The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) mediates the major pathway for cholesterol exit from non-hepatic cells and thereby controls the rate-limiting step in the biogenesis of high density lipoprotein (HDL) particles. In humans,ABCA1 deficiency results in Tangier disease, characterized by low levels of HDL cholesterol, cellular cholesterol accumulation and increased risk for atherosclerosis. More than 100 coding variants have been described in the ABCA1 gene. We attempted to understand how both naturally occurring and engineered mutations in ABCA1 impact its role in cholesterol transport in a variety of in vitro and in vivo systems. We attempted to correlate specific genetic variants in ABCA 1 with phenotypes in patients carrying the sevariants, and used an evolutionary approach to predict which specific variants in ABCA1would impact its function. We then turned to the study of tissue-specific genetic deletion of ABCA1 in mice to study its role in HDL biogenesis, atherosclerosis and glucose metabolism. We found that intestinal ABCA1 is an important site of HDL biogenesis and that activation of intestinal ABCA1 raises HDL levels in vivo. Hepatic ABCA1, which is a major site of HDL biogenesis, was shown to significantly contribute to susceptibility to atherosclerosis. Finally, we show that ABCA1 plays an unsuspected role in B-cell function and insulin secretion. These studies have contributed to our understanding of the impact of genetic variation in ABCA1 on diverse biological and pathological processes, and have identified novel aspects of ABCA 1 function in specific cell types. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

A long term study of fish populations on the Bonaparte Plateau, B.C., has revealed the possibility of 2-year cyclic recruitment variation in the pygmy pikeminnow (Ptychocheilus oregonensis). This thesis reviews possible causes of the cycle, and evaluates an inexpensive and non-destructive visual survey method to estimate juvenile population numbers over short summer periods while pikeminnow juveniles are recruiting to the lakes and dying rapidly, for use in future studies of the cyclic pattern. To provide an index of the abundance of juvenile pikeminnow, strip-transect surveys were conducted from shore. Each strip transect area was a full circumference of each of three study lakes, and extended from shore to a distance of up to 3 meters offshore. The visual surveys were shown to be accurate and repeatable when estimating the number of fish and the lengths of the fish in a shoal. The strip transects provide an index of abundance for juvenile northern pikeminnow and this index of abundance can be used to calculate daily summer and interannual mortality rates, providing estimates close to those predicted from the Lorenzen model for size-dependent mortality rates of fish in general. Stationary point surveys were also conducted to investigate juvenile pikeminnow behaviour, and these point surveys reveal a link between sunlight intensity and pikeminnow activity, and provide evidence of direct agonistic interactions between age 0 and age 1 juveniles, which could result in higher mortality rates of age 0 fish when age 1 fish are abundant. Analysis of survey data collected to date over five years from three lakes supports the possibility of a recruitment cycle with lakes out of phase with each other, suggesting that ecological interactions drive the cycles. These interactions are worthy of further investigation. / Science, Faculty of / Zoology, Department of / Graduate

This thesis reports on a design and modeling of a micro-machined gyroscope. The proposed sensor is a dual mass type, electro-statically driven to primary mode oscillation and senses, capacitively, the output signal. Full decoupling between drive and sense modes minimizes the mechanical crosstalk and based on this a novel gyroscope is designed and modeled which has separate sensing and driving masses. The dual mass gyroscope is designed such that driving and sensing resonant frequency is 23101 Hz with 0% mismatch (in simulation)with quality factor of 31.6227 and bandwidth of 730.51Hz. The gyroscope when actuated in simulation with 25V ac and 10V dc showed sensing capacitance variation of 126aF for 1 rad/s with base capacitance of 244.16fF. To the design of the gyroscope a new semi automatic tool was formulated for the noise analysis and noise based optimization of the resonant MEMS structures. Design of a sensitive gyroscope needs to take into account the noise shaping induced by damping phenomena at micro scale and is critical for optimization. The analysis was further extended to the design of the gyroscope and estimation shows that there is a trade of between the S/N ratio and the sensitivity and the design could be made much better in-terms of S/N by tuning its resonant frequency to 10⁶Hz. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate

