Kathleen Hill

The University of Western Ontario | UWO · Department of Biology

The progression of primary tumors to metastases remains a significant roadblock to the treatment of most cancers. Emerging evidence has identified genes that specifically affect metastasis and are potential therapeutic targets for managing tumor progression. However, these genes can have dual tumor promoter and suppressor functions that are context...

Astroviruses are a family of genetically diverse viruses associated with disease in humans and birds with significant health effects and economic burdens. Astrovirus taxonomic classification includes two genera, Avastrovirus and Mamastrovirus. However, with next-generation sequencing, broader interspecies transmission has been observed necessitatin...

Bidirectional communication between the mitochondria and the nucleus is required for several physiological processes, and the nuclear epigenome is a key mediator of this relationship. ncRNAs are an emerging area of discussion for their roles in cellular function and regulation. In this review, we highlight the role of mitochondrial-encoded ncRNAs a...

Abstract This study provides comprehensive quantitative evidence suggesting that adaptations to extreme temperatures and pH imprint a discernible environmental component in the genomic signature of microbial extremophiles. Both supervised and unsupervised machine learning algorithms were used to analyze genomic signatures, each computed as the k-me...

We present an interactive Deep Learning-based software tool for Unsupervised Clustering of DNA Sequences (iDeLUCS), that detects genomic signatures and uses them to cluster DNA sequences, without the need for sequence alignment or taxonomic identifiers. iDeLUCS is scalable and user-friendly: Its graphical user interface, with support for hardware a...

Background RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are po...

This study presents a machine learning-based analysis supporting the hypothesis that microbial adapta- tions to extreme temperatures and pH conditions can result in a pervasive environmental component within their genomic signatures. To this end, an alignment-free method was used in conjunction with both supervised and unsupervised machine learning...

We present an interactive Deep Learning-based software tool for Unsupervised Clustering of DNA Sequences ( i DeLUCS), that detects genomic signatures and uses them to cluster DNA sequences, without the need for sequence alignment or taxonomic identifiers. i DeLUCS is scalable and user-friendly: Its graphical user interface, with support for hardwar...

BACKGROUND The emergence of SARS-CoV-2 variants with mutations associated with increased transmissibility and virulence is an ongoing public health concern in Ontario, Canada. Characterizing how the mutational patterns of the SARS-CoV-2 genome have changed over time can shed light on the driving factors, including selection for increased fitness an...

Background The emergence of SARS-CoV-2 variants with mutations associated with increased transmissibility and virulence is a public health concern in Ontario, Canada. Characterizing how the mutational patterns of the SARS-CoV-2 genome have changed over time can shed light on the driving factors, including selection for increased fitness and host im...

SomaticSiMu is an in silico simulator of single and double base substitutions, and single base insertions and deletions in an input genomic sequence to mimic mutational signatures. SomaticSiMu outputs simulated DNA sequences and mutational catalogues with imposed mutational signatures. The tool is the first mutational signature simulator featuring...

Gluconacetobacter diazotrophicus is a nitrogen (N) fixing bacterium originally isolated from sugarcane in Brazil. Understanding the interactions between this bacterium and plants is important to exploit the nitrogen-fixing feature of G. diazotrophicus in different crops. Research was conducted to establish, monitor and optimize methods for introduc...

Analyzing the information-rich content of RNA can help uncover genetic events associated with social insect castes or other social polymorphisms. Here, we exploit a series of cDNA libraries previously derived from whole-body tissue of different castes as well as from three behaviourally distinct populations of the Eastern subterranean termite Retic...

We present a novel De ep L earning method for the U nsupervised C lustering of DNA S equences (DeLUCS) that does not require sequence alignment, sequence homology, or (taxonomic) identifiers. DeLUCS uses Frequency Chaos Game Representations ( FCGR ) of primary DNA sequences, and generates “mimic” sequence FCGRs to self-learn data patterns (genomic...

