The role of evolution in the genetic susceptibility of intracranial aneurysm

Les Inuits du Nunavik regroupent des peuples autochtones de l'Arctique qui au fil de l’histoire ont formé une petite population isolée dans la région du Nunavik (nord de la province de Québec, Canada). Le profil génétique unique des Inuits du Nunavik est le résultat d’une adaptation à leur milieu de vie et il est considéré comme lié à certaines de leurs susceptibilités pathologiques. Une évolution neutre, ainsi qu’une suite d’événements adaptatifs, ont façonné le génome de ces Inuits et indirectement engendré leur prédisposition accrue à certains troubles cardio-vasculaires et cérébro-vasculaires (ex : hypertension et anévrismes intracrâniens (AI)). Les AI sont des faiblesses cérébro-vasculaires localisées pouvant mener à des dilatations et renflements localisés de la paroi vasculaire. De telles distorsions sont susceptibles de perturber les vaisseaux et entrainer des hémorragies sous-arachnoïdiennes. Les AI sont un désordre complexe dont la prévalence est élevée (4-8%) et différentes populations (non reliées aux Inuits) ont aussi un risque accru de développer des AI. Le développement des AI est associé à la fois à des facteurs environnementaux et génétiques; plusieurs études génomiques ont identifié des régions associées aux AI. Une grande part de l'héritabilité génétique des AI demeure encore inexpliquée, en particulier dans des populations autres que les finnois et les japonais. Toutefois il est à noter que peu d’études génétiques des AI ont tenu compte de la contribution de variations génétiques spécifiques à la population étudiée. Pour améliorer nos connaissances sur la part encore inexpliquée de l'héritabilité des AI (qui implique une grande hétérogénéité génétique et des variations peu pénétrantes), nous avons combiné le séquençage à haut débit au génotypage des polymorphismes sur puces afin d’établir la signature génétique des deux populations fondatrices du Québec prédisposées aux AI (Inuits du Nunavik et Canadiens français). Comme ces populations ont des caractéristiques distinctes, nous avons utilisé des approches différentes pour tenter d’identifier des facteurs de risque génétiques. Les Inuits du Nunavik représentent une population autochtone et de nombreux aspects de leur signature génétique diffèrent de celles des principales populations, nous avons choisi d’approfondir leur histoire et profil génomique avant de vérifier si des associations génomiques pouvaient être établies avec les IA. Nous avons tout d'abord examiné les régions codantes du génome et observé de nombreuses composantes génétiques spécifiques aux Inuits du Nunavik qui reflètent que la population s’est adaptée à son environnement (ex: ascendance Inuit homogène, augmentation du déséquilibre de liaison et signature génétique). Des signes de sélection naturelle, jusqu’alors non-identifiés, ont révélé une accumulation de variations génétiques dans des gènes impliqués dans le processus d'adhésion cellulaire et de la réponse immunitaire (ex. CPNE7 et ICAM5). D'autres analyses ont révélé un variant dans le gène CCM2 qui présente une sélection positive et est significativement associé aux AI chez les Inuits du Nunavik. En ce qui concerne l'étiologie génétique des AI dans la population des Canadiens français, nous avons adopté une approche différente et utilisé des variations spécifiques aux Canadiens français, qui ont été identifiées par le séquençage complet de l'exome. Ces variations ont permis de générer une liste de gènes à risque potentiel, qui ont ensuite été priorisés en utilisant un test d'association par gène de type « burden ». RNF213 est apparu comme le meilleur gène candidat; il est vraisemblablement la conséquence d’une dérive génétique. Les mesures génétiques et fonctionnelles subséquentes ont validé la contribution possible de RNF213 au développement des AI chez les Canadiens français. Les résultats présentés dans cette thèse soulignent l'importance de prendre en compte le contexte génétique spécifique apporté par l'évolution lorsqu'une maladie complexe est étudiée. Il a également été montré que les variations d’un gène spécifique (ex. CCM2 et RNF213) peuvent contribuer au développement de différentes pathologies lorsqu'ils sont observés dans des populations distinctes. D'une manière générale, nos découvertes génétiques ont permis d’identifier de nouvelles « pièces » génétiques et pour avancer le « casse-tête » incomplet de l'héritabilité génétique des AI ; la génétique des populations a été un élément clé pour cette avancée.Nunavik Inuit is a group of Arctic indigenous people, who have historically presented as a small and isolated population across the Nunavik region of northern Quebec (Canada). The unique genetic profile of Nunavik Inuit is the result of years of adaptation to their living condition, and it is likely responsible for their increased susceptibility to certain pathological conditions. Prior studies have shown that as a consequence of neutral evolution or past adaptive events, today’s Inuit are predisposed to cardio-cerebrovascular disorders, e.g. hypertension and intracranial aneurysm (IA). IA is defined as localized cerebrovascular weakness which leads to vascular dilation or ballooning, and such distortions are susceptible to disrupt the affected vessels and lead to subarachnoid hemorrhage. It is a complex disorder with a high prevalence (4-8%) and certain populations have been observed to present an increased risk of developing IA. Both environmental and genetic factors are deemed to contribute to the development of IA and in regards to the latter, independent genome-wide association studies (GWAS) have identified multiple loci associated with IA. Nonetheless, there is still a large portion of the genetic heritability of IA, especially in different populations other than Finnish and Japanese that remains unexplained. However, fewer IA genetic studies have taken in consideration the contribution of population specific genetic variants. To address some of the IA missing heritability that is deemed to be accountable to its genetic heterogeneity and low penetrance, we have combined high throughput sequencing (HTS) with SNP-chip genotyping to examine the genetic signatures of two founder populations from Quebec that are predisposed to IA, including Nunavik Inuit and French-Canadians (FC). Because these populations have distinct genetic characteristics, we used different approaches for the identification of genetic risk factors. Nunavik Inuit is an indigenous population and many aspects of its genetic signatures differ from those of separate world-wide major populations; therefore we chose to conduct extensive population genetic studies in regards to their genetic history and genomic profile before we undertook to test if any association could be established between genomic loci and disease susceptibility. We observed many genetic components that are specific to the Nunavik Inuit population, including its homogeneous Inuit ancestry, increased linkage disequilibrium (LD) and genetic signatures which reflect the population had a long history of adaptations to their environment. Previously unidentified signals of natural selection, which focused on coding regions of the genome revealed an accumulation of genetic variants in genes involved in the processes of cell adhesion and immune responses (e.g. CPNE7 and ICAM5). Further analyses revealed a variant in CCM2 to be under positive selection and significantly associated with IA in Nunavik Inuit. In regard to the genetic etiology of IA in the French-Canadian population, we took a different approach and used French-Canadian specific variants that were identified by whole exome sequencing to generate a list of potential risk genes; which were further prioritized using a gene based burden association test. RNF213 emerged as a prime candidate gene that had undergone possible genetic drift and the follow-up genetic and functional examinations further supported its potential contribution to the development of IA among French-Canadians. The results presented in this thesis highlighted the importance of taking into consideration the specific genetic background brought by natural selection or genetic drift, both are driving forces of evolution, when a complex disease is being studied. It also further confirmed that variants in a specific gene (e.g. RNF213 or CCM2) may contribute to the development of different pathogenesis when examined in distinct populations. Overall as our genetic findings identified new genetic “pieces” that further completed the missing heritability “puzzle” of IA genetics; evidence for these “pieces” were interestingly highlighted through population genetics

