Evolvable Neuronal Paths: A Novel Basis for Information and Search in the Brain

We propose a previously unrecognized kind of informational entity in the brain that is capable of acting as the basis for unlimited hereditary variation in neuronal networks. This unit is a path of activity through a network of neurons, analogous to a path taken through a hidden Markov model. To prove in principle the capabilities of this new kind of informational substrate, we show how a population of paths can be used as the hereditary material for a neuronally implemented genetic algorithm, (the swiss-army knife of black-box optimization techniques) which we have proposed elsewhere could operate at somatic timescales in the brain. We compare this to the same genetic algorithm that uses a standard ‘genetic’ informational substrate, i.e. non-overlapping discrete genotypes, on a range of optimization problems. A path evolution algorithm (PEA) is defined as any algorithm that implements natural selection of paths in a network substrate. A PEA is a previously unrecognized type of natural selection that is well suited for implementation by biological neuronal networks with structural plasticity. The important similarities and differences between a standard genetic algorithm and a PEA are considered. Whilst most experiments are conducted on an abstract network model, at the conclusion of the paper a slightly more realistic neuronal implementation of a PEA is outlined based on Izhikevich spiking neurons. Finally, experimental predictions are made for the identification of such informational paths in the brain

Inferring Determinants of Viral Transmission using Short-Read Sequence Data

In order to spread, pathogens must not only be able to grow within an infected host, but also transmit to found new infections. In this thesis, I present a new population genetic framework generating insights into viral transmission events based upon genome sequence data collected before and after transmission. Previous attempts at bottleneck estimation have neglected the underlying genetic structure of viruses, considering instead less informative single-locus statistics. Here I examine the problem of constructing reliable haplotypes from short-read sequence data, considering the performance of both exhaustive and minimal approaches in capturing linkage characteristics of the viral population. I present a simple method for bottleneck inference rooted in a multi-locus context supported by haplotype inference. I next develop this model to incorporate selection for increased transmissibility, the effects of within-host growth, and noise arising from the sequencing process. Central to the method is a probabilistic model where unknown variables are marginalised over using compound distributions. A maximum likelihood scheme is employed in model selection where a machine-learning approach, referred to as adaptive BIC, was invented for the interpretation of likelihood statistics. I rigorously validate the performance of my model, identifying regimes wherein selection inference is feasible, and benchmark it against current state-of-the-art bottleneck inference algorithms, demonstrating a higher degree of realism and specificity within my approach. I next extend the transmission model to account for advanced aspects such as selection for within-host viral adaptation, constructing a more realistic description of within-host growth processes. Accounting for within-host selection, I apply my transmission model to an experimental influenza transmission dataset in ferrets, providing novel quantitative insights. I further explore limitations inherent to my model and consider regimes wherein the neutral version of my algorithm may be applied. I define and infer effective within-host selection for an influenza transmission study in pigs, employing my model to deduce a generally narrow transmission bottleneck in these animals. Finally, I consider an influenza human challenge study and compute an effective single-segment within-host selection profile on the basis of an existing multi-segment characterisation. I discuss the relationship between human challenge studies and influenza infections occurring in a natural context.My PhD was funded by a Wellcome Trust Studentship with grant number 105365/Z/14/Z

Explicit Building Block Multiobjective Evolutionary Computation: Methods and Applications

This dissertation presents principles, techniques, and performance of evolutionary computation optimization methods. Concentration is on concepts, design formulation, and prescription for multiobjective problem solving and explicit building block (BB) multiobjective evolutionary algorithms (MOEAs). Current state-of-the-art explicit BB MOEAs are addressed in the innovative design, execution, and testing of a new multiobjective explicit BB MOEA. Evolutionary computation concepts examined are algorithm convergence, population diversity and sizing, genotype and phenotype partitioning, archiving, BB concepts, parallel evolutionary algorithm (EA) models, robustness, visualization of evolutionary process, and performance in terms of effectiveness and efficiency. The main result of this research is the development of a more robust algorithm where MOEA concepts are implicitly employed. Testing shows that the new MOEA can be more effective and efficient than previous state-of-the-art explicit BB MOEAs for selected test suite multiobjective optimization problems (MOPs) and U.S. Air Force applications. Other contributions include the extension of explicit BB definitions to clarify the meanings for good single and multiobjective BBs. A new visualization technique is developed for viewing genotype, phenotype, and the evolutionary process in finding Pareto front vectors while tracking the size of the BBs. The visualization technique is the result of a BB tracing mechanism integrated into the new MOEA that enables one to determine the required BB sizes and assign an approximation epistasis level for solving a particular problem. The culmination of this research is explicit BB state-of-the-art MOEA technology based on the MOEA design, BB classifier type assessment, solution evolution visualization, and insight into MOEA test metric validation and usage as applied to test suite, deception, bioinformatics, unmanned vehicle flight pattern, and digital symbol set design MOPs

A Multiobjective Approach Applied to the Protein Structure Prediction Problem

Interest in discovering a methodology for solving the Protein Structure Prediction problem extends into many fields of study including biochemistry, medicine, biology, and numerous engineering and science disciplines. Experimental approaches, such as, x-ray crystallographic studies or solution Nuclear Magnetic Resonance Spectroscopy, to mathematical modeling, such as minimum energy models are used to solve this problem. Recently, Evolutionary Algorithm studies at the Air Force Institute of Technology include the following: Simple Genetic Algorithm (GA), messy GA, fast messy GA, and Linkage Learning GA, as approaches for potential protein energy minimization. Prepackaged software like GENOCOP, GENESIS, and mGA are in use to facilitate experimentation of these techniques. In addition to this software, a parallelized version of the fmGA, the so-called parallel fast messy GA, is found to be good at finding semi-optimal answers in reasonable wall clock time. The aim of this work is to apply a Multiobjective approach to solving this problem using a modified fast messy GA. By dividing the CHARMm energy model into separate objectives, it should be possible to find structural configurations of a protein that yield lower energy values and ultimately more correct conformations

Statistical Genetics and Direct Coupling Analysis beyond Quasi-Linkage Equilibrium

This work is about statistical genetics, an interdisciplinary topic between Statistical Physics and Population Biology. Our focus is on the phase of Quasi-Linkage Equilibrium (QLE) which has many similarities to equilibrium statistical mechanics, and how the stability of that phase is lost. The QLE phenomenon was discovered by Motoo Kimura and was extended and generalized to the global genome scale by Neher & Shraiman (2011). What we will refer to as the Kimura-Neher-Shraiman (KNS) theory describes a population evolving due to the mutations, recombination, genetic drift, natural selection (pairwise epistatic fitness). The main conclusion of KNS is that QLE phase exists at sufficiently high recombination rate ($r$) with respect to the variability in selection strength (fitness). Combining these results with the techniques of the Direct Coupling Analysis (DCA) we show that in QLE epistatic fitness can be inferred from the knowledge of the (dynamical) distribution of genotypes in a population. Extending upon our earlier work Zeng & Aurell (2020) here we present an extension to high mutation and recombination rate. We further consider evolution of a population at higher selection strength with respect to recombination and mutation parameters ($r$ and $\mu$). We identify a new bi-stable phase which we call the Non-Random Coexistence (NRC) phase where genomic mutations persist in the population without either fixating or disappearing. We also identify an intermediate region in the parameter space where a finite population jumps stochastically between QLE-like state and NRC-like behaviour. The existence of NRC-phase demonstrates that even if statistical genetics at high recombination closely mirrors equilibrium statistical physics, a more apt analogy is non-equilibrium statistical physics with broken detailed balance, where self-sustained dynamical phenomena are ubiquitous