a number of neurological disorders. The expanded repeats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance--particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of dynamic mutation is discussed, and a number of observations of simple tandem repeat mutation that could assist in understanding this phenomenon are commented on.
人类基因组包含许多重复的DNA序列，其重复单元的复杂程度从单个核苷酸到整个基因不等。重复序列可以广泛分布，也可以呈简单串联阵列形式。长度达5或6个核苷酸的阵列被称为简单串联重复序列，它们广泛分布且具有高度多态性。简单串联重复序列中的一组，即三核苷酸重复序列，可通过动态突变过程增加拷贝数。CCG三核苷酸的动态突变会导致人类染色体上出现一组脆性位点，即罕见的对叶酸敏感的那一组。该组中的一个成员，脆性X（FRAXA），是导致最常见的家族性智力迟钝的原因。该组中的另一个成员FRAXE则导致一种较罕见的轻度智力迟钝。AGC重复序列的类似突变会引发多种神经疾病。扩增的重复序列在代与代之间以及体细胞中都是不稳定的。代际不稳定性会导致异常的遗传模式——尤其是遗传早现现象，即该疾病在连续几代中严重程度增加和/或发病年龄提前。动态突变仅在人类中被发现，并对其可能的原因进行了探讨。文中讨论了动态突变的机制，并对一些有助于理解这一现象的简单串联重复突变的观察结果进行了评论。
