Rare variants contribute disproportionately to quantitative trait variation in yeast.

How variants with different frequencies contribute to trait variation is a central question in genetics. We use a unique model system to disentangle the contributions of common and rare variants to quantitative traits. We generated ~14,000 progeny from crosses among 16 diverse yeast strains and identified thousands of quantitative trait loci (QTLs) for 38 traits. We combined our results with sequencing data for 1011 yeast isolates to show that rare variants make a disproportionate contribution to trait variation. Evolutionary analyses revealed that this contribution is driven by rare variants that arose recently, and that negative selection has shaped the relationship between variant frequency and effect size. We leveraged the structure of the crosses to resolve hundreds of QTLs to single genes. These results refine our understanding of trait variation at the population level and suggest that studies of rare variants are a fertile ground for discovery of genetic effects

CRISPR/CASTE: Functional Genomic Studies of the Major Evolutionary Innovations of Ants

Ants are social organisms that live in groups and depend intimately on their nestmates for growth and survival. Ants have evolved a number of highly sophisticated, social phenotypes that allow them to form coherent colonies. This thesis explores two particularly derived features of ant biology: complex chemical communication and caste plasticity. To study these features, I had a particular focus on generating and characterizing germ-line mutants. I believe that the study of mutants, and applying molecular biology methods more generally, can lead to insights in ant biology that would not be possible with more traditional methods. I first describe my efforts to develop a CRISPR protocol to make the first germ-line mutant ant lines. I conducted this work using a unique, clonal ant species, Ooceraea biroi, that has many properties making it favorable for laboratory genetics studies. Establishing this protocol required a multi-year optimization process to account for many of the particular features of ant biology, such as egg production and incubation, growing and maintaining lines, and optimizing experimental treatments to produce high mutagenesis rates. I next describe the mutants I generated using these methods, null mutants of a highly conserved insect protein called orco. Orco, or olfactory receptor co-receptor, is required for the function of an important class of chemosensory proteins, the odorant receptors, in insects. I created orco mutant ants and found that they have striking deficiencies in their social behavior and fitness, including an inability to nest with other ants or follow chemical pheromone trails and severely reduced life span and fecundity. These results supported the growing consensus that odorant receptors are key chemosensory proteins for pheromone perception in ants, and provided a new window into ant social behavior and collective organization. Unexpectedly, and unlike orco mutants in other types of insects, I also found that orco mutant ants have severe neuro-anatomical deficiencies, including a loss of most antennal lobe glomeruli and sensory neurons in the antenna. This surprising result implies that orco may play an important role in antennal lobe morphology in ants, and could provide insights into the development and evolution of complex olfactory systems. The following chapter is a critical literature review of the development and evolution of morphological castes, such as workers and queens, in ants. I describe a stereotyped and previously overlooked pattern of morphological variation in ants, and illustrate how this pattern may provide some early insights into the molecular mechanisms of caste plasticity. This chapter provides a falsifiable, mechanistic framework for caste development and suggests a route to start looking for the actual molecules that regulate this interesting process. Finally, I start to realize this promise by characterizing a caste mutant in the laboratory. I discovered a spontaneous ‘winged mutant’ that belongs to one of the known clonal lineages of O. biroi and aberrantly expresses queen-like morphology and behavior at worker-like body sizes. These mutants bear a striking resemblance to one class of ant species with derived caste systems, the recurrently evolved workerless social parasites. They could thus provide a window into the mutations that give rise to these unique ants. Overall, this thesis represents the first characterization of mutant lines in ants, and I hope it demonstrates how this approach can be used to generate robust conclusions about ant biology

The role of visual adaptation in cichlid fish speciation

D. Shane Wright (1) , Ole Seehausen (2), Ton G.G. Groothuis (1), Martine E. Maan (1) (1) University of Groningen; GELIFES; EGDB(2) Department of Fish Ecology & Evolution, EAWAG Centre for Ecology, Evolution and Biogeochemistry, Kastanienbaum AND Institute of Ecology and Evolution, Aquatic Ecology, University of Bern.In less than 15,000 years, Lake Victoria cichlid fishes have radiated into as many as 500 different species. Ecological and sexual sel ection are thought to contribute to this ongoing speciation process, but genetic differentiation remains low. However, recent work in visual pigment genes, opsins, has shown more diversity. Unlike neighboring Lakes Malawi and Tanganyika, Lake Victoria is highly turbid, resulting in a long wavelength shift in the light spectrum with increasing depth, providing an environmental gradient for exploring divergent coevolution in sensory systems and colour signals via sensory drive. Pundamilia pundamila and Pundamilia nyererei are two sympatric species found at rocky islands across southern portions of Lake Victoria, differing in male colouration and the depth they reside. Previous work has shown species differentiation in colour discrimination, corresponding to divergent female preferences for conspecific male colouration. A mechanistic link between colour vision and preference would provide a rapid route to reproductive isolation between divergently adapting populations. This link is tested by experimental manip ulation of colour vision - raising both species and their hybrids under light conditions mimicking shallow and deep habitats. We quantify the expression of retinal opsins and test behaviours important for speciation: mate choice, habitat preference, and fo raging performance

