Genetic, evolutionary, and genomic analysis of homocysteine and folate pathway regulation

Abnormalities in homocysteine and folate metabolism are associated with increased risk for several common human diseases. Both elevated serum homocysteine and low dietary folate intake increase the risk for cardiovascular diseases, neural tube defects, cancers, and neurodegeneration. Although common mutations in these pathways have been identified, they do not fully account for the variety of disease types that are associated with increased homocysteine or low folate levels. Mouse models allow us to control many of the genetic and environmental variables inherent in human studies, allowing us to dissect genes, pathways, and nutrients important for disease pathogenesis. Previous mouse studies showed that mutations in other pathways can significantly modulate functions of homocysteine and folate metabolism and modify disease phenotypes suggesting that these pathway interactions and their regulations are crucial to understanding the role of homocysteine and folate metabolism in complex diseases. To study these pathway interactions and their regulation, I used genetic, evolutionary, and genomic approaches. I first used a unique mouse strain PL/J to dissect the genetic control of key enzyme methylenetetrahydrofolate reductase (MTHFR) and its potential role in disease phenotypes. I found that seizure and kinky tail phenotype in these mice were polygenic and showed strong environmental contributions. Next, I used evolutionary approaches to address whether biochemical interactions in metabolic pathways buffer deleterious mutations. I found that redundant metabolic paths do not provide genetic buffering as inferred from estimates of variation in gene evolution rates. However, higher level interactions explained some of the evolutionary rate variability. Lastly, I used genomic approaches to identify pathways that modulate homeostatic responses to dietary folate perturbations in two genetically distinct inbred strains. I found striking strain differences in homeostatic responses on folate retention and global gene expression profiles. I also found that cholesterol and choline metabolisms are involved in the folate perturbation response, which may play a more general role in complex disease mechanisms. Overall, these analyses revealed pathway interactions that are important for functionality of homocysteine and folate metabolism and highlighted some future strategies for dissecting the role of these pathways in complex diseases.