quantiNemo: an individual-based program to simulate quantitative traits with explicit genetic architecture in a dynamic metapopulation

Summary: quantiNemo is an individual-based, genetically explicit stochastic simulation program. It was developed to investigate the effects of selection, mutation, recombination and drift on quantitative traits with varying architectures in structured populations connected by migration and located in a heterogeneous habitat. quantiNemo is highly flexible at various levels: population, selection, trait(s) architecture, genetic map for QTL and/or markers, environment, demography, mating system, etc. quantiNemo is coded in C++ using an object-oriented approach and runs on any computer platform. Availability: Executables for several platforms, user's manual, and source code are freely available under the GNU General Public License at http://www2.unil.ch/popgen/softwares/quantinemo Contact: [email protected]

Is Impact of Statin Therapy on All-Cause Mortality Different in HIV-Infected Individuals Compared to General Population? Results from the FHDH-ANRS CO4 Cohort

French Hospital Database on HIVInternational audienceBackgroundThe effect of statins on all-cause mortality in the general population has been estimated as 0.86 (95%CI 0.79-0.94) for primary prevention. Reported values in HIV-infected individuals have been discordant. We assessed the impact of statin-based primary prevention on all-cause mortality among HIV-infected individuals.MethodsPatients were selected among controls from a multicentre nested case-control study on the risk of myocardial infarction. Patients with prior cardiovascular or cerebrovascular disorders were not eligible. Potential confounders, including variables that were associated either with statin use and/or death occurrence and statin use were evaluated within the last 3 months prior to inclusion in the case-control study. Using an intention to continue approach, multiple imputation of missing data, Cox’s proportional hazard models or propensity based weighting, the impact of statins on the 7-year all-cause mortality was evaluated.ResultsAmong 1,776 HIV-infected individuals, 138 (8%) were statins users. During a median follow-up of 53 months, 76 deaths occurred, including 6 in statin users. Statin users had more cardiovascular risk factors and a lower CD4 T cell nadir than statin non-users. In univariable analysis, the death rate was higher in statins users (11% vs 7%, HR 1.22, 95%CI 0.53-2.82). The confounders accounted for were age, HIV transmission group, current CD4 T cell count, haemoglobin level, body mass index, smoking status, anti-HCV antibodies positivity, HBs antigen positivity, diabetes and hypertension. In the Cox multivariable model the estimated hazard ratio of statin on all-cause mortality was estimated as 0.86 (95%CI 0.34-2.19) and it was 0.83 (95%CI 0.51-1.35) using inverse probability treatment weights.ConclusionThe impact of statin for primary prevention appears similar in HIV-infected individuals and in the general population

Méthodes de construction de génotypes assistée par marqueurs

Les marqueurs moléculaires sont des outils aujourd'hui couramment utilisés pour déterminer la localisation de gènes d'intérêt agronomique sur le génome des espèces cultivées (détection de QTL. L'utilisation en sélection des associations détectées entre les gènes et les marqueurs, en plus des phénotypes des individus porteurs de ces gènes, pourrait permettre d'augmenter l'efficacité de la sélection des caractères quantitatifs, en particulier on limitant son coût. Cette démarche est appelée sélection assistée par marqueurs. Dans le cas où les phénotypes des individus ne sont pas du tout utilisés pour sélectionner les individus, la sélection se résume à construire des génotypes cumulant les gènes intéressant d'une population parentale. Pour pouvoir mettre en oeuvre efficacement des programmes de construction de génotypes, il est nécessaire de développer des méthodes qui leurs sont adaptés. Cette thèse présente différentes méthodes permettant de construire des génotypes à partir de populations parentales variées. Lorsque la population parentale ne contient que deux parents, l'un donneur de gènes d'intérêt et l'autre receveur de ces gènes, le programme adapté est le backcross assisté par marqueurs. Cette thèse présente une revue bibliographique ainsi que des travaux originaux sur les principes d'optimisation du backcross assisté par marqueurs. Lorsque le nombre de gènes à cumuler et le nombre de parents sont grands, le backcross assisté par marqueurs n'est plus un programme de sélection efficace. Cette thèse présente des travaux originaux permettant de définir un cadre général d'optimisation de plans de croisements complexes permettant de cumuler de nombreux gènes dans un soul génotype.Molecular markers are presently widely used to infer the location of genes of agronomical interest on the genome of cultivated species (QTL mapping). The use, for selection purpose, of the known associations between markers and genes, together with the phenotypes of individuals carrying the genes, may increase selection efficiency, particularly by limiting its cost. This process is refered to as marker?assisted selection. In the extreme case where phenotypic information is not used to select between individuals, the selection process can be reduced to building genotypes that cumulate the genes identified in a parental population. In order to perform efficient genotype building programmes, it is needed to develop relevant methods. This thesis introduces various methods, regarding the composition of the parental population, to build genotypes. When the population is only composed of two parents, one donor of favorable genes and one recipient of these genes, the best method is marker?assisted backcrossing. This thesis introduces a bibliographical review and original work on the optimization principles of marker?assisted backcrossing. When the number of favorable genes and the number of parents are important, markerassisted backcrossing is no longer an efficient method. This thesis introduces a general framework for the optimization of complex breeding schemes aimed at cumulating many genes into a single genotype.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

