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3. Neocortex Expansion in Mammalian Lineages Explains Gene Family Size Variations Associated with Larger Brain Size

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University of Bath PHD Genomic signatures of neurodegeneration and the evolution of mammalian brain. Castillo Morales, Atahualpa Award date: 2015 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 09. Oct. 2021 Genomic signatures of neurodegeneration and the evolution of mammalian brain. Atahualpa Castillo Morales A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Biology June 2015 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with the author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that they must not copy it or use material from it except as permitted by law or with the consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. I II Table of Contents Acknowledgments .......................................................................................................... VI Contributions ............................................................................................................... VIII Abstract .......................................................................................................................... IX List of Figures ................................................................................................................. X List of Tables ................................................................................................................. XI List of Supplementary Tables ....................................................................................... XII Abbreviations .............................................................................................................. XIII 1 Introduction ................................................................................................................... 1 1.1 The genomic basis of complex phenotypes ....................................................... 1 1.2 Trade-offs in the evolution of large brains ............................................................. 3 1.4 Genetic signatures of brain evolution ..................................................................... 8 1.5 Neocorticalization, differential scaling of large brains ........................................ 12 1.6 Neurodegeneration and cellular longevity ........................................................... 14 1.7 Objectives & approach of this thesis .................................................................... 15 2. Increased brain size in mammals is associated with size variations in gene families with cell signalling, chemotaxis and immune-related functions .................................... 21 2.1 Abstract ................................................................................................................ 22 2.2 Introduction .......................................................................................................... 23 2.3 Methods ................................................................................................................ 24 2.3.1 Gene family annotations ................................................................................ 24 2.3.2 Encephalization index .................................................................................... 25 2.3.3 Correlation coefficients of gene family size and encephalization index ....... 25 2.3.4 Gene ontology terms analysis ........................................................................ 25 2.3.5 Maximum lifespan and partial correlation coefficients ................................. 26 2.3.6 Phylogenetic relatedness test ......................................................................... 26 2.3.7 Gene expression in human brain.................................................................... 27 2.3.8 Co-expression network analysis .................................................................... 27 III 2.4 Results .................................................................................................................. 28 2.4.1 Gene family size variations in line with encephalization are over-represented in mammals ............................................................................................................. 28 2.4.2 Association between gene family size and encephalization is not explained by lifespan variations ................................................................................................... 31 2.4.3 Phylogenetic relatedness does not explain the observed bias in the distribution of gene families associated with encephalization ............................... 33 2.4.4 Gene families with size increases in line with encephalization show expression signatures consistent with brain functions ............................................ 33 2.5 Discussion ............................................................................................................ 39 2.6 Conclusion ............................................................................................................ 41 3. Neocortex expansion in mammalian lineages explains gene family size variations associated with larger brain size .................................................................................... 44 3.1 Abstract ................................................................................................................ 45 3.2 Introduction .......................................................................................................... 46 3.3 Methods ................................................................................................................ 49 3.3.1 Gene Family annotations ............................................................................... 49 3.3.2 Encephalization index, Neocortex ratio and Maximum Lifespan ................. 49 3.3.3 Correlation coefficients of gene family size and phenotypes ........................ 50 3.3.4 Gene Ontology terms enrichment .................................................................. 50 3.3.5 Phylogenetically controlled regression .......................................................... 51 3.3.6 Gene expression prior and after peak in neocortex thickness. ....................... 51 3.4 Results .................................................................................................................. 52 3.5 Discussion ............................................................................................................ 58 4. Post-mitotic cell longevity-associated genes: a transcriptional signature of post- mitotic maintenance in neural and non-neural tissues ................................................... 62 4.1 Abstract ................................................................................................................ 63 4.2 Background .......................................................................................................... 64 4.3 Results .................................................................................................................. 66 4.4 Discussion ............................................................................................................ 81 4.5 Conclusions .......................................................................................................... 88 4.6 Materials and Methods ......................................................................................... 89 4.6.1 Cellular longevity estimates. ......................................................................... 89 4.6.2 Human tissues gene expression data.............................................................. 89 IV 4.6.3 Co-expression analyses. ................................................................................. 91 4.6.4 Enrichment of disease down regulated genes. ............................................... 91 4.6.5 Functional enrichment analysis. .................................................................... 91 4.6.7 Statistical analysis. ......................................................................................... 92 5. General Discussion .................................................................................................... 96 5.1 Variations in gene family size and encephalization ............................................. 97 5.2 Changes in gene family size and neocorticalization. ........................................... 98 5.3. Molecular basis
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