Ellis, DA;
(2017)
A Search for Prions and Analyses of Genomic Rearrangements in Fission Yeast Cells.
Doctoral thesis , UCL (University College London).
Abstract
Prion-proteins exist in two conformations: one normal isoform, and another abnormal, self-propagating isoform. One particularly well-documented prion- protein is PrP, whose infectious isoform is associated with various spongiform encephalopathies in mammals. Human prion diseases are more common amongst the elderly than the young. Furthermore, the progression of Parkinson’s and Alzheimer’s – both age-related neurodegenerative diseases – show parallels with prion diseases. A number of prions have also been found in budding yeast. Whilst sharing common characteristics with their mammalian counterpart, these proteins have notable differences – for instance the Q/N-richness of their prion domains. To complement work in budding yeast and increase the diversity of known prion- related functions and phenotypes, we sought to identify and functionally characterise prions in fission yeast. To understand the genetic basis of cellular lifespan, gene deletion screens in budding and fission yeast have been used to great effect. However, these screens focus on coding regions, overlooking the impact of regulatory intergenic regions and ncRNAs. Just as genetic manipulation can affect a cell’s lifespan, so too can naturally occurring polymorphisms. Using large pools of recombinant fission yeast cells with substantial phenotypic diversity, we sought to uncover naturally occurring longevity alleles by monitoring allele frequencies in ageing cultures. A handful of intriguing variants were identified and are discussed in chapter two. A cell's genome can affect its age, but how does age affect its genome? Ageing cells have long been associated with genome instability. Furthermore, various types of genomic rearrangements can both result from, and intensify genome instability. However, the changing genomic landscape of an ageing population of cells has never been documented, genome-wide. Using sequencing data from the above study, I show that rearrangements increase as a function of time. I also show that these rearrangements are non-randomly distributed, occurring preferentially at hotspots and in the 3' UTR of genes - particularly those that bind, or whose transcripts are bound by, 3' UTR RNA-binding proteins. The role of transcription and replication in these rearrangements is discussed.
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