Devil Facial Tumor Disease (DFTD) is an aggressive cancer notorious for its rare etiology and its impact on Tasmanian devil populations. Two regions underlying an evolutionary response to this cancer were recently identified using genomic time-series pre- and post-DTFD arrival. Here, we support that DFTD shaped the genome of the Tasmanian devil in an even more extensive way than previously reported. We detected 97 signatures of selection, including 148 protein coding genes having a human orthologue, linked to DFTD. Most candidate genes are associated with cancer progression, and an important subset of candidate genes has additional influence on social behavior. This confirms the influence of cancer on the ecology and evolution of the Tasmanian devil. Our work also demonstrates the possibility to detect highly polygenic footprints of short-term selection in very small populations

Blocks of chromosomes identical by descent in a population: Models and predictions.

With the highly dense genomic data available nowadays, ignoring linkage between genes would result in a huge loss of information. One way to prevent such a loss is to focus on the blocks of chromosomes shared identical by descent (IBD) in populations. The development of the theoretical framework modelling IBD processes is essential to support the advent of new tools such as haplotype phasing, imputation, inferring population structure and demographic history, mapping loci or detecting signatures of selection. This article aims to present the relevant models used in this context, and specify the underlying definitions of identity by descent that are yet to be gathered at one place. In light of this, we derived a general expression for the expected IBD block length, for any population model at any generation after founding

The Hitchhiking Effect of an Autosomal Meiotic Drive Gene

Transmission-ratio distortion is a departure from a 1:1 segregation of alleles in the gametes of a heterozygous individual. The so-called driving allele is strongly selected regardless of its effect on the fitness of the carrying individual. It may then have an important impact on neutral polymorphism due to the genetic hitchhiking effect. We study this hitchhiking effect in the case of true meiotic drive in autosomes and show that it is more dependent on the recombination rate than in the classical case of a gene positively selected at the organism level

Génétique de l'adaptation (de l'évolution des caractères phénotypiques aux signatures moléculaires de la sélection)

