Found at: doi:10.1371/journal.pone.0013095.s001 (0.03 MB DOC) Author Contributions Insights into the Evolution and Emergence of a Novel Infectious Disease Many zoonotic, novel infectious diseases in humans appear as sporadic infections with spatially and temporally restricted outbreaks, as seen with influenza A(H5N1). Adaptation is often a key factor for successfully establishing sustained human-to-human transmission. Here we use simple mathematical models to describe different adaptation scenarios with particular reference to spatial heterogeneity within the human population. We present analytical expressions for the probability of emergence per introduction, as well as the waiting time to a successful emergence event. Furthermore, we derive general analytical results for the statistical properties of emergence events, including the probability distribution of outbreak sizes. We compare our analytical results with a stochastic model, which has previously been studied computationally. Our results suggest that, for typical connection strengths between communities, spatial heterogeneity has only a weak effect on outbreak size distributions, and on the risk of emergence per introduction. For example, if [Image: see text] or larger, any village connected to a large city by just ten commuters a day is, effectively, just a part of the city when considering the chances of emergence and the outbreak size distribution. We present empirical data on commuting patterns and show that the vast majority of communities for which such data are available are at least this well interconnected. For plausible parameter ranges, the effects of spatial heterogeneity are likely to be dominated by the evolutionary biology of host adaptation. We conclude by discussing implications for surveillance and control of emerging infections. Zoonotic emergence of novel human infections poses a significant risk to global public health. For example, the 'Spanish flu' pandemic of 1918 probably originated in birds and caused millions of deaths worldwide [1] . While much less virulent, the subsequent influenza pandemics of 1957, 1968 and 2009 [2, 3] are potent reminders of the capacity of the influenza virus to cross the species barrier into humans. Many other pathogens share this capacity: the SARS outbreak of 2003 [4] [5] [6] has been linked to bats and palm civets [7, 8] . In 2008, a novel arenavirus which killed four out of five patients in South Africa was linked to rodents [9] .