Numerical Security Analysis of Three-State Quantum Key Distribution Protocol with Realistic Devices

Quantum key distribution (QKD) is a secure communication method that utilizes the principles of quantum mechanics to establish secret keys. The central task in the study of QKD is to prove security in the presence of an eavesdropper with unlimited computational power. In this work, we successfully solve a long-standing open question of the security analysis for the three-state QKD protocol with realistic devices, i,e, the weak coherent state source. We prove the existence of the squashing model for the measurement settings in the three-state protocol. This enables the reduction of measurement dimensionality, allowing for key rate computations using the numerical approach. We conduct numerical simulations to evaluate the key rate performance. The simulation results show that we achieve a communication distance of up to 200 km.Comment: 14 pages, 5 figure

A hybrid algorithm for quadratically constrained quadratic optimization problems

Quadratically Constrained Quadratic Programs (QCQPs) are an important class of optimization problems with diverse real-world applications. In this work, we propose a variational quantum algorithm for general QCQPs. By encoding the variables on the amplitude of a quantum state, the requirement of the qubit number scales logarithmically with the dimension of the variables, which makes our algorithm suitable for current quantum devices. Using the primal-dual interior-point method in classical optimization, we can deal with general quadratic constraints. Our numerical experiments on typical QCQP problems, including Max-Cut and optimal power flow problems, demonstrate a better performance of our hybrid algorithm over the classical counterparts.Comment: 8 pages, 3 figure