Copy number variation (CNV) is a class of genetic variation where large segments of the genome vary in copy number among different individuals. It has become clear in the past decade that CNV affects a significant proportion of the human genome and can play an important role in human disease. With array-based copy number detection and the current generation of sequencing technologies, our ability to discover genetic variants is running far ahead of our ability to interpret their functional impact. One approach to close this gap is to explore statistical association between genetic variants and phenotypes. In contrast to the successes of genome-wide association studies for common disease using common single nucleotide polymorphism (SNP) as markers, the majority of disease CNVs discovered so far have low population frequencies and are mainly involved in rare developmental disorders. Another strategy to improve interpretation of genomic variants is to establish a predictive understanding of their functional impact. Large heterozygous deletions are of particular interest, since (i) loss-of-function (LOF) of coding sequences encompassed by large deletions can be relatively unambiguously ascribed and (ii) haploinsufficiency (HI), wherein only one functional copy of a gene is not sufficient to maintain normal phenotype, is a major cause of dominant diseases. This thesis explored both approaches. Initially, I developed an informatics pipeline for robust discovery of CNVs from large numbers of samples genotyped using the Affymetrix whole-genome SNP array 6.0, to support both the association-based and prediction-based study. For the disease association strategy, I studied the role of both common and rare CNVs in severe early-onset obesity using a case-control design, from which a rare 220kb heterozygous deletion at 16p11.2 that encompasses SH2B1 was found causal for the phenotype and an 8kb common deletion upstream of NEGR1 was found to be significantly associated with the disease, particularly in females. Using the prediction-based approach, I characterized the properties of HI genes by comparing with genes observed to be deleted in apparently healthy individuals and I developed a prediction model to distinguish HI and haplosufficient (HS) genes using the most informative properties identified from these comparisons. An HI-based pathogenicity score was devised to distinguish pathogenic genic CNVs from benign genic CNVs. Finally, I proposed a probabilistic diagnostic framework to incorporate population variation, and integrate other sources of evidence, to enable an improved, and quantitative, identification of causal variants.

The objectives of this study were to describe the variability, to evaluate the combining ability, and to calculate the heritability values for certain characteristics of Coastal Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco var. menziesii. Four trees (A, B, E, and 11) were selected on the University of British Columbia Campus. Three of them were selected from the local natural population while the fourth came from an unknown provenance. The investigation of variation included phonological observations on flushing and flowering times, and quantitative descriptions of pollen, seed and cone size. A survey of Campus trees showed that Douglas-fir is extremely variable in the time of flushing and flowering, the size of pollen, seed and cones, and the total number of filled seeds. Times of flushing did not determine times of flowering. There was a strong negative correlation between pollen size and time of flowering. This suggests existence of adaptive significance to adverse climatic condition. Variation in width of the cone was greater than in cone length. Seed germination percentage appeared to be inherited on a single factor basis, and the results from Fl crosses substantiated the suggestion that tree E might possess a homozygous dominant state. Filled seeds have not been obtained from tree B when it was self-pollinated. This supports Orr-Ewing's theory, that self-sterility might be an inbreeding effect caused by the action of lethal genes, when brought together in a homozygous state. Combining ability of the four study trees was tested by a polyallel cross with all sixteen possible combinations. The cross was completed in 1962, using three different pollination methods; dry, wet and dry-wet. Mortality of conelets was lowest in the case of wet pollination. Losses were doubled with dry pollination. Of 302 seed conelets pollinated, 201 were collected and 8,004 seeds were extracted from them. The number of filled seeds per cone was lowest in the cases of self-pollination (1.91) and wind pollination (3.05). Cross pollination on the average surpassed wind pollination by 4.6 times, and the self-pollination by 7.3 times, producing 13.81 filled seeds per cone. In order to minimize and test the variability due to environmental effects, the seedlings were grown under controlled environmental conditions. Two Percival (PGC-78) units were employed, one of them simulated long-day (15 hours illumination) and the other short-day (10 hours illumination) effects for 132 days. Tree 11, which was different in origin from the local provenance trees, showed the best combining ability as a seed parent. Progeny from crosses between trees from the same populations showed smaller values compared to progenies from crosses between trees from different populations. Epicotyls, for example, were 73-78 per cent longer on seedlings from tree 11 compared to seedlings from trees B and E, when pollen from tree A was applied. Obviously, further investigation of intra-specific crosses has practical merit. Heritability values in the narrow sense were calculated for twelve different juvenile seedling characteristics, and the practical application in relation to forest tree improvement was briefly discussed. / Forestry, Faculty of / Graduate

Many studies have reported individual differences in resting metabolic rate (RMR), the energetic cost of self-maintenance. Differences among individuals in the energetic cost of self-maintenance may influence life-history decisions and hence, fitness. In this study, we examined potential causes of intra-specific variation in RMR in zebrafish, Danio rerio. First, the repeatability of RMR was determined to check whether a single measure was reflective of future physiological performance. As predicted, RMR was repeatable over a period of three weeks. However, none of stress-coping style, baseline cortisol levels, metabolically-active organ (gill, heart, intestine and liver) mass, aggression or activity levels were correlated with RMR, i.e. none of these factors were significant contributors to individual variation in RMR. These results imply that other factors must be sought to explain the inter-individual variation in RMR observed in zebrafish.

