Automatic Inference of Graph Models for Complex Networks with Genetic Programming

Complex networks can arise naturally and spontaneously from all things that act as a part of a larger system. From the patterns of socialization between people to the way biological systems organize themselves, complex networks are ubiquitous, but are currently poorly understood. A number of algorithms, designed by humans, have been proposed to describe the organizational behaviour of real-world networks. Consequently, breakthroughs in genetics, medicine, epidemiology, neuroscience, telecommunications and the social sciences have recently resulted. The algorithms, called graph models, represent significant human effort. Deriving accurate graph models is non-trivial, time-intensive, challenging and may only yield useful results for very specific phenomena. An automated approach can greatly reduce the human effort required and if effective, provide a valuable tool for understanding the large decentralized systems of interrelated things around us. To the best of the author's knowledge this thesis proposes the first method for the automatic inference of graph models for complex networks with varied properties, with and without community structure. Furthermore, to the best of the author's knowledge it is the first application of genetic programming for the automatic inference of graph models. The system and methodology was tested against benchmark data, and was shown to be capable of reproducing close approximations to well-known algorithms designed by humans. Furthermore, when used to infer a model for real biological data the resulting model was more representative than models currently used in the literature.

The bridging of pluralistic visions of science and ethics for bioethics - Tibetan medicine as compared with the Western research on longevity and human genetic enhancement

La thèse examine les liens entre la vision pluraliste de la science et l’éthique de la médecine tibétaine et les nouvelles pratiques en médecine occidentale, soit la longévité et la recherche sur la génétique amélioratrice. Elle cherche à cerner l’apport que la médecine tibétaine peut apporter aux recherches occidentales sur la longévité et la génétique humaine amélioratrice. Elle traite donc d’un enjeu social clé et du débat qui s’y rattache. La découverte et la description sont centrales à la méthodologie et informent l’analyse. Nous avons examiné dans un premier temps, les travaux de recherche sur la longévité reliée à la génétique amélioratrice (mémoire et muscles). Nous nous sommes penchés également sur les fondements de la médecine tibétaine en tant que système intégré. Pour ce faire, nous avons traité des notions telles que la santé, l’identité, la perfection et l’immortalité. Notre cadre conceptuel repose sur la théorie bouddhiste de l’interdépendance qui se caractérise par la formulation de catégories qui ensuite sont synthétisées dans l’essence; les deux niveaux d’interprétation de la théorie sont décrits en détail avant de passer à une comparaison avec la notion de complexité occidentale. La médecine tibétaine de fait présente un système où l’éthique et la science sont intégrées et se prête bien à une comparaison avec la vision pluraliste de la science à partir d’une perspective éthique/bioéthique. Les commentaires recueillis auprès des experts nous ont permis de cerner comment la science, l’éthique et l’amélioration de la longévité sont définies au sein des deux paradigmes de l’Est et de l’Ouest. Nos résultats montrent six points qui se dégagent au terme de cette recherche permettent de jeter un pont sur la vision pluraliste de ces paradigmes. Ceux-ci transcendent les points de vue doctrinaux individuels de religions ainsi que du monde scientifique occidental. Plus que tout, ils laissent entrevoir un cadre de références novatrices qui contribuera à la prise de décision à l’égard de questionnements bioéthiques.

Speciation as an active force in promoting genetic evolution

There is a growing appreciation among evolutionary biologists that the rate and tempo of molecular evolution might often be altered at or near the time of speciation, i.e. that speciation is in some way a special time for genes. Molecular phylogenies frequently reveal increased rates of genetic evolution associated with speciation and other lines of investigation suggest that various types of abrupt genomic disruption can play an important role in promoting speciation via reproductive isolation. These phenomena are in conflict with the gradual view of molecular evolution that is implicit in much of our thinking about speciation and in the tools of modern biology. This raises the prospect of studying the molecular evolutionary consequences of speciation per se and studying the footprint of speciation as an active force in promoting genetic divergence. Here we discuss the reasons to believe that speciation can play such a role and elaborate on possible mechanisms for accelerated rates of evolution following speciation. We provide an example of how it is possible detect whether accelerated bursts of evolution occur in neutral and/or adaptive regions of genes and discuss the implications of rapid episodes of change for conventional models of molecular evolution. Speciation might often owe more to ephemeral and essentially arbitrary events that cause reproductive isolation than to the gradual and regular tug of natural selection that draws a species into a new niche.

