病原性细菌严重威胁人类健康，但其致病性如何进化而来、涉及哪些分子事件？这是300多年来悬而未决的问题，又是人类从源头上控制细菌感染的潜在切入点。我们从比较细菌基因组学研究开始，提出获取-适应模型。我们发现了细菌基因组结构保守性和可塑性之间的调控，探讨了细菌通过遗传开关来调控遗传稳定性和变异性之间的平衡，阐述了伤寒样疾病致病菌的趋同进化模式，并通过实验论证了遗传界限把自然界中的细菌分隔成遗传上不连续的种系群。在本项目中，我们拟综合这些研究发现，以沙门菌和埃希菌为主要模型、细菌间遗传界限的识别为主要手段、独立基因池的形成为工作假说，对致病菌的起源和进化做深入探讨，重点解析细菌病原性进化中致病因子的获得、基因组结构和内容的适应性调整、基因组的趋异变化以及最终与亲代遗传隔离而成为新物种等关键环节。本研究基于前期工作基础，用本团队独特的研究手段验证新的假说，有望为病原性细菌的控制提供新的理念和方法。

Pathogenic bacteria pose enormous threats to human health. Since the first sight of bacteria under a microscope, human beings have tried to understand how pathogenic bacteria evolve from non-pathogenic ancestors. Our investigation on this issue began with the construction and comparison of bacterial physical genome maps, findings in which led us to hypothesize mechanisms of bacterial evolution and speciation with a model, i.e., the Adopt-Adapt Model. When whole genome analysis became available for studies of bacteria, we combined this technology with physical mapping in our research and made a series of discoveries, including the genetic switch that bacteria use to modulate and maintain a balance between genetic stability and mutability, the convergent evolutionary mode that Salmonella took to evolve into genetically distinct but phenotypically similar typhoid agents, and the genetic boundary that delineate bacteria into discrete phylogenetic clusters. In this proposed project, we aim at elucidating the origin of pathogenic bacterial species and the molecular mechanisms that they use to evolve, using Salmonella and Escherichia as the main models, recognition of borderlines separating bacteria into clear-cut genetic clusters, and the formation of independent gene pools during bacterial speciation as our working theory. Our focus is to identify and analyze the genomic events that might have facilitated the evolution of pathogens from their commensal ancestors, including the acquisition (Adopt) of pathogenic traits, structural and functional streamlining (Adapt) of the genome, and genetic divergence and isolation from the ancestors to become novel bacterial species dwelling in non-overlapping gene pools. Based on solid previous work and unique discoveries, this project is anticipated to provide new evidence to our research hypothesis, and updated concept and measures for the control of pathogenic bacteria.