Expansion des familles de gènes impliquées dans des maladies par duplication du génome chez les premiers vertébrés

The emergence and evolutionary expansion of gene families implicated in cancers and other severegenetic diseases is an evolutionary oddity from a natural selection perspective. In this thesis, wehave shown that gene families prone to deleterious mutations in the human genome have beenpreferentially expanded by the retention of "ohnolog" genes from two rounds of whole‐genomeduplication (WGD) dating back from the onset of jawed vertebrates. Using advanced inferenceanalysis, we have further demonstrated that the retention of many ohnologs suspected to be dosagebalanced is in fact indirectly mediated by their susceptibility to deleterious mutations. This enhancedretention of "dangerous" ohnologs, defined as prone to autosomal‐dominant deleterious mutations,is shown to be a consequence of WGD‐induced speciation and the ensuing purifying selection inpost‐WGD species. We have also developed a statistical approach to identify ohnologs in vertebrategenomes with high confidence. These ohnologs can be easily accessed from a web server. Ourfindings highlight the importance of WGD‐induced non‐adaptive selection for the emergence ofvertebrate complexity, while rationalizing, from an evolutionary perspective, the expansion of genefamilies frequently implicated in genetic disorders and cancers. The high confidence ohnologsidentified by our approach will also pave the way for novel functional genomic analysesdistinguishing gene duplicates according to their origin.L'expansion au cours de l'évolution de familles de gènes impliquées dans les cancers et d'autresmaladies génétiques graves est surprenante du point de vue de la sélection naturelle. Dans cettethèse, nous avons montré que des familles de gènes sujettes à des mutations délétères dans legénome humain se sont principalement agrandies par rétention de gènes "ohnologues" issus dedeux duplications globales du génome (GGD) datant de l'origine des vertébrés à mâchoires. Enutilisant une méthode d'inférence avancée, nous avons aussi démontré que la rétention denombreux ohnologues soupçonnés d'être susceptibles aux équilibres de dosage d'expression était enfait plus directement liée à leur sensibilité aux mutations délétères. Cette rétention priviligiéed'ohnologues "dangereux", définis comme sujets à des mutations délétères dominantes, semble êtreune conséquence des évênements de spéciation provoqués par ces GGD et la sélection depurification qui a suivi dans les espèces post‐GGD. Nous avons également développé une approchequantitative pour identifier les ohnologues dans le génome des vertébrés. Ces ohnologues sontfacilement accessibles à partir d'un serveur Web. Nos résultats soulignent l' importance de lasélection non adaptative induite par GGD dans l'émergence de la complexité des vertébrés, tout enrationalisant, d'un point de vue évolutif, l'extension des familles de gènes fréquemment impliquéesdans les maladies génétiques et les cancers. Les ohnologues identifiés par notre approche ouvrentégalement la voie à de nouvelles analyses de génomique fonctionnelle distinguant l'origine desgènes dupliqués

Considerations for reproducible omics in aging research.

Technical advancements over the past two decades have enabled the measurement of the panoply of molecules of cells and tissues including transcriptomes, epigenomes, metabolomes and proteomes at unprecedented resolution. Unbiased profiling of these molecular landscapes in the context of aging can reveal important details about mechanisms underlying age-related functional decline and age-related diseases. However, the high-throughput nature of these experiments creates unique analytical and design demands for robustness and reproducibility. In addition, omic experiments are generally onerous, making it crucial to effectively design them to eliminate as many spurious sources of variation as possible as well as account for any biological or technical parameter that may influence such measures. In this Perspective, we provide general guidelines on best practices in the design and analysis of omic experiments in aging research from experimental design to data analysis and considerations for long-term reproducibility and validation of such studies

OHNOLOGS v2: a comprehensive resource for the genes retained from whole genome duplication in vertebrates

International audienc

Identification of Ohnolog Genes Originating from Whole Genome Duplication in Early Vertebrates, Based on Synteny Comparison across Multiple Genomes