Alternative splicing and genetic diversity: silencers are more frequently modified by SNVs associated with alternative exon/intron borders

With the availability of a large amount of genomic data it is expected that the influence of single nucleotide variations (SNVs) in many biological phenomena will be elucidated. Here, we approached the problem of how SNVs affect alternative splicing. First, we observed that SNVs and exonic splicing regulators (ESRs) independently show a biased distribution in alternative exons. More importantly, SNVs map more frequently in ESRs located in alternative exons than in ESRs located in constitutive exons. By looking at SNVs associated with alternative exon/intron borders (by their common presence in the same cDNA molecule), we observed that a specific type of ESR, the exonic splicing silencers (ESSs), are more frequently modified by SNVs. Our results establish a clear association between genetic diversity and alternative splicing involving ESSs.

The genetic polymorphism of diabetic nephropathy

Introduction: The Diabetic Nephropathy (DN) affects approximately 40% of patients diagnosed with DM is associated with increased mortality from cardiovascular phenomena and is considered the main cause of Chronic Renal Failure (CRF) in patients dialectics. Methods: Searches were performed on Medline, SciELO, Lilacs and Cochrane databases using the crossing between the key-words: “genetic polymorphism” and “diabetic nephropathy”. Results: The selected studies indicated that diabetic nephropathy is the leading cause of chronic renal failure, which significantly reduces the life expectancy of diabetics. Currently, some factors may have connection with DN. They are: genetic predisposition based on family history, hypertension, and cardiovascular events, quality of glycemic control and lipid levels and blood pressure and smoking. Conclusion: Studies constants are essential to add new elements in the literature for the definition (s) of factor (s) gene (s) specific (s) of diabetic nephropathy.

Central autonomic control in spontaneously hypertensive rats: a study on phasic phenomena during rapid-eye-movement sleep

The cardiovascular regulation undergoes wide changes in the different states of sleepwake cycle. In particular, the relationship between spontaneous fluctuations in heart period and arterial pressure clearly shows differences between the two sleep states. In non rapid-eye-movement sleep, heart rhythm is under prevalent baroreflex control, whereas in rapid-eye-movement sleep central autonomic commands prevail (Zoccoli et al., 2001). Moreover, during rapid-eye-movement sleep the cardiovascular variables show wide fluctuations around their mean value. In particular, during rapid-eyemovement sleep, the arterial pressure shows phasic hypertensive events which are superimposed upon the tonic level of arterial pressure. These phasic increases in arterial pressure are accompanied by an increase in heart rate (Sei & Morita, 1996; Silvani et al., 2005). Thus, rapid-eye-movement sleep may represent an “autonomic stress test” for the cardiovascular system, able to unmask pathological patterns of cardiovascular regulation (Verrier et al. 2005), but this hypothesis has never been tested experimentally. The aim of this study was to investigate whether rapid-eye-movement sleep may reveal derangements in central autonomic cardiovascular control in an experimental model of essential hypertension. The study was performed in Spontaneously Hypertensive Rats, which represent the most widely used model of essential hypertension, and allow full control of genetic and environmental confounding factors. In particular, we analyzed the cardiovascular, electroencephalogram, and electromyogram changes associated with phasic hypertensive events during rapid-eyemovement sleep in Spontaneously Hypertensive Rats and in their genetic Wistar Kyoto control strain. Moreover, we studied also a group of Spontaneously Hypertensive Rats made phenotypically normotensive by means of a chronic treatment with an angiotensin converting enzyme inhibitor, the Enalapril maleate, from the age of four weeks to the end of the experiment. All rats were implanted with electrodes for electroencephalographic and electromyographic recordings and with an arterial catheter for arterial pressure measurement. After six days for postoperative recovery, the rats were studied for five days, at an age of ten weeks.The study indicated that the peak of mean arterial pressure increase during the phasic hypertensive events in rapid-eye-movement sleep did not differ significantly between Spontaneously Hypertensive Rats and Wistar Kyoto rats, while on the other hand Spontaneously Hypertensive Rats showed a reduced increase in the frequency of theta rhythm and a reduced tachicardia with respect to Wistar Kyoto rats. The same pattern of changes in mean arterial pressure, heart period, and theta frequency was observed between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate. Spontaneously Hypertensive Rats do not differ from Wistar Kyoto rats only in terms of arterial hypertension, but also due to multiple unknown genetic differences. Spontaneously Hypertensive Rats were developed by selective breeding of Wistar Kyoto rats based only on the level of arterial pressure. However, in this process, multiple genes possibly unrelated to hypertension may have been selected together with the genetic determinants of hypertension (Carley et al., 2000). This study indicated that Spontaneously Hypertensive Rats differ from Wistar Kyoto rats, but not from Spontaneously Hypertensive Rats treated with Enalapril maleate, in terms of arterial pH and theta frequency. This feature may be due to genetic determinants unrelated to hypertension. In sharp contrast, the persistence of differences in the peak of heart period decrease and the peak of theta frequency increase during phasic hypertensive events between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate demonstrates that the observed reduction in central autonomic control of the cardiovascular system in Spontaneously Hypertensive Rats is not an irreversible consequence of inherited genetic determinants. Rather, the comparison between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate indicates that the observed differences in central autonomic control are the result of the hypertension per se. This work supports the view that the study of cardiovascular regulation in sleep provides fundamental insight on the pathophysiology of hypertension, and may thus contribute to the understanding of this disease, which is a major health problem in European countries (Wolf-Maier et al., 2003) with its burden of cardiac, vascular, and renal complications.

