Effects of Ploidy and Recombination on Evolution of Robustness in a Model of the Segment Polarity Network

Many genetic networks are astonishingly robust to quantitative variation, allowing these networks to continue functioning in the face of mutation and environmental perturbation. However, the evolution of such robustness remains poorly understood for real genetic networks. Here we explore whether and how ploidy and recombination affect the evolution of robustness in a detailed computational model of the segment polarity network. We introduce a novel computational method that predicts the quantitative values of biochemical parameters from bit sequences representing genotype, allowing our model to bridge genotype to phenotype. Using this, we simulate 2,000 generations of evolution in a population of individuals under stabilizing and truncation selection, selecting for individuals that could sharpen the initial pattern of engrailed and wingless expression. Robustness was measured by simulating a mutation in the network and measuring the effect on the engrailed and wingless patterns; higher robustness corresponded to insensitivity of this pattern to perturbation. We compared robustness in diploid and haploid populations, with either asexual or sexual reproduction. In all cases, robustness increased, and the greatest increase was in diploid sexual populations; diploidy and sex synergized to evolve greater robustness than either acting alone. Diploidy conferred increased robustness by allowing most deleterious mutations to be rescued by a working allele. Sex (recombination) conferred a robustness advantage through “survival of the compatible”: those alleles that can work with a wide variety of genetically diverse partners persist, and this selects for robust alleles

Reproducibility and FAIR Principles: The Case of a Segment Polarity Network Model

The issue of reproducibility of computational models and the related FAIR principles (findable, accessible, interoperable, and reusable) are examined in a specific test case. I analyze a computational model of the segment polarity network in Drosophila embryos published in 2000. Despite the high number of citations to this publication, 23 years later the model is barely accessible, and consequently not interoperable. Following the text of the original publication allowed successfully encoding the model for the open source software COPASI. Subsequently saving the model in the SBML format allowed it to be reused in other open source software packages. Submission of this SBML encoding of the model to the BioModels database enables its findability and accessibility. This demonstrates how the FAIR principles can be successfully enabled by using open source software, widely adopted standards, and public repositories, facilitating reproducibility and reuse of computational cell biology models that will outlive the specific software used

Systems Evolutionary Biology of Waddington’s Canalization and Genetic Assimilation

In recent years, there has been growing interest in computer modeling of the evolution of gene and cell regulatory networks, in general, and in computational studies of the classic ideas of Baldwin, Schmalhausen, Waddington, and followers, in particular. Two related aspects of Waddington’s evolutionary theories are the concepts of canalization and of genetic assimilation. Canalization is associated with the robust development of an individual to diverse perturbations and noise, though, when fluctuations in developmental factors exceed a particular limit, the normal developmental trajectory can be “thrown out” of the robust canal, resulting in an altered phenotype. If selective pressure favors the new phenotype, an initial individual loss of canalization can lead to phenotypic changes in the population (with canalization then becoming established for the new phenotype). Genetic assimilation is the subsequent genetic fixing of the new trait in the population. Recent experimental and theoretical works have established a quantitative basis for these classic concepts of Waddington; this chapter will review these new developments in systems evolutionary biology

Redundancy and the Evolution of Cis-Regulatory Element Multiplicity

The promoter regions of many genes contain multiple binding sites for the same transcription factor (TF). One possibility is that this multiplicity evolved through transitional forms showing redundant cis-regulation. To evaluate this hypothesis, we must disentangle the relative contributions of different evolutionary mechanisms to the evolution of binding site multiplicity. Here, we attempt to do this using a model of binding site evolution. Our model considers binding sequences and their interactions with TFs explicitly, and allows us to cast the evolution of gene networks into a neutral network framework. We then test some of the model's predictions using data from yeast. Analysis of the model suggested three candidate nonadaptive processes favoring the evolution of cis-regulatory element redundancy and multiplicity: neutral evolution in long promoters, recombination and TF promiscuity. We find that recombination rate is positively associated with binding site multiplicity in yeast. Our model also indicated that weak direct selection for multiplicity (partial redundancy) can play a major role in organisms with large populations. Our data suggest that selection for changes in gene expression level may have contributed to the evolution of multiple binding sites in yeast. We conclude that the evolution of cis-regulatory element redundancy and multiplicity is impacted by many aspects of the biology of an organism: both adaptive and nonadaptive processes, both changes in cis to binding sites and in trans to the TFs that interact with them, both the functional setting of the promoter and the population genetic context of the individuals carrying them

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

Macroevolution: Explanation, Interpretation and Evidence

info:eu-repo/semantics/publishedVersio

Study of the rate and spectrum of spontaneous mutations

Mutations are the initial force responsible for all aspects of genetic variation, and are a central part to evolution in all organisms. Yet despite its importance, the previously high cost that is associated with surveying mutations at a genome-wide scale has limited the understanding of the mutation process in eukaryotes. However, recent high-throughput sequencing technology has greatly reduced the cost of surveying mutations. By applying high-throughput sequencing to mutation accumulation experiments, we have begun to characterize the genome-wide mutation spectrum of eukaryotes. Across all eukaryotes, we observe a biased rate of G/C-\u3e A/T mutations that exceeds the number of A/T-\u3eG/C mutations. This finding is consistent with spontaneous deamination of cytosine or methylated cytosine. Alternate forces such as selection or G/C biased gene conversion must be driving eukaryotic genomes toward a higher G/C composition than expected from mutation bias. In Paramecium tetraurelia, we observe a nuclear mutation rate ∼75 fold lower than previously expected. When the base substitution rate per generation is extrapolated to the rate per expressed sexual cycle, it is equivalent to that observed in multicellular species with comparable genome sizes. This suggests that natural selection operates at germline expression, and favors a minimum rate that opposes random genetic drift. Using a natural population of Daphnia pulex we catalogue simple sequence repeats (SSR) and determine average heterozygosity of each SSR type. We find that SSR heterozygosity is motif specific, and positively correlated with repeat number as well as motif length. We identify a motif-dependent end-nucleotide polymorphism bias. Our observations also confirm the high frequency of multiple unit variation at large microsatellite loci. We observe that structural variants in C. elegans and S. cerevisiae, which are ∼1000 fold larger than base substitution rates on a per nucleotide basis, occur on the same order of magnitude as base substitutions. The rate and direction of structural gains and losses differ between yeast and C. elegans, and we hypothesize that the rate of structural variants corresponds with the coding portion of the genome. We also confirm a high rate of gene inversion and gene loss in the life history of C. elegans