Moloney D
Department of Plastic and Reconstructive Surgery, The Radcliffe Infirmary, Oxford, UK.
Ann R Coll Surg Engl. 2001 Jan;83(1):1-9.
Mutation may be defined simply as structural change affecting the genetic material. The generation of genetic variety by spontaneous mutational events has been the driving force behind evolution--without such mutation our complex human genome could not have evolved. However, as doctors, we more frequently encounter mutation in the context of human disease, whether in somatic cells as a cause of cancer, or in the germline as a cause of inheritable disease. In these contexts, the processes of mutagenesis are relevant to every field of medicine. Scientific study of mutational mechanisms has logically been founded in the relatively simple genetic systems of the prokaryotes and such lowly eukaryotes as the fruit-fly. The study of human clinical genetics approaches the problem from quite the opposite direction--from that of the most highly evolved genetic system. Whilst this approach may be dependent less on logical progression and more on phenomenology, it nevertheless provides a complementary avenue for the observation and study of mutational mechanisms. The genetic research described in this article is firmly rooted in such phenomenology, based as it is on rare craniosynostosis syndromes. Over the past decade, there has been a deluge of molecular discoveries in the field of craniosynostosis. This promises improvements in classification, prognostication, pre-natal diagnosis, and perhaps ultimately for potential avenues for cure. However, exciting as these clinical prospects are, the research presented here has a different focus: it investigates the mechanistic basis underlying the craniosynostosis mutations, in the hope that such study may lead to insights applicable generally to the field of mutagenesis.
突变可以简单地定义为影响遗传物质的结构变化。自发突变事件产生的基因多样性一直是进化背后的驱动力——没有这种突变，我们复杂的人类基因组就不可能进化。然而，作为医生，我们更常在人类疾病的背景下遇到突变，无论是在体细胞中作为癌症的病因，还是在生殖细胞中作为可遗传疾病的病因。在这些情况下，诱变过程与医学的各个领域都相关。对突变机制的科学研究在逻辑上是基于原核生物以及诸如果蝇等低等真核生物相对简单的遗传系统建立的。人类临床遗传学的研究则从完全相反的方向——从进化程度最高的遗传系统的方向来探讨这个问题。虽然这种方法可能较少依赖逻辑推导，更多地依赖现象学，但它仍然为观察和研究突变机制提供了一条互补的途径。本文所述的遗传学研究深深扎根于这种现象学，因为它基于罕见的颅缝早闭综合征。在过去十年中，颅缝早闭领域有大量的分子发现。这有望在分类、预后、产前诊断方面取得进展，也许最终还能找到潜在的治疗途径。然而，尽管这些临床前景令人兴奋，但这里展示的研究有不同的重点：它研究颅缝早闭突变背后的机制基础，希望这样的研究能带来普遍适用于诱变领域的见解。
