Cell Culture Models of Genetic Variation

Studying genetic variation presents a dilemma. While the genetic variation of greatest interest is that causing variation in traits and disease risk in natural populations, natural populations have characteristics that make them challenging to study. In this work, I have assessed the use of cell culture methods as a solution to some of these challenges. In particular, I studied genetic variation in the budding yeast Saccharomyces cerevisiae that was generated by selection in the lab as a model for natural genetic variation. I have found that even simplistic selection programs in the laboratory, including the use of chemical mutagenesis to introduce genetic variation, can be used to rapidly generate genetic variation with the same characteristics as that observed in natural populations of budding yeast. I also explored the use of human-derived lymphoblastoid cell lines as source of genetic variation that eliminates some of the most challenging problems that arise from the use of humans as research subjects. In addition to the ethical limitations, there are also severe technical limitations to the study of human subjects, not least of which is the difficulty of direct experimentation to confirm hypotheses. I found that lymphoblastoid cell lines are a reliable experimental system in which phenotypic variation, at the cellular level, primarily represents differences between lines, a significant portion of which is due to additive genetic variation. Due to the growth of publicly available genotype data, these lines can be used to locate genetic variants with phenotypic effects by linkage-association mapping. In addition to the shared database resources, cell lines are amenable to distribution from central repositories, suggesting that cell culture could form the basis of a community resource for the study of human genetic variation. While cell culture methods have share weaknesses with traditional genetic model systems, the use of a variety of cell culture approaches, including microorganisms and human-derived cell lines, represents an important, complementary approach to the investigation of genetic variation both for basic, mechanistic questions and for understanding the genetic causes of diversity in human phenotypes