Alternatives to synthetic nitrogen fertilizer are needed to reduce the costs of crop production and offset environmental damage. Nitrogen-fixing bacterium Gluconacetobacter diazotrophicus has been proposed as a possible biofertilizer for monocot crop production. However, the colonization of G. diazotrophicus in most monocot crops is limited and dee...

SomaticSiMu is an in silico simulator of single and double base substitutions, and single base insertions and deletions in an input genomic sequence to mimic mutational signatures. SomaticSiMu outputs simulated DNA sequences and mutational catalogues with imposed mutational signatures. The tool is the first mutational signature simulator featuring...

We present a novel Deep Learning method for the Unsupervised Classification of DNA Sequences (DeLUCS) that does not require sequence alignment, sequence homology, or (taxonomic) identifiers. DeLUCS uses Chaos Game Representations (CGRs) of primary DNA sequences, and generates “mimic” sequence CGRs to self-learn data patterns (genomic signatures) th...

The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some...

In the study of genetic diversity in non-model species there is a notable lack of the low-cost, high resolution tools that are readily available for model organisms. Genotyping microarray technology for model organisms is well-developed, affordable, and potentially adaptable for cross-species hybridization. The Mouse Diversity Genotyping Array (MDG...

The 2019 novel coronavirus (renamed SARS-CoV-2, and generally referred to as the COVID-19 virus) has spread to 184 countries with over 1.5 million confirmed cases. Such major viral outbreaks demand early elucidation of taxonomic classification and origin of the virus genomic sequence, for strategic planning, containment, and treatment. This paper i...

As of February 3, 2020, the 2019 Novel Coronavirus (2019-nCoV) spread to 27 countries with 362 deaths and more than 17000 confirmed cases. 2019-nCoV is being compared to the infamous SARS coronavirus outbreak. Between November 2002 and July 2003, SARS resulted in 8098 confirmed cases worldwide with a 9.6% death rate and 774 deaths. Mainland China a...

MLDSP-GUI (Machine Learning with Digital Signal Processing) is an open-source, alignment-free, ultrafast, computationally lightweight, standalone software tool with an interactive Graphical User Interface (GUI) for comparison and analysis of DNA sequences. MLDSP-GUI is a general-purpose tool that can be used for a variety of applications such as ta...

MLDSP-GUI (Machine Learning with Digital Signal Processing) is an open-source, alignment-free, ultrafast, computationally lightweight, standalone software tool with an interactive Graphical User Interface (GUI) for comparison and analysis of DNA sequences. MLDSP-GUI is a general-purpose tool that can be used for a variety of applications such as ta...

Background Although software tools abound for the comparison, analysis, identification, and classification of genomic sequences, taxonomic classification remains challenging due to the magnitude of the datasets and the intrinsic problems associated with classification. The need exists for an approach and software tool that addresses the limitations...

This paper considers how an interdisciplinary approach to the “wicked problem” of plastics pollution offers unique and important collaborative possibilities. Specially, the paper considers the approach of the Synthetic Collective, a group comprising artists, humanities scholars, and scientists. Considering first how artists and scientists might res...

Mutation cluster analysis is critical for understanding certain mutational mechanisms relevant to genetic disease, diversity, and evolution. Yet, whole genome sequencing for detection of mutation clusters is prohibitive with high cost for most organisms and population surveys. Single nucleotide polymorphism (SNP) genotyping arrays, like the Mouse D...

Power of the tests under alternative hypothesis (1) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05....

Power of the tests under alternative hypothesis (2) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05....

Data example 3. Chromosomal positions of SNP genotype differences observed along chromosome 1 for a comparison of primary mammary tumor and lung tissue with metastases from the same MMTV-PyMT transgenic mouse. (CSV)

Power performance of statistics related to R¯(d), R˜(d), and C(d) under alternative hypothesis (3) with parameter μo = 1125. Only maximum powers of R¯(d), R˜(d), and C(d) over values of d considered are displayed; dmax refers to the value of d yielding the largest power. σ. (TIF)

Power of the tests under alternative hypothesis (2) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05. (...

