We consider the state of knowledge on pathogen evolution of novel virulence activities, broadly defined as anything that increases pathogen fitness with the consequence of causing disease in either the qualitative or quantitative senses, including adaptation of pathogens to host immunity and physiology, host species, genotypes, or tissues, or the environment. The evolution of novel virulence activities as an adaptive trait is based on the selection exerted by hosts on variants that have been

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... erated de novo or arrived from elsewhere. In addition, the biotic and abiotic environment a pathogen experiences beyond the host may influence pathogen virulence activities. We consider pathogen evolution in the context of host-pathogen evolution, host range expansion, and external factors that can mediate pathogen evolution. We then discuss the mechanisms by which pathogens generate and recombine the genetic variation that leads to novel virulence activities, including DNA point mutation, transposable element activity, gene duplication and neofunctionalization, and genetic exchange. In summary, if there is an (epi)genetic mechanism that can create variation in the genome, it will be used by pathogens to evolve virulence factors. Our knowledge of virulence evolution has been biased by pathogen evolution in response to major gene resistance, leaving other virulence activities underexplored. Understanding the key driving forces that give rise to novel virulence activities, and the integration of evolutionary concepts and methods with mechanistic research on plant-microbe interactions, can help inform crop protection. Soledad Sacristan MPMI Box 1: Definitions of terms. Effector: secreted protein or other molecule that contributes to pathogen fitness in its host(s). Virulence activities: anything that enables pathogens to infect and multiply (i.e. increases pathogen fitness), with the consequence of causing disease in either the qualitative or quantitative senses. Virulence factors: genes that directly contribute to a pathogen's ability to infect and multiply within the host Virulence-related factors: genes that indirectly contribute to pathogen fitness. (similar to van der Planck), and virulence as a quantitative measure of the degree of pathogenicity (similar to the meaning of virulence in other disciplines). Causing disease is a definitive property of pathogens, and it is frequently assumed to be a consequence of pathogen fitness. In this review, we consider virulence activities to be anything that enables pathogens to infect and multiply (i.e. increases pathogen fitness), with the consequence of causing disease in either the qualitative or quantitative senses (Figure 1) . Therefore, novel virulence activities can include the adaptation of pathogens to: host immunity and physiology; host species, genotypes, or tissues; the environment; and may include production of more efficient reproductive structures or competing/cooperating better with other microorganisms in the ecosystem (Figure 1 ). These novel virulence activities may evolve by acquisition or adaptation of virulence factors (i.e. genes that contribute to a pathogen's ability to infect and multiply within the host) or virulence-related factors (i.e. genes indirectly involved in virulence activities). The evolution of novel virulence activities as an adaptive trait is based on the selection exerted on variants that have been generated de novo or arrived from elsewhere. In this review we will first address the selective factors that affect virulence activities and then the mechanisms that generate diversity in pathogen populations.