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Dans l’histoire évolutive, deux gènes paralogues sont issus d’un évènement de duplication de leur ancêtre commun. Les gènes paralogues sont caractérisés par des duplications globales de génome (WGD) ou à petite échelle (SSD) et par leur datation. Les WGDs ont lieu à deux reprises à la base de la lignée des vertébrés. Les évènements de SSD ont lieu à plusieurs moments pouvant être plus récents, plus anciens ou contemporain de la période des évènements de WGD. La rétention des paralogues dans le génome, associée à une divergence de l’expression spatiale est une contribution importante pour l’augmentation de la complexité de l’organisme au cours de l’évolution. Certaines études ont montré que les duplications anciennes seraient plus associées aux maladies. L’objectif de la première partie de la thèse est de créer une ressource sur les paralogues en collectant et en analysant différentes annotations. Nous avons construit une ressource robuste de paralogues humains à partir de listes publiées mais aussi à partir d’annotations externes. L’exploration de différentes annotations nous a permis d’identifier une identité de séquence élevée entre gènes paralogues pouvant biaiser la mesure d’expression des gènes et diminuer leur expression. L’objectif de la seconde partie, est d’explorer l’expression spatiale et la co- expression des paralogues au sein du cerveau humain, à partir des données RNA-seq du consortium GTEx. Les données d’expression GTEx de 13 tissus cérébraux, nous ont permis de montrer que la datation récente mais aussi que le type SSD contribuaient à une expression plus tissu-spécifique. Nous avons utilisé l’analyse de la co-expression (WGCNA) afin de regrouper les paralogues possédant une expression similaire au travers des tissus et nous avons pu suggérer une co-expression des SSD récents. Nos études sur les maladies ont montré que les SSD récents accumulaient des mutations associées à des maladies cérébrales. Finalement, nous avons trouvé que la co-expression des paralogues et leur tissu-spécificité au travers des régions cérébrales pouvaient enrichir nos connaissances sur les gènes associés à des maladies cérébrales. / In evolution history, two paralogous genes originate from the duplication event of a common ancestor gene. Paralogous genes are characterized by whole genome (WGD) or small-scale (SSD) duplications and their duplication date. The WGDs happened twice in the early vertebrate lineage. SSD events take place at any moment in evolutionary history and can be younger, older or dating to the same period than WGD events. Retention of paralogs in the genome associated with divergence of spatial expression is an important contributor to the increase of organism complexity through evolution. Different studies found that old duplications are more associated with diseases. The objective of the first part of the thesis is to create a resource on paralogs by collecting and analyzing annotations. We built a robust resource of human paralogs from published lists of paralogous genes and also from external annotations. Annotation exploration allowed us to identify a high sequence identity between paralogous genes impacting the gene expression measurement from RNA-seq data and decreasing the gene expression. The objective of the second part is to explore spatial expression and co-expression of paralogs in the human brain, from the GTEx consortium RNA-seq data. The GTEx expression data of 13 brain tissues allowed us to show that duplication youth and SSD type contributed to a more tissue-specific expression. We used co-expression analyses (WGCNA) to group paralogs with similar expression across tissues and we suggested the co-expression of younger SSDs. Our disease studies showed the younger SSD accumulation of mutations associated with brain diseases. We finally found that paralog co-expression and their tissue-specificity across brain regions could enrich information of known brain disease-associated genes.