Genetic analysis of tumour initiation and progression in a Drosophila model of epithelial cancer

Neoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. The molecular crosstalk occurring between precancerous and normal cells strongly influences the early steps of the tumourigenic process as well as later stages of the disease. Precancerous cells are often removed by cell death from normal tissues but the mechanisms responsible for such fundamental safeguard processes remain in part elusive. To gain insight into these phenomena I took advantage of the clonal analysis methods available in Drosophila for studying the phenotypes due to loss of function of the neoplastic tumour suppressor lethal giant larvae (lgl). I found that lgl mutant cells growing in wild-type imaginal wing discs are subject to the phenomenon of cell competition and are eliminated by JNK-dependent cell death because they express very low levels of dMyc oncoprotein compared to those in the surrounding tissue. Indeed, in non-competitive backgrounds lgl mutant clones are able to overgrow and upregulate dMyc, overwhelming the neighbouring tissue and forming tumourous masses that display several cancer hallmarks. These phenotypes are completely abolished by reducing dMyc abundance within mutant cells while increasing it in lgl clones growing in a competitive context re-establishes their tumourigenic potential. Similarly, the neoplastic growth observed upon the oncogenic cooperation between lgl mutation and activated Ras/Raf/MAPK signalling was found to be characterised by and dependent on the ability of cancerous cells to upregulate dMyc with respect to the adjacent normal tissue, through both transcriptional and post-transcriptional mechanisms, thereby confirming its key role in lgl-induced tumourigenesis. These results provide first evidence that the dMyc oncoprotein is required in lgl mutant tissue to promote invasive overgrowth in developing and adult epithelial tissues and that dMyc abundance inside versus outside lgl mutant clones plays a key role in driving neoplastic overgrowth.

Genetic in long QT syndromes

The long QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT interval in the electrocardiogram (ECG) and a propensity to "torsades de pointes" ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. LQTS caused by mutations of predominantly potassium and sodium ion channel genes or channel-interacting proteins leading to positive overcharge of myocardial cell with consequent heterogeneous prolongation of repolarization in various layers and regions of myocardium. These conditions facilitate the early after-depolarization and reentry phenomena underlying development of polymorphic ventricular tachycardia observed in patients with LQTS. Obtaining detailed patient history regarding cardiac events in the patient and his/her family members combined with careful interpretation of standard 12-lead ECG (with precise measurement of QT interval in all available ECGs and evaluation of T-wave morphology) usually is sufficient to diagnose the syndrome. The LQTS show great genetic heterogeneity and has been identified more than 500 mutations distributed in 10 genes: KCNQ1, HERG, SCN5A, KCNE1, KCNE2, ANKB, KCNJ2, CACNA1A, CAV3 and SCN4B. Despite advances in the field, 25-30% of patients remain undiagnosed genetic. Genetic testing plays an important role and is particularly useful in cases with nondiagnostic or borderline ECG findings.

