Discovering molecular regulators of ageing using mixture models with RNA-sequencing data

Identifying the molecular regulators that control ageing is challenging because the ageing process is influenced by a combination of genetic and environmental factors which makes it difficult to source the contribution of a single gene. Multiple studies have demonstrated that as humans age, increased gene expression heterogeneity results in the dysregulation of key regulators and pathways. Given the dynamic nature of gene expression, it is vital that this data be modelled by statistical approaches that can appropriately account for changes in variability to understand the contribution of heterogeneity during the aging process and properly identify its regulators. This study demonstrates the utility of using mixture models to model biological variability of gene expression occurring during ageing and how novel potential regulators of ageing can be identified.

Our mixture modelling approach was applied to gene expression data from the Genotype-Tissue Expression (GTEx) cohort. For every gene, the expression profile was modelled using a mixture model across the cohort where the subset of donors corresponding to each mode was tested for a significant change in age group. The multi-tissue aspect of GTEx was leveraged to find ageing regulators based on this mixture model approach genes that were common across multiple tissues, suggesting that the regulation of ageing may also be controlled through a set of genes that have non-tissue-specific activity.

Our approach identified well-documented ageing regulators mTOR and RICTOR and other potential ageing regulators such as IL4 and GPR4 which were detected only by our approach. Genes identified by edgeR, DESeq2 and the mixture model-based approach were enriched for similar biological pathways. This suggests that while the specific ageing regulators identified from our approach may be distinct, they generally belong in the same pathways as the genes identified by standard approaches. Overall, these results indicate that modelling gene expression variability using mixture models in conjunction with standard differential gene expression can help uncover new regulators that have a potential role for understanding human ageing.

I