Due to the complex adaptive costs and benefits of large brains and large neocortical volume, mammalian species exhibit huge variation in brain size. However, the precise nature of the genomic changes accounting for these variations remains poorly understood. Using genome-wide comparative analysis of gene family size of more than 39 fully sequenced mammalian species, I studied whether changes in the number of copies of genes involved in distinct cellular and developmental functions has contributed to shaping the morphological, physiological and metabolic machinery supporting brain evolution in mammalians. My results reveal an overrepresentation of gene families displaying a positive association between GFS and level of encephalization. This bias occurs most prominently in families associated with specific biological functions, such as cell-cell signalling, chemotaxis and immune system. Moreover, I find that most gene family size variations associated with increased brain size are mostly explained by the link between neocortex ratio and gene family size variations. The results in this study suggest that variations in gene family size underlie morphological adaptations during brain evolution in mammalian lineages.Lastly, using comparative transcriptomics analysis across different human tissue types with cellular longevities ranging from 120 days to over 70 years, I set out to identify the molecular signature of long term post-mitotic cell maintenance. I found that genes down regulated in Alzheimer’s and Parkinson’s disease are significantly enriched in genes whose expression levels are associated with increased post-mitotic cellular longevity (PMCL). This holds true also for genes down regulated in Hutchinson-Gilford progeria-derived fibroblasts. The work here presented suggest that PMCL-associated genes are part of a generalized machinery of post-mitotic maintenance and functional stability in both neural and non-neural that becomes compromised in two specific neurodegenerative conditions and supports the notion of a common molecular repertoire for cell maintenance differentially engaged in different cell types with differing survival requirements.
|Date of Award||28 Sept 2015|
|Supervisor||Araxi Urrutia (Supervisor) & Humberto Gutierrez (Supervisor)|
Genomic signatures of neurodegeneration and the evolution of mammalian brain.
Castillo Morales, A. (Author). 28 Sept 2015
Student thesis: Doctoral Thesis › PhD