Houlston R S, Tomlinson I P
Institute of Cancer Research, Sutton, Surrey, UK.
Eur J Hum Genet. 1998 Jan;6(1):80-8. doi: 10.1038/sj.ejhg.5200156.
A number of genetic disorders exhibit inter- and intra-familial variability. Understanding the factors that control the expression of disease genes should provide insight into the fundamental disease processes and will have implications for counselling patients. Different mechanisms can account for this variability, including environmental factors, genotype-phenotype correlations and imprinting. There is also evidence that, in a number of genetic diseases, gene expression is under the control of modifier loci. In cases where the biological basis of the genetic disease is understood, any genes involved in the pathogenic process represent candidate modifier genes which can easily be evaluated. Alternatively, modifiers can be identified through approaches such as mouse models. Since modifier genes will generally be common and because of confounding environmental influences, linkage analyses in humans will generally be based upon affected or discordant sib pairs. Discordant sib pairs represent an attractive option for linkage studies, because recurrence rates are high and the reduced survival characteristics associated with severe phenotypes will make the likelihood of obtaining clinical material from two living cases difficult. Furthermore, the use of discordant siblings will select for those siblings which possess sufficient dissimilarity at the modifier locus to overcome any shared environmental influence.
许多遗传疾病表现出家族间和家族内的变异性。了解控制疾病基因表达的因素应能深入了解基本的疾病过程，并将对患者咨询产生影响。不同的机制可以解释这种变异性，包括环境因素、基因型-表型相关性和印记。也有证据表明，在一些遗传疾病中，基因表达受修饰位点的控制。在了解遗传疾病生物学基础的情况下，任何参与致病过程的基因都代表可以轻松评估的候选修饰基因。或者，可以通过小鼠模型等方法鉴定修饰基因。由于修饰基因通常较为常见，且存在混杂的环境影响，人类连锁分析通常将基于患病或不一致的同胞对。不一致的同胞对是连锁研究的一个有吸引力的选择，因为复发率很高，与严重表型相关的生存特征降低将使得从两个存活病例中获取临床材料变得困难。此外，使用不一致的兄弟姐妹将选择那些在修饰位点具有足够差异以克服任何共同环境影响的兄弟姐妹。