In this thesis, we review the basic notions related to univariate regular variation and study some fundamental properties of regularly varying random variables. We then consider the notion of regular variation in the multivariate case. After collecting some results from multivariate regular variation for random vectors with values in $\mathbb{R}_{+}^{d}$, we discuss its properties and examine several examples of multivariate regularly varying random vectors such as independent and identically distributed random vectors, fully dependent random vectors and other models. We also present the elements of univariate and multivariate extreme value theory and emphasize the connection with multivariate regular variation. Some measures of extreme dependence such as the stable tail dependence function and the Pickands dependence function are presented. We end the study by conducting a data analysis using financial data. In the univariate case, graphical tools such as quantile-quantile plots, mean excess plots and Hill plots are used in order to determine the underlying distribution of the univariate data. In the multivariate case, non-parametric estimators of the stable tail dependence function and the Pickands dependence function are used to describe the dependence structure of the multivariate data.

This study investigates variable positioning of adverbs in compound verb tenses in vernacular Quebec French using the sociolinguistic framework of Variation Theory (Weinreich et al. 1968; Labov 1969). While variable adverb placement is addressed in both the prescriptive and linguistic literature, whether their explanations for it hold in practice remains to be determined; quantitative research of this phenomenon in usage-based corpora is limited, and rare in French. The research objectives are therefore to determine the productivity of variable adverb placement in French in these verbal contexts, to uncover the linguistic and/or social factors which constrain it, and to evaluate the extent to which current treatments of this variable in the literature accurately reflect what occurs in speech. Data is thus extracted from a corpus of spontaneous discourse, is coded for several linguistic and social factors, and is quantitatively analysed using standard variationist methodology (Poplack & Tagliamonte 2001). Overall rates of variant use suggest that variable adverb placement is robust, with adverbs occurring just slightly more frequently after the past participle than between the auxiliary and the participle; placement at the beginning of the sentence is rare. The results of the distributional and multivariate analyses largely confirm the purported conditioning effects of the tested linguistic factors, suggesting that prescriptive and theoretical linguistic approaches are generally correct in their accounts of this phenomenon. However, closer investigation reveals these effects to be sensitive to the lexical identity of the adverb, namely, their particular placement preferences; once these positioning predilections are taken into consideration, the conditioning effects of the linguistic factors essentially disappear. Sociodemographic factors are also found to be mildly implicated in variable adverb placement, and these too are sensitive to the influence of the lexical identity of the adverb. Ultimately, it is argued that this variable is primarily lexically-constrained, a finding which can be only minimally and indirectly inferred from the relevant literature. Taken together, the results of this study provide new and vital insight into the mechanisms underlying variable adverb placement in French, and also highlight the importance of quantitatively investigating such variable language phenomena in corpora of vernacular speech.

By definition "adaptability" is the ability of living systems to cope with change. Genetic adaptability requires the production of genetic variation. The view that variation production is undirected or random, i.e. unconnected with selection, implies that selection does not tailor genetic adaptability. But many genetic elements are known to modify processes of variation production, and secondary selection can act on them, so that view is not justified. Over the longer term, natural selection 'favors' properties important, in maintaining immediate fitness, as well as properties important for persistence in the short term. Genetic adaptability is less important in the short term, and is ignored in models based on short term definitions of fitness (e.g. relative effective rate of increase). If "fitness" is to be "the properties favored by natural selection", then its definition should be time scale dependent. Currently prevalent short term definitions of the action of natural selection should not be allowed to hamper consideration of the role of slow processes in determining long term evolutionary patterns. A review of patterns in genome size, and the existing explanations for them, reveals that most explanations are based on notions of adaptedness to the state of the environment. An explanation of genome size patterns based on the rate of change of environments is proposed. It is hypothesized that part of the genome is involved in regulating variation production, and that more DNA means slower production of additive genetic variation. This new hypothesis is simple, general, and testable, but requires more evidence. The question is raised of whether genomes might be organized to facilitate the adjustment of genetic variation production by natural selection. / Science, Faculty of / Zoology, Department of / Graduate

Sense amplifiers are important circuit components of a dynamic random access memory (DRAM), which forms the main memory of digital computers. The ability of the sense amplifier to detect and amplify voltage signals to correctly interpret data in DRAM cells cannot be understated. The sense amplifier plays a significant role in the overall speed of the DRAM. Sense amplifiers require matched transistors for optimal performance. Hence, the effects of mismatch through process variations must be minimized. This thesis presents a research which leads to optimal nanoscale CMOS sense amplifiers by incorporating the effects of process variation early in the design process. The effects of process variation on the performance of a standard voltage sense amplifier, which is used in conventional DRAMs, is studied. Parametric analysis is performed through circuit simulations to investigate which parameters have the most impact on the performance of the sense amplifier. The figures-of-merit (FoMs) used to characterize the circuit are the precharge time, power dissipation, sense delay and sense margin. Statistical analysis is also performed to study the impact of process variations on each FoM. By analyzing the results from the statistical study, a method is presented to select parameter values that minimize the effects of process variation. A design flow algorithm incorporating dual oxide and dual threshold voltage based techniques is used to optimize the FoMs for the sense amplifier. Experimental results prove that the proposed approach improves precharge time by 83.9%, sense delay by 80.2% sense margin by 61.9%, and power dissipation by 13.1%.