McKerlie Colin
Pathology Core of the Centre for Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
ILAR J. 2006;47(2):156-62. doi: 10.1093/ilar.47.2.156.
Over the next several decades, biology is embarking on its most ambitious project yet: to annotate the human genome functionally, prioritizing and focusing on those genes relevant to development and disease. Model systems are fundamental prerequisites for this task, and genetically engineered mice (GEM) are by far the most accessible mammalian system because of their anatomical, physiological, and genetic similarity to humans. The scientific utility of GEM has become commonplace since the technology to produce them was established in the early 1980s. Conceptually, however, an efficiently coordinated high-throughput approach that permits correlation between newly discovered genes, functional properties of their protein products, and biological relevance of these products as drug targets has yet to be established. The discipline of veterinary anatomical pathology (hereafter referred to as pathology) is not immune to this requirement for evolution and adaptation, and to address relationships and tissue consequences between tens of thousands of genes and their cognate proteins, novel interdisciplinary technologies and approaches must emerge. Although many of the techniques of pathology are well established, in the context of pathology's contribution to functional annotation of the genome, several conceptually important and unresolved issues remain to be addressed. While an ever-increasing arsenal of genetic and molecular tool-sets are available to evaluate and understand the function of genes and their pathophysiological mechanisms, pathology will continue to play an essential role in confirming cause and effect relationships of gene function in development and disease. This role will continue to be dependent on keen observation, a systematic but disciplined approach, expert knowledge of strain-dependent anatomical differences and incidental lesions, and relevant tissue-based evidence. Miniaturization and high-throughput adaptation of these methods must also continue so that they can complement parallel phenotyping efforts, provide pathology-based data in pace with concurrent phenotyping efforts, and continue to find new utility in the collective effort of functional annotation.
在接下来的几十年里，生物学正着手开展其有史以来最雄心勃勃的项目：对人类基因组进行功能注释，优先并聚焦于那些与发育和疾病相关的基因。模式生物是完成这项任务的基本前提，而基因工程小鼠（GEM）因其在解剖学、生理学和遗传学上与人类的相似性，是目前最易获取的哺乳动物系统。自20世纪80年代初生产基因工程小鼠的技术建立以来，其科学实用性已变得十分普遍。然而，从概念上讲，一种能有效协调的高通量方法尚未建立，这种方法需能将新发现的基因、其蛋白质产物的功能特性以及这些产物作为药物靶点的生物学相关性联系起来。兽医解剖病理学（以下简称病理学）也不能忽视这种进化和适应的需求，为了解决数万个基因与其同源蛋白质之间的关系及组织后果，必须出现新的跨学科技术和方法。尽管病理学的许多技术已成熟，但在病理学对基因组功能注释的贡献方面，仍有几个概念上重要且未解决的问题有待解决。虽然有越来越多的遗传和分子工具集可用于评估和理解基因功能及其病理生理机制，但病理学在确认基因功能在发育和疾病中的因果关系方面仍将发挥重要作用。这一作用将继续依赖于敏锐的观察、系统而严谨的方法、对品系依赖性解剖差异和偶发性病变的专业知识以及相关的基于组织的证据。这些方法的小型化和高通量适应也必须继续，以便它们能够补充并行的表型分析工作，与同步的表型分析工作同步提供基于病理学的数据，并在功能注释的集体努力中继续找到新的用途。