Association between -238 but not -308 polymorphism of Tumor necrosis factor alpha (TNF-alpha)v and unexplained recurrent spontaneous abortion (URSA) in Chinese population

<p>Abstract</p> <p>Objectives</p> <p>TNF-alpha is a critical cytokine produced by Th1 cells while altered T helper 1 (Th1)-Th2 balance is found crucial for a successful pregnancy.</p> <p>Study Design</p> <p>A cohort of 132 Southern Chinese Han RSA patients and 152 controls constituted the subjects of this study. Two functional polymorphisms -308 and -238 of TNF-alpha were studied by association analysis.</p> <p>Results</p> <p>lack of association was found in TNF-alpha -308 SNP yet a significant difference was discovered in -238 polymorphism.</p> <p>Conclusion</p> <p>This study suggested that TNF-alpha may be a risk factor in Chinese RSA patients. However the ethnic differences may also contribute to the results.</p

Mutation analysis of the WNT4 gene in Han Chinese women with premature ovarian failure

BACKGROUND: The WNT4 gene plays an important role in female sex determination and differentiation. It also contributes to maintaining of the ovaries and the survival of follicles. METHODS: We sequenced the coding region and splice sites of WNT4 in 145 Han Chinese women with premature ovarian failure (POF) and 200 healthy controls. RESULTS: Only one novel variation, in Exon 2 (195C > T), was detected among the women with POF. However, this synonymous variation did not result in a change in amino acid sequence (65 Asp > Asp). No further variants were found in any of the samples. CONCLUSION: Although we cannot provide any evidence that it is a possible disease-causing gene, this study is the first attempt to investigate the possible role of WNT4 in Han Chinese women with POF

ASSIST: Interactive Scene Nodes for Scalable and Realistic Indoor Simulation

We present ASSIST, an object-wise neural radiance field as a panoptic representation for compositional and realistic simulation. Central to our approach is a novel scene node data structure that stores the information of each object in a unified fashion, allowing online interaction in both intra- and cross-scene settings. By incorporating a differentiable neural network along with the associated bounding box and semantic features, the proposed structure guarantees user-friendly interaction on independent objects to scale up novel view simulation. Objects in the scene can be queried, added, duplicated, deleted, transformed, or swapped simply through mouse/keyboard controls or language instructions. Experiments demonstrate the efficacy of the proposed method, where scaled realistic simulation can be achieved through interactive editing and compositional rendering, with color images, depth images, and panoptic segmentation masks generated in a 3D consistent manner

Direct-Current Generator Based on Dynamic Water-Semiconductor Junction with Polarized Water as Moving Dielectric Medium

There is a rising prospective in harvesting energy from water droplets, as microscale energy is required for the distributed sensors in the interconnected human society. However, achieving a sustainable direct-current generating device from water flow is rarely reported, and the quantum polarization principle of the water molecular remains uncovered. Herein, we propose a dynamic water-semiconductor junction with moving water sandwiched between two semiconductors as a moving dielectric medium, which outputs a sustainable direct-current voltage of 0.3 V and current of 0.64 uA with low internal resistance of 390 kilohm. The sustainable direct-current electricity is originating from the dynamic water polarization process in water-semiconductor junction, in which water molecules are continuously polarized and depolarized driven by the mechanical force and Fermi level difference, during the movement of the water on silicon. We further demonstrated an encapsulated portable power-generating device with simple structure and continuous direct-current voltage, which exhibits its promising potential application in the field of wearable electronic generators

A Novel CRYGD Mutation (p.Trp43Arg) Causing Autosomal Dominant Congenital Cataract in a Chinese Family

To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family, molecular genetic investigation via haplotype analysis and direct sequencing were performed Sequencing of the CRYGD gene revealed a c.127T>C transition, which resulted in a substitution of a highly conserved tryptophan with arginine at codon 43 (p.Trp43Arg). This mutation co-segregated with all affected individuals and was not observed in either unaffected family members or in 200 normal unrelated individuals. Biophysical studies indicated that the p.Trp43Arg mutation resulted in significant tertiary structural changes. The mutant protein was much less stable than the wild-type protein, and was more prone to aggregate when subjected to environmental stresses such as heat and UV irradiation. © 2010 Wiley-Liss, Inc