Identify putative ohnolog pairs

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Table of contents

Acknowledgements
Abbreviations & Definitions
I Introduction
1 Preamble
1.1 Résumé de la thèse
1.2 Thesis summary
1.3 Organization of the thesis
1.4 Publications resulted/forthcoming from this thesis
2 Evolution by Gene Duplication
2.1 Mechanisms of gene duplication
2.1.1 Unequal crossing over
2.1.2 Retroposition
2.1.3 Non-homologous mechanisms
2.1.4 Whole genome duplication
3 Evolutionary Constraints & Retention of Duplicated Genes
3.1 Neofunctionalization
3.2 Subfunctionalization
3.3 Buffering against deleterious mutations
3.4 Dosage balance hypothesis
4 Whole Genome Duplications & Evolution of Vertebrates
5 Objectives of This Thesis
II Materials & Methods
6 Identification of Ohnologs
6.1 Input genomes, orthologs and paralogs
6.1.1 Protein coding genes and their genomic coordinates
6.1.2 Orthologs and paralogs
6.2 Identification of the synteny blocks and anchors
6.3 Calculation of P-value to rule out spurious synteny
6.4 Identify putative ohnolog pairs
6.5 Combine P-value from anchors
6.6 Sample genomes with multiple window sizes
6.7 Combine P-value from all outgroups
6.8 Filter ohnolog pairs to remove false positives
6.9 Construction of ohnolog families
6.10 Randomization of the human genome
6.11 Small Scale Duplicates (SSD)
6.12 Ohnologs in the teleost fish genomes: the 3R-WGD
6.12.1 The 2R-WGD
6.12.2 The 3R-WGD
6.13 Development of the OHNOLOGS server
7 Collection of Cancer/Disease Genes & Functional Genomic Data
7.1 Cancer genes
7.1.1 Oncogenes and tumor suppressors
7.1.2 “Core” cancer genes
7.2 Dominant & recessive disease genes
7.3 Haploinsufficient and dominant negative genes
7.4 Genes with autoinhibitory protein folds
7.5 Genes coding for protein complexes
7.5.1 Human protein reference database
7.5.2 Comprehensive resource of mammalian protein complexes
7.5.3 Gene ontology
7.5.4 Census of soluble human protein complexes
7.5.5 Permanent complexes
7.6 Essential genes
7.6.1 Human orthologs of Mouse essential genes
7.6.2 Human essential genes from In-vitro knock-out experiments
7.7 Genes with copy number variations
7.8 Expression Level
7.9 Disease genes in other vertebrates
7.9.1 Mouse
7.9.2 Rat
7.10 Analysis of ohnologs conservation using Ka/Ks ratios
8 Causal Inference Analysis
8.1 Mediation Analysis
8.1.1 Total, direct & indirect effects
8.1.2 Mediation calculations
8.1.3 Interpretation of Mediation results
8.1.4 Application on genomic properties
III Results
9 Characterization of Vertebrate Ohnologs
9.1 Combining information from Multiple outgroups improves ohnolog detection
9.1.1 Comparison with randomized human genome
9.2 Comparison of ohnologs with published datasets
9.3 Ohnolog family size distribution
9.4 Ohnolog pairs for other vertebrates
9.5 The OHNOLOGS server
9.5.1 Search
9.5.2 Interpretation of an ohnolog family
9.5.3 Browse & Download
9.6 Ohnologs in the Teleost fish genomes
9.6.1 Ohnologs from the 2R-WGD
9.6.2 Ohnologs from the 3R-WGD
10 Enhanced Retention of “Dangerous” Genes by WGD
10.1 The Majority of “dangerous” genes retain more ohnologs
10.1.1 Ohnolog–disease association is consistent for high confidence ohnolog datasets
10.1.2 Enhanced retention of “dangerous” ohnologs in Mouse & Rat genomes .
10.2 “Dangerous” genes show no biased retention by SSD or CNV
10.2.1 Small scale duplicates from Ensembl
10.2.2 Small scale duplicates from sequence comparisons
10.2.3 Ohnolog and SSD retention bias in different human primary tumors
10.3 Mapping cancer and disease gene duplications on Ensembl duplication nodes .
10.4 Ohnologs are more conserved than non-ohnologs
10.5 Dominant, and not recessive disease genes have retained more ohnologs
10.5.1 Recessive disease genes
10.5.2 Essential genes
11 Dosage Balance, Expression level & Human Ohnologs
11.1 Mixed susceptibility of human ohnologs to dosage balance
11.1.1 High retention of protein complexes in ohnologs
11.1.2 Transient versus permanent complexes
11.1.3 Susceptibility of human protein complexes to disease mutations
11.2 Gene expression level and human ohnologs
11.3 Sequence conservation and ohnolog retention
12 Indirect Causes of Ohnolog Retention
12.1 The effect of dosage balance is mediated by mutation susceptibility
12.1.1 Mediation of ‘Dosage.Bal.’ Æ) ‘Ohnolog’ by ‘Delet.Mut.’ genes
12.1.2 Mediation of ‘Delet.Mut.’ Æ) ‘Ohnolog’ by ‘Dosage.Bal.’ genes
12.1.3 Mediation of ‘Dosage.Bal.’ Æ) ‘Ohnolog’ by ‘Delet.Mut.’ genes after excluding SSD and CNV genes
12.1.4 Mediation of ‘Delet.Mut.’ Æ) ‘Ohnolog’ by ‘Dosage.Bal.’ genes after excluding SSD and CNV genes
12.2 Small effect of essentiality on ohnolog retention
12.3 Negative causal effect of high expression on ohnolog retention
12.4 Sequence conservation & ohnolog retention
12.4.1 Mediation with low Ka/Ks values
12.4.2 Mediation with high Ka/Ks values
13 Population Genetic Model for the Retention of “Dangerous” Ohnologs
IV Discussion & Perspectives
14 Discussion & Perspectives
A Articles
List of Figures
List of Tables
Bibliography