Discovering Higher-order SNP Interactions in High-dimensional Genomic Data

In this thesis, a multifactor dimensionality reduction based method on associative classification is employed to identify higher-order SNP interactions for enhancing the understanding of the genetic architecture of complex diseases. Further, this thesis explored the application of deep learning techniques by providing new clues into the interaction analysis. The performance of the deep learning method is maximized by unifying deep neural networks with a random forest for achieving reliable interactions in the presence of noise

Evolution of a supergene that regulates a trans-species social polymorphism

Supergenes are clusters of linked genetic loci that jointly affect the expression of complex phenotypes, such as social organization. Little is known about the origin and evolution of these intriguing genomic elements. Here we analyse whole-genome sequences of males from native populations of six fire ant species and show that variation in social organization is under the control of a novel supergene haplotype (termed Sb), which evolved by sequential incorporation of three inversions spanning half of a 'social chromosome'. Two of the inversions interrupt protein-coding genes, resulting in the increased expression of one gene and modest truncation in the primary protein structure of another. All six socially polymorphic species studied harbour the same three inversions, with the single origin of the supergene in their common ancestor inferred by phylogenomic analyses to have occurred half a million years ago. The persistence of Sb along with the ancestral SB haplotype through multiple speciation events provides a striking example of a functionally important trans-species social polymorphism presumably maintained by balancing selection. We found that while recombination between the Sb and SB haplotypes is severely restricted in all species, a low level of gene flux between the haplotypes has occurred following the appearance of the inversions, potentially mitigating the evolutionary degeneration expected at genomic regions that cannot freely recombine. These results provide a detailed picture of the structural genomic innovations involved in the formation of a supergene controlling a complex social phenotype

A genetic perspective on social insect castes: A synthetic review and empirical study

The process of caste differentiation is central to understanding insect sociality because it is castes that enable division of labor. Presumably selection favors colonies that can divide labor in response to environmental demands, and for many taxa genetic factors are an important part of this equation. In my thesis, I first provide a framework for understanding genetic and epigenetic effects on caste. From mostly ant, bee and termite examples, I make clear that genotype-caste associations can evolve in different and sometimes complex ways and can involve additive or non-additive genetic effects that, in turn, may arise directly from focal individuals or indirectly via their social partners. I use this framework to launch my empirical analysis of my own. In my second chapter, I test alternative hypotheses that describe how genes evolve under direct versus indirect selection. I predict that genes associated with reproductive castes will evolve mostly under direct selection and show patterns of nucleotide substitution that differ from those associated with non-reproductive helper castes and thus evolving under indirect selection. Using an RNA-Seq dataset for the Eastern subterranean termite, I found that caste-biased and un-biased genes evolve at similar rates, most consistent with purifying selection. I therefore did not detect an obvious pattern of molecular evolution that is diagnostic of indirect or \u27kin\u27 selection. I did discover other, more subtle patterns of nucleotide substitution that I discuss in the context of termite social biology

AI Solutions for MDS: Artificial Intelligence Techniques for Misuse Detection and Localisation in Telecommunication Environments

This report considers the application of Articial Intelligence (AI) techniques to the problem of misuse detection and misuse localisation within telecommunications environments. A broad survey of techniques is provided, that covers inter alia rule based systems, model-based systems, case based reasoning, pattern matching, clustering and feature extraction, articial neural networks, genetic algorithms, arti cial immune systems, agent based systems, data mining and a variety of hybrid approaches. The report then considers the central issue of event correlation, that is at the heart of many misuse detection and localisation systems. The notion of being able to infer misuse by the correlation of individual temporally distributed events within a multiple data stream environment is explored, and a range of techniques, covering model based approaches, `programmed' AI and machine learning paradigms. It is found that, in general, correlation is best achieved via rule based approaches, but that these suffer from a number of drawbacks, such as the difculty of developing and maintaining an appropriate knowledge base, and the lack of ability to generalise from known misuses to new unseen misuses. Two distinct approaches are evident. One attempts to encode knowledge of known misuses, typically within rules, and use this to screen events. This approach cannot generally detect misuses for which it has not been programmed, i.e. it is prone to issuing false negatives. The other attempts to `learn' the features of event patterns that constitute normal behaviour, and, by observing patterns that do not match expected behaviour, detect when a misuse has occurred. This approach is prone to issuing false positives, i.e. inferring misuse from innocent patterns of behaviour that the system was not trained to recognise. Contemporary approaches are seen to favour hybridisation, often combining detection or localisation mechanisms for both abnormal and normal behaviour, the former to capture known cases of misuse, the latter to capture unknown cases. In some systems, these mechanisms even work together to update each other to increase detection rates and lower false positive rates. It is concluded that hybridisation offers the most promising future direction, but that a rule or state based component is likely to remain, being the most natural approach to the correlation of complex events. The challenge, then, is to mitigate the weaknesses of canonical programmed systems such that learning, generalisation and adaptation are more readily facilitated