Institute of Pathology, School of Medicine, Dentistry and Biomedical Science, Queen's University of Belfast, Belfast BT12 6BL, UK.
J Pathol. 2010 Jan;220(2):109-13. doi: 10.1002/path.2652.
The human and other genome projects and subsequent resequencing programmes have provided new perspectives on the nature of the gene and how genes function. Understanding the complexity of the eukaryotic nucleus and the diversity of genetic regulatory mechanisms, including the role of non-coding RNAs, translational control mechanisms and the extraordinary prevalence of splicing, will be central to understanding how genes function, as will the recognition of gene dosage issues. This introduction to the 2010 Annual Review Issue, Genes, Genomes and Disease, provides overviews of these areas and then considers their relevance to a range of human diseases, including cardiovascular and renal disease, neural tube defects and cancer. The p53 gene is considered as an example of a massively regulated gene and the genetic perturbations in cancer are considered in a historical perspective. High-throughput genomic and transcriptomic methods have led to a paradigm shift in the way cancers are perceived and have changed the way translational research is performed. The progress in our understanding of chromosomal rearrangements in cancer, once believed to be incredibly rare events in epithelial malignancies, is discussed. The identification of low-penetrance cancer susceptibility genes through genome-wide association studies and their implications are reviewed. The contribution and limitations of expression profiling are discussed. In the last series of reviews, future challenges are addressed: the promise of synthetic lethality strategies in cancer therapy, a case for 'systems' approaches to genetic networks and the potential of single molecule genetic technologies. Finally, the question 'Does massively parallel DNA resequencing signify the end of histopathology as we know it?' is posed. Readers should find that the 2010 Annual Review Issue is an invaluable resource on contemporary genetics and its applications to understanding disease.
人类和其他基因组计划以及随后的重测序计划为基因的本质以及基因如何发挥作用提供了新的视角。理解真核细胞核的复杂性以及遗传调控机制的多样性，包括非编码 RNA 的作用、翻译控制机制以及剪接的非凡普遍性，对于理解基因如何发挥作用至关重要，认识基因剂量问题也同样如此。本 2010 年年鉴特刊《基因、基因组与疾病》的介绍性文章概述了这些领域，然后考虑了它们与一系列人类疾病的相关性，包括心血管和肾脏疾病、神经管缺陷和癌症。p53 基因被认为是一个受到广泛调控的基因，癌症中的遗传扰动从历史角度进行了考虑。高通量基因组和转录组学方法导致了人们对癌症的看法发生了范式转变，并改变了转化研究的方式。讨论了癌症中染色体重排的进展，这些重排曾经被认为是上皮恶性肿瘤中极其罕见的事件。通过全基因组关联研究鉴定出低外显率癌症易感性基因及其意义进行了综述。讨论了表达谱分析的贡献和局限性。在最后一系列评论中，探讨了未来的挑战：癌症治疗中合成致死策略的前景、遗传网络“系统”方法的案例以及单分子遗传技术的潜力。最后，提出了“大规模并行 DNA 重测序是否标志着我们所知道的组织病理学的终结？”这个问题。读者应该发现，2010 年年鉴特刊是当代遗传学及其在理解疾病方面的应用的宝贵资源。