Origins of Shared Genetic Variation in African Cichlids

Cichlid fishes have evolved tremendous morphological and behavioral diversity in the waters of East Africa. Within each of the Great Lakes Tanganyika, Malawi, and Victoria, the phenomena of hybridization and retention of ancestral polymorphism explain allele sharing across species. Here, we explore the sharing of single nucleotide polymorphisms (SNPs) between the major East African cichlid assemblages. A set of approximately 200 genic and nongenic SNPs was ascertained in five Lake Malawi species and genotyped in a diverse collection of 160 species from across Africa. We observed segregating polymorphism outside of the Malawi lineage for more than 50% of these loci; this holds similarly for genic versus nongenic SNPs, as well as for SNPs at putative CpG versus non-CpG sites. Bayesian and principal component analyses of genetic structure in the data demonstrate that the Lake Malawi endemic flock is not monophyletic and that river species have likely contributed significantly to Malawi genomes. Coalescent simulations support the hypothesis that river cichlids have transported polymorphism between lake assemblages. We observed strong genetic differentiation between Malawi lineages for approximately 8% of loci, with contributions from both genic and nongenic SNPs. Notably, more than half of these outlier loci between Malawi groups are polymorphic outside of the lake. Cichlid fishes have evolved diversity in Lake Malawi as new mutations combined with standing genetic variation shared across East Africa.

Predictive genetic test decisions for Huntington's disease: context, appraisal and new moral imperatives

Predictive testing is one of the new genetic technologies which, in conjunction with developing fields such as pharmacogenomics, promises many benefits for preventive and population health. Understanding how individuals appraise and make genetic test decisions is increasingly relevant as the technology expands. Lay understandings of genetic risk and test decision-making, located within holistic life frameworks including family or kin relationships, may vary considerably from clinical representations of these phenomena. The predictive test for Huntington's disease (HD), whilst specific to a single-gene, serious, mature-onset but currently untreatable disorder, is regarded as a model in this context. This paper reports upon a qualitative Australian study which investigated predictive test decision-making by individuals at risk for HD, the contexts of their decisions and the appraisals which underpinned them. In-depth interviews were conducted in Australia with 16 individuals at 50% risk for HD, with variation across testing decisions, gender, age and selected characteristics. Findings suggested predictive testing was regarded as a significant life decision with important implications for self and others, while the right not to know genetic status was staunchly and unanimously defended. Multiple contexts of reference were identified within which test decisions were located, including intra- and inter-personal frameworks, family history and experience of HID, and temporality. Participants used two main criteria in appraising test options: perceived value of, or need for the test information, for self and/or significant others, and degree to which such information could be tolerated and managed, short and long-term, by self and/or others. Selected moral and ethical considerations involved in decision-making are examined, as well as the clinical and socio-political contexts in which predictive testing is located. The paper argues that psychosocial vulnerabilities generated by the availability of testing technologies and exacerbated by policy imperatives towards individual responsibility and self-governance should be addressed at broader societal levels. (C) 2003 Elsevier Science Ltd. All rights reserved.

Genetic viability of Nabugabo lakes (LVR satellite lakes) fish species

Natural populations of fish species in Lake Victoria Region (LVR) have under gone dramatic changes including severe reduction in sizes, division of original stocks into disjunct subunits, and segregation into several isolated population units either within a single water body or even worse into separate waters. In addition, these changes have been either preceded or precipitated by introductions of non-indigenous species that out competed the native forms and in case of closely related species genetically swamped them through hybridisation. The latter is especially the case in Nabugabo lakes. Such events lead to fragmentation of populations, which results in reduction in genetic diversity due to genetic drift, inbreeding and reduced or lack of gene flow among independent units. Such phenomena make the continued existence of fisheries stocks in the wild precarious, more so in the face of the competition from exotic species. Species introductions coupled with growing exploitation pressure of the fisheries of these lakes have put the native stocks at risk. Nabugabo lakes harbor cichlid species that are unique to these lakes more so species of the cichlid complex. In this paper the ecological status and genetic viability of key Nabugabo lakes fish species is examined and management options are discussed.