Background: The Atlantic salmon, Salmo salar L., is a prominent member of the Salmonidae family, and has been the focus of intense research because of its environmental and economic significance as an iconic sporting species and its global importance as an aquaculture species. Furthermore, salmonids constitute ideal organisms for the study of evolution by gene duplication as they are pseudotetraploid descendants of a common ancestor whose genome was duplicated some 25 to 100 million years ago. Whole-genome duplication is considered a major evolutionary force capable of creating vast amounts of new genetic material for evolution to act upon, promoting speciation by acquisition of new traits. Recently, large-scale comparison of paralogous genes in Atlantic salmon suggested that asymmetrical selection was acting on a significant proportion of them. However, to elucidate the physiological consequences of gene and genome duplications, studies integrating molecular evolution and functional biology are crucial. To this end, sequence and molecular analyses were performed on duplicated Elovl5 fatty-acyl elongases of Atlantic salmon, as they are responsible for a rate-limiting reaction in the elongation process of long-chain polyunsaturated fatty acids (LC-PUFA), critical components of all vertebrates. The aim of the research presented here was to investigate the role of gene duplication as an evolutionary process capable of creating genetic novelty, and to identify the potential ecological and physiological implications. Results: Linkage analyses indicated that both fatty-acyl elongases segregated independently and located elovl5 duplicates on different linkage groups. Genetic mapping using microsatellites identified in each elovl5 locus assigned elovl5a and elovl5b to chromosomes ssa28 and ssa13, respectively. In silico sequence analysis and selection tests indicated that both salmon Elovl5 proteins were subject to purifying selection, in agreement with previous results showing indistinguishable substrate specificities. Gene expression and promoter analysis indicated that Elovl5 duplicates differed in response to dietary lipids and tissue expression profile. Lipid biosynthesis and metabolic gene expression profiling performed in Atlantic salmon SHK-1 cells, suggested that the control of lipid homeostasis in fish is similar to that described in higher vertebrates, and revealed the particular importance of Lxr and Srebp transcription factors (TFs) in the regulation of LC-PUFA biosynthetic enzymes. Sequence comparison of upstream promoter regions of elovl5 genes showed intense differences between duplicates. Promoter functional analysis by co-transfection and transcription factor transactivation showed that both elovl5 duplicates were upregulated by Srebp overexpression. However, elovl5b exhibited a higher response and its promoter contained a duplication of a region containing response elements for Srebp and NF-Y cofactors. Furthermore, these studies indicated an Lxr/Rxr dependant response of elovl5a, which was not observed in elovl5b. Analysis of the genomic sequences of elovl5 duplicates by comparison to various sequence databases showed an asymmetrical distribution of transposable elements (TEs) in both introns and promoter regions. Further comparison to introns of the single elovl5 gene in pike indicated much higher TE distribution in salmon genes compared to the pike. Conclusions: Although not conclusive, the most parsimonious origin for the salmon elovl5 duplicates is that they are derived from a WGD event. This conclusion is also supported by the close similarity of two elovl5 paralogs in the recently available rainbow trout genome. Regardless of their origin, Atlantic salmon elovl5 genes have been efficiently retained in the genome under strong functional constraints indicating a physiological requirement for both enzymes to be functionally active. In contrast, upstream promoter regions have strongly diverged from one another, indicating a relaxation of purifying selection following the duplication event. This divergence of cis-regulatory regions has resulted in regulatory diversification of the elovl5 duplicates and regulatory neofunctionalisation of elovl5a, which displayed a novel Lxr/Rxr-dependant response not described in sister or other vertebrate lineages. Promoter analysis indicated that the observed elovl5 differential response to dietary variation could be partly attributed to varying transcriptional regulation driven by lipid-modulated TFs. The distribution of TEs in elvol5 genes of Atlantic salmon shows a clear increase in TE mobilisation after the divergence of esocids and salmonids. This must have occurred after the elongase duplication and thus the salmonid WGD event and contributes to the observed regulatory divergence of elovl5 paralogs.

A beta-tubulin gene (benA) is widely used in taxonomy and identification of Aspergillus spp. and other Fungi.Across Aspergillus spp. There is either one (benA) or two beta-tubulin paralogs (benA and tubC). The risk ofcontemporary use of sequences of paralogous genes with non-homologous function in the same phylogeneticanalysis is well known. It is evident that it had happened repeatedly in Aspergillus section Nigri. It is alarmingthat conventional primers for amplification of partial benA sequence can specifically amplify tubC paralog insome species. In this work, both paralogs were characterised in a set of species. The beta-tubulin primers in usewere revised and new, more benA specific primers were designed. Applicability of some markers such as basecomposition, codon usage and length of introns for distinguishing -tubulin paralogs benA and tubC is tested. Alarge study on molecular diversity of 349 isolates of Aspergillus (PCR-fingerprint, sequence data - ITS, benA,rpb2, caM) originating from Czech culture collections and from clinical material is also included. 82 specieswere identified, togetherwith nine tentative new taxa belonging to sections with high economic impact - Nigri,Fumigati or Aspergillus (Eurotium spp.). Five species from Section Aspergillus could be synonymised withexisting taxa. A study...