Power of the tests under alternative hypothesis (3) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05. (...

Optimal argument settings under alternative hypothesis (2) with μo = 375. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (2) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

Optimal argument settings under alternative hypothesis (3) with μo = 375. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (3) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

SNP loci positions over the entire mouse genome on MDGA. (CSV)

Data example 2. Chromosomal positions of SNP genotype differences along chromosome 1 between cerebellar and splenic tissue from a healthy C57BL/6J inbred mouse. (CSV)

Power performance of statistics related to R¯(d), R˜(d), and C(d) under alternative hypothesis (2) with parameter μo = 375. Only maximum powers of R¯(d), R˜(d), and C(d) over values of d considered are displayed; dmax refers to the value of d yielding the largest power. (TIF)

Power performance of statistics related to R¯(d), R˜(d), and C(d) under alternative hypothesis (2) with parameter μo = 1125. Only maximum powers of R¯(d), R˜(d), and C(d) over values of d considered are displayed; dmax refers to the value of d yielding the largest power. σ. (TIF)

Power of the tests under alternative hypothesis (1) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05. (...

Optimal argument settings under alternative hypothesis (1) with μo = 375. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (1) with μo = 375 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

Optimal argument settings under alternative hypothesis (1) with μo = 1125. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (1) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

Optimal argument settings under alternative hypothesis (3) with μo = 1125. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (3) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

Data example 1. Chromosomal positions of SNP genotype differences in normal cerebellar tissue from chromosome 6 of a mouse with a known mixed genetic background of two common inbred mouse strains (75% C57BL/6J and 25% CBA/CaJ). (CSV)

Power performance of statistics related to R¯(d), R˜(d), and C(d) under alternative hypothesis (3) with parameter μo = 375. Only maximum powers of R¯(d), R˜(d), and C(d) over values of d considered are displayed; dmax refers to the value of d yielding the largest power. (TIF)

Power performance of statistics related to R¯(d), R˜(d), and C(d) under alternative hypothesis (1) with parameter μo = 1125. Only maximum powers of R¯(d), R˜(d), and C(d) over values of d considered are displayed; dmax refers to the value of d yielding the largest power. σ. (TIF)

Power of the tests under alternative hypothesis (3) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. For R¯(d), R˜(d), Dmin(n), Nmax(d) and C(d), only the maximum power across the values considered for d or n is shown. The significance level of the test is set as α = 0.05....

Optimal argument settings under alternative hypothesis (2) with μo = 1125. Optimal argument settings of d or n for Neyman-Scott (NS) process under alternative hypothesis (2) with μo = 1125 under various σ choices. Under each parameter setting, h is set as h = 3σ and μp is set to match with η = 50. (PDF)

Background: Although methods and software tools abound for the comparison, analysis, identification, and taxonomic classification of the enormous amount of genomic sequences that are continuously being produced, taxonomic classification remains challenging. The difficulty lies within both the magnitude of the dataset and the intrinsic problems asso...

Background: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting choli...

Background Copy number variation is an important dimension of genetic diversity and has implications in development and disease. As an important model organism, the mouse is a prime candidate for copy number variant (CNV) characterization, but this has yet to be completed for a large sample size. Here we report CNV analysis of publicly available, h...

We propose a computational process to measure and simultaneously visualize the interrelationships among any number of DNA sequences which allows, for example, the examination of hundreds or thousands of complete mtDNA genomes. The process starts by computing an image distance between graphical representations of DNA sequences' composition and proce...

PurposeCharacterization of the biomechanical properties of the human eye has a number of potential utilities. One novel purpose is to provide the basis for development of suitable tissue-mimicking material. The purpose of this study was to determine the indentation and needle insertion characteristics on human eye globes and tissue strips.Methods A...

