The evolution of a gene’s expression profile is commonly assumed to be independent of its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between expression of neighboring genes in extant taxa. Indeed, in all eukaryotic genomes, genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this, I consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. I find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, chromatin level mechanisms are likely regulators of this phenomenon. Firstly established in Primates and then expanded to compacted genome of yeasts, the phenomenon of correlation in change in gene expression of the neighbouring genes I describe as “expression piggy-backing”, an analog of hitchhiking. Extending the same principle to non-coding genes I find a possible role of lincRNAs in regulating expression of their neighbours, mediated by a coupling between splicing and chromatin modification. Finally I employ insertions of human endogenous retroviruses (HERVs), as a naturally occurring transgene experiment, to find out how randomly scattered sequences would affect the expression profile of their neighboring genes. I show these retroviruses to be the focus of transcription in human ES cells and define a transcription factor, LBP9, as a novel pluripotency-associated agent. Transcription results in neighbourhood modification including the generation of chimaeric transcripts. Predictions were confirmed experimentally by collaborators.
|Date of Award||29 May 2015|
|Supervisor||Laurence Hurst (Supervisor)|
- Gene Expression
- transposable element