L adaptation est l augmentation du succès reproducteur des organismes vivants sous l effet de leur adéquation croissante à leur environnement. Son mécanisme, la sélection naturelle, agit sur le phénotype mais se répercute sur les gènes. La recherche de gènes impliqués dans l adaptation, et potentiellement d intérêt (agronomique, médical ) suscite actuellement un vif intérêt. Mais les méthodes de détection de signatures moléculaires de la sélection ne prennent souvent pas en compte le phénotype, ni la possibilité d une réponse polygénique des caractères à la sélection. J ai développé dans ma thèse plusieurs modèles de génétique des populations incorporant ces aspects. J ai d abord étudié les conséquences d une sélection positive à deux locus proches sur le polymorphisme neutre. Cette situation peut diminuer notre capacité à détecter la sélection, mais peut aussi être exploitée pour obtenir des informations complémentaires sur la chronologie des substitutions favorables ou l interaction entre gènes. Par ailleurs, comme la plupart des caractères adaptatifs varient de manière continue, j ai étudié comment la signature moléculaire d un locus sous sélection était affectée par la sélection à beaucoup d autres locus affectant le même caractère. J ai aussi mis au point une méthode préliminaire pour estimer la distribution des coefficients de sélection des mutations favorables à partir d approches génomiques de détection de la sélection. Enfin, j ai utilisé un modèle de mutation pléiotrope (affectant de nombreux caractères) pour comprendre comment l hétérogénéité phénotypique de la mutation entre locus influe sur la probabilité que chacun d eux soit utilisé lors de l adaptation.Adaptation is the increase in reproductive success of living organisms that results from their growing match to their environment. Its underlying mechanism, natural selection, acts on phenotypes, but is transmitted to the genes. The search for the genes involved in adaptation, and of putative agronomical or medical interest, has been a matter of intense research recently. However, most methods to detect molecular signatures of selection overlook the phenotype, and do not consider the consequences of a possible polygenic response to selection. During this PhD, I developed several population genetic models that allow taking those aspects into account. I first studied the consequence of positive selection at two close loci on neutral polymorphism. This situation can paradoxically hinder our ability to detect selection, but can also be exploited to obtain additional information about the chronology of beneficial substitutions, or the interaction between genes. Since most adaptive traits vary quantitatively, I studied how the molecular signature left by a locus under positive selection is affected by selection at many other loci that affect the same trait. I also designed a preliminary method to estimate the distribution of the selection coefficients of beneficial mutations from genome scans for selection. Finally, I used a model of pleiotropic mutation to understand how the phenotypic heterogeneity of mutation across loci influences the probability that each locus is used during adaptation.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Two- and Three-Locus Tests for Linkage Analysis Using Recombinant Inbred Lines

We consider fixed recombinant inbred lines (RILs) derived either by selfing or by full-sib mating; when applicable, we also consider intermated recombinant inbreds (IRIs). First, we show that the usual estimate of recombination fraction based on RIL data is biased, and we provide an estimate where the major part of that bias is removed. Second, we derive simple formulas to compute the frequencies of genotypes at three loci in RILs. We describe the nonindependence of multiple recombinations arising in RIL recombination data even though there may be no interference in each meiosis. Finally, we give formulas for interference tests, gene mapping, or QTL detection in RIL populations

Selective Sweep at a Quantitative Trait Locus in the Presence of Background Genetic Variation

ABSTRACT We model selection at a locus affecting a quantitative trait (QTL) in the presence of genetic variance due to other loci. The dynamics at the QTL are related to the initial genotypic value and to the background genetic variance of the trait, assuming that background genetic values are normally distributed, under three different forms of selection on the trait. Approximate dynamics are derived under the assumption of small mutation effect. For similar strengths of selection on the trait (i.e, gradient of directional selection b) the way background variation affects the dynamics at the QTL critically depends on the shape of the fitness function. It generally causes the strength of selection on the QTL to decrease with time. The resulting neutral heterozygosity pattern resembles that of a selective sweep with a constant selection coefficient corresponding to the early conditions. The signature of selection may also be blurred by mutation and recombination in the later part of the sweep. We also study the race between the QTL and its genetic background toward a new optimum and find the conditions for a complete sweep. Overall, our results suggest that phenotypic traits exhibiting clear-cut molecular signatures of selection may represent a biased subset of all adaptive traits

Selective Sweep at a Quantitative Trait Locus in the Presence of Background Genetic Variation

We model selection at a locus affecting a quantitative trait (QTL) in the presence of genetic variance due to other loci. The dynamics at the QTL are related to the initial genotypic value and to the background genetic variance of the trait, assuming that background genetic values are normally distributed, under three different forms of selection on the trait. Approximate dynamics are derived under the assumption of small mutation effect. For similar strengths of selection on the trait (i.e, gradient of directional selection β) the way background variation affects the dynamics at the QTL critically depends on the shape of the fitness function. It generally causes the strength of selection on the QTL to decrease with time. The resulting neutral heterozygosity pattern resembles that of a selective sweep with a constant selection coefficient corresponding to the early conditions. The signature of selection may also be blurred by mutation and recombination in the later part of the sweep. We also study the race between the QTL and its genetic background toward a new optimum and find the conditions for a complete sweep. Overall, our results suggest that phenotypic traits exhibiting clear-cut molecular signatures of selection may represent a biased subset of all adaptive traits