With few exceptions, spontaneous mutation frequency and pattern are similar across tissue types and relatively constant in young to middle adulthood in wild type mice. Underrepresented in surveys of spontaneous mutations across murine tissues is the diversity of epithelial tissues. For the first time, spontaneous mutations were detected in pancreas...

Copy number variants (CNVs) constitute a recently discovered but significant source of genomic variation. Technological capabilities for CNV detection and characterization in mice have lagged behind methods for humans. The Mouse Diversity Genotyping Array (MDGA) provides a high-resolution array-based approach to genotype over 400,000 single nucleot...

We propose a novel combination of methods that (i) portrays quantitative characteristics of a DNA sequence as an image, (ii) computes distances between these images, and (iii) uses these distances to output a map wherein each sequence is a point in a common Euclidean space. In the resulting "Molecular Distance Map" each point signifies a DNA sequen...

Purpose: To identify anomalous features that impact drug delivery in the eye as a result of intravitreal injections using micro-computed tomography imaging. Methods: Three-dimensional micro-computed tomography images were acquired following an intravitreal injection of 0.03 mL of contrast agent into ex vivo porcine eyes (n = 24). A baseline scan...

Copy number variants (CNVs) are a major source of genetic variation. Comparing CNVs between samples is important in elucidating their potential effects in a wide variety of biological contexts. HD-CNV (hotspot detector for copy number variants) is a tool for downstream analysis of previously identified CNV regions from multiple samples, and it dete...

This study uses micro-computed tomography (micro-CT) imaging for assessment of concentration and transport mechanisms of ocular drug surrogates following intravitreal injection. Injections of an iodinated contrast agent were administered to enucleated porcine eyes prior to scanning over 192 min. Image analysis was performed using signal profiles an...

Purpose: Oculodentodigital dysplasia (ODDD) is characterized by ocular abnormalities including microphthalmia, enophthalmia, iris malformation and microcornea. A recent clinical report (Gabriel et al, 2011. Arch Ophthalmol 129: 781) examined two ODDD patients and found optic nerve and retinal aberrations not emphasized previously. Also, ciliary bod...

Current animal models of retinal disease often involve the rapid development of a retinal disease phenotype; however, this is at odds with age-related diseases that take many years to manifest clinical symptoms. The present study was performed to examine an apoptosis-inducing factor (Aif)-deficient model, the harlequin carrier mouse (X(hq)X), and d...

The importance of understanding the effects of radiation exposure on wildlife is a critical responsibility of our stewardship of nuclear energy production. We tested the hypothesis that songbirds respond to exogenous radiation exposure with changes in plasma 8-hydroxy-2'-deoxyguanosine (8-OH-dG). We exposed two species of songbirds, house sparrows...

Oculodentodigital dysplasia (ODDD) is a human disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding the connexin43 (Cx43) gap junction protein. Causal links between GJA1 mutations and glaucoma are not understood. The purpose in this study was to examine the ocular phenotype for Gja1(Jrt/+) mice harboring a Cx43 G60S mutation...

The harlequin (hq)/Big Blue(®) mouse is a model of premature aging with neurodegeneration and a transgenic mutation target (λcII gene) for in vivo mutation analysis in individual tissues. The hq mutation results in downregulation of the apoptosis-inducing factor (Aif) gene with conflicting reports of elevated oxidative stress in neurons. Previously...

Age is a major risk factor for heart disease, and cardiac aging is characterized by elevated mitochondrial reactive oxygen species (ROS) with compromised mitochondrial and nuclear DNA integrity. To assess links between increased ROS levels and mutations, we examined in situ levels of ROS and cII mutation frequency, pattern and spectrum in the heart...

The harlequin (hq)/Big Blue mouse is a novel model of premature ageing distinguished by a patchy coat, early-onset neurodegeneration, stress-induced heart disease and a mutation detection assay applicable to individual tissues. The hq mutation causes down-regulation of apoptosis-inducing factor and an elevation of reactive oxygen species (ROS). Neu...