International audienceWhole genome duplications (WGD) have now been firmly established in all major eukary-otic kingdoms. In particular, all vertebrates descend from two rounds of WGDs, that occurred in their jawless ancestor some 500 MY ago. Paralogs retained from WGD, also coined 'ohnologs' after Susumu Ohno, have been shown to be typically associated with development, signaling and gene regulation. Ohnologs, which amount to about 20 to 35% of genes in the human genome, have also been shown to be prone to dominant deleterious mutations and frequently implicated in cancer and genetic diseases. Hence, identifying ohnologs is central to better understand the evolution of vertebrates and their susceptibility to genetic diseases. Early computational analyses to identify vertebrate ohnologs relied on content-based synteny comparisons between the human genome and a single invertebrate outgroup genome or within the human genome itself. These approaches are thus limited by lineage specific rearrangements in individual genomes. We report, in this study, the identification of vertebrate ohnologs based on the quantitative assessment and integration of syn-teny conservation between six amniote vertebrates and six invertebrate outgroups. Such a synteny comparison across multiple genomes is shown to enhance the statistical power of ohnolog identification in vertebrates compared to earlier approaches, by overcoming line-age specific genome rearrangements. Ohnolog gene families can be browsed and down-loaded for three statistical confidence levels or recompiled for specific, user-defined, significance criteria at http://ohnologs.curie.fr/. In the light of the importance of WGD on the genetic makeup of vertebrates, our analysis provides a useful resource for researchers interested in gaining further insights on vertebrate evolution and genetic diseases

On the retention of gene duplicates prone to dominant deleterious mutations

Recent studies have shown that gene families from different functional categories have been preferentially expanded either by small scale duplication (SSD) or by whole-genome duplication (WGD). In particular, gene families prone to dominant deleterious mutations and implicated in cancers and other genetic diseases in human have been greatly expanded through two rounds of WGD dating back from early vertebrates. Here, we strengthen this intriguing observation, showing that human oncogenes involved in different primary tumors have retained many WGD duplicates compared to other human genes. In order to rationalize this evolutionary outcome, we propose a consistent population genetics model to analyze the retention of SSD and WGD duplicates taking into account their propensity to acquire dominant deleterious mutations. We solve a deterministic haploid model including initial duplicated loci, their retention through sub-functionalization or their neutral loss-of-function or deleterious gain-of-function at one locus. Extensions to diploid genotypes are presented and population size effects are analyzed using stochastic simulations. The only difference between the SSD and WGD scenarios is the initial number of individuals with duplicated loci. While SSD duplicates need to spread through the entire population from a single individual to reach fixation, WGD duplicates are de facto fixed in the small initial post-WGD population arising through the ploidy incompatibility between post-WGD individuals and the rest of the pre-WGD population. WGD duplicates prone to dominant deleterious mutations are then shown to be indirectly selected through purifying selection in post-WGD species, whereas SSD duplicates typically require positive selection. These results highlight the long-term evolution mechanisms behind the surprising accumulation of WGD duplicates prone to dominant deleterious mutations and are shown to be consistent with cancer genome data on the prevalence of human oncogenes with WGD duplicates

Evolution after WGD and identification of ohnologs.

<p>Evolution after WGD and identification of ohnologs using content-based synteny comparison. The genomes of three lineages sharing a common ancestor are shown. Orthologs and paralogs have been depicted by the same color. The WGD lineage (A) underwent whole genome duplication (B) followed by non-functionalization (C) and genome rearrangements (D) leading to the current intragenomic content-based synteny (I). By contrast, the two outgroup genomes without WGD (E, G) experienced lineage specific genome rearrangements (F, H) leading to 1-to-2 content-based synteny pattern with the WGD lineage (J, K). Note, that some ohnolog pairs (D) are only identified by one of the two outgroups (J or K) due to lineage specific rearrangements.</p

Venn diagram of the distribution of amniote ohnologs.

<p>A six-way Venn diagram showing the distribution in percentages of the ohnologs identified in at least one amniote and predicted from the relaxed criteria. 36.6% of ohnologs are found in all six amniotes. Each shaded sectors in red contributes to more than 2% of all consensus ohnologs in amniotes (numbers of ohnologs are given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004394#pcbi.1004394.s011" target="_blank">S10 Fig</a>).</p

Venn diagram of distribution of human ohnologs with respect to outgroups.

<p>A six-way Venn diagram showing the distribution in percentages of the 7,715 of the total 8,178 human ohnolog pairs that are identified by at least one outgroup and predicted from the relaxed criteria. Only 3.8% of human ohnolog pairs are identified by all outgroup. Each of the shaded sectors in green contributes to more than 2% of all ohnolog pairs (numbers of ohnolog pairs are given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004394#pcbi.1004394.s009" target="_blank">S8 Fig</a>).</p