Human Gene Expression Variability and Its Dependence on Methylation and Aging

Abstract

The phenotypic variability in human populations is partly the result of gene polymorphisms and differential gene expression. Studying the variability of gene expression across human populations is essential to understanding the molecular basis for diversity. However, key issues remain unanswered with respect to human expression variability. For example, the role of gene methylation in expression variability is uncertain, nor is it clear what role tissue-specific factors may have. Moreover, the contribution that expression variability has in aging and development is unknown. Here we classified human genes based on their expression variability in normal human breast and brain samples and identified functional aspects associated with high and low expression variability. Interestingly, both high variability and low variability gene sets are enriched for developmentally essential genes. There is limited overlap between the variably expressed genes of different tissues, indicating that tissue-specific rather than individual-specific factors are at work. We also find that methylation likely has a key role in controlling expression variability insofar as genes with low expression variability are likely to be non-methylated. Importantly, we find that genes with high population expression variability are likely to have age-, but not sex-dependent expression. Taken together, our work indicates that gene expression variability is tissue-specific, methylation-dependent, and is an important component of the natural aging process.