Transgenic mouse mutation detection systems allow investigation of the origins and mechanisms of mutation associated with exogenous and endogenous mutagen exposures in individual tissues and cell types. In the past, selection assays for transgenic mutants have been contaminated with nonmurine-derived mutations and assay validation is critical to en...

Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOV...

The Big Blue lacI mutation detection assay is well validated and has permitted detailed analysis of spontaneous mutations in individual tissues over the lifespan of the mouse. In a recent assay of spontaneous mutations, a novel lacI mutation (C354T) recurred in six of seven mutants with a second mutation. The frequency of spontaneous doublets (muta...

Somatic microindels (microdeletions with microinsertions) have been studied in normal mouse tissues using the Big Blue lacI transgenic mutation detection system. Here we analyze microindels in human cancers using an endogenous and transcribed gene, the TP53 gene. Microindel frequency, the enhancement of 1–2 microindels and other features are genera...

Aminoglycosides can bypass nonsense mutations and are the prototypic agents for translational bypass therapy (TBT). Initial results demonstrate the need for more potent drugs and an in vivo model system for quantitative assessment of TBT. Herein, we present an in vivo system for evaluating the efficacy of premature stop codon management therapies:...

We created an Epidermal Growth Factor Receptor (EGFR) Mutation Database (http://www.cityofhope.org/cmdl/egfr_db) that curates a convenient compilation of somatic EGFR mutations in non-small-cell lung cancer (NSCLC) and associated epidemiological and methodological data, including response to the tyrosine kinase inhibitors Gefitinib and Erlotinib. H...

Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kil...

Microindels, defined as mutations that result in a colocalized microinsertion and microdeletion with a net gain or loss of between 1 and 50 nucleotides, may be an important contributor to cancer. We report the first comprehensive analysis of somatic microindels. Our large database of mutations in the lacI transgene of Big Blue((R)) mice contains 0....

Mutations are the substrate of cancer. Yet, little is known about the degree and nature of mutations in tumors because measurement of mutation load in tumors and normal tissues was generally not possible until the advent of transgenic mouse mutation detection systems. Herein, we present the first analysis of mutation frequency and pattern in thymic...

Viruses compress their genome to reduce space. One of the main techniques is overlapping genes. We model this process by the shortest common superstring problem, that is, we look for the shortest genome which still contains all genes. We give an algorithm for computing optimal solutions which is slow in the number of strings but fast (linear) in th...

Microindels are unique, infrequent mutations that result in inserted and deleted sequences of different sizes (between one and 50 nucleotides) at the same nucleotide position. Little is known about the mutational mechanisms that are responsible for these mutations. From our database of 6,016 independent somatic mutational events in the lacI gene in...

To better define the time course of spontaneous mutation frequency in middle to late adulthood of the mouse, measurements were made at 10, 14, 17, 23, 25, and 30 months of age in samples of adipose tissue, liver, cerebellum (90% neurons), and the male germline (95% germ cells). A total of 46 million plaque-forming units (pfus) were screened at the...

In the post genomic era, access to complete genome sequence data for numerous diverse species has opened multiple avenues for examining and comparing primary DNA sequence organization of entire genomes. Previously, the concept of a genomic signature was introduced with the observation of species-type specific Dinucleotide Relative Abundance Profile...

Analysis of spontaneous multiple mutations in normal and tumor cells may constrain hypotheses about the mechanisms responsible for multiple mutations and provide insight into the mutator phenotype. In a previous study, spontaneous doublets in Big Blue mice were dramatically more frequent than expected by chance and exhibited a mutation pattern simi...

Transgenic mouse mutation detection systems permit rapid determination of the frequency and type of mutations allowing direct examination of mutational markers for aging, neurodegeneration, and cancer. The Big Blue transgenic mouse mutation detection system was used to determine the frequency and nature of spontaneous mutations versus age in multip...