Helicobacter pylori is a human-specific bacterial pathogen that infects and colonizes the stomach for decades. H. pylori causes chronic gastritis in hosts, that in 10-20% of cases will progress to severe disease including peptic ulcers and/or gastric cancers. Because H. pylori is thought to infect ~50% of humans in the world and 33% in the US, it is a major global cause of gastric cancers. My project uses whole genome sequencing to investigate the processes that H. pylori uses to adapt to new hosts. I compare the results of two different adaptation experiments: 1) Adapting the bacterium to a colonize the stomach of mice in a laboratory setting (wild type is not capable of long term infection in mice). H. pylori is serially passaged in mice for increasing colonization loads. Mice are infected with wild type bacteria as well as several mutants defective for recombination mechanisms. H. pylori typically has very high rates of recombination and this study examines whether recombination aids in adaptation to a new host. 2) Examining long term adaptation to a human host. Patient J99 was infected with H. pylroi and samples collected by endoscopy, refused treatment, and came back to the clinic 6 years later and had many further samples collected from specifically labeled anatomic regions. I have sequenced dozens of strains from this collection from the different time points and regions. This study examines differences in adaptation resulting from colonizing different niches of the gastric anatomy. Comparing this approach with the mouse adaptation study gives insights into how different environments affect adaptation in this organism.