PROJECT SUMMARY Understanding what shapes patterns of genetic diversity in natural populations is an inherently challenging problem. Despite the challenges, studying variation in DNA sequences within individuals in a population has the power to yield insights into selective pressures operating in the natural environment of a species, uncover historical events like the migration of humans and their pathogens across the world, and identify the genetic basis of traits like human diseases. One major challenge facing population-genomic inference is that most current state-of-the-art approaches have been developed to study human-like genomes, that are sparsely populated with functionally important elements and thus effects of selection on nearby sites can be ignored. These assumptions however do not apply to compact (gene-dense) genomes where direct and indirect effects of selection are pervasive. My research program is geared towards understanding how the joint effects of selection with other evolutionary processes operating simultaneously in a population, shape patterns of variation across the genome. As many pathogenic species tend to have highly compact genomes, experience strong bouts of selection as well as drastic repeated bottlenecks, and undergo asexual reproduction or self- fertilization often (which further increases the effects of selection), our methods would be absolutely essential to perform inference in such species. We will employ computational, statistical, and theoretical approaches to broach these questions, utilizing the development of new methods and their applications to publicly available whole-genome sequence variation data. The strength of selection against new mutations, a crucial piece of information for modeling how selection shapes variation, has been estimated predominantly for coding regions, despite the fact that in many species the majority of functional DNA that impacts fitness is non-coding. My first goal will therefore be to generate a better estimate of the shape of the genome-wide fitness effects of new mutations. As lower rates of recombination result in stronger effects of selection, my second goal is to better understand how selection against deleterious mutations affects genome-wide patterns of variation in species that undergo high rates of self-fertilization and to develop methods that account for the effects of selection. My third goal is to apply our methods to perform inference of demography and identification of recent selective sweeps in species with compact genomes, like those of Plasmodium falciparum and vivax. My work will result in a better understanding of how natural selection shapes genomic variation, as well as the development and application of methods that jointly account for multiple evolutionary processes. This will be crucial to perform accurate evolutionary inference in compact genomes. My long-term vision is to apply our methodological advances to human pathogens to learn about their pop...