Matching Items (10)
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- All Subjects: Genetics
- Creators: Wilson, Melissa
- Creators: Watkins, Payton
- Status: Published
Description
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, diagnosed late in
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
ContributorsHenderson, Adrienne Rose (Author) / Huentelman, Matthew J (Thesis advisor) / Newbern, Jason (Thesis advisor) / Dunckley, Travis L (Committee member) / Jensen, Kendall (Committee member) / Wilson, Melissa (Committee member) / Arizona State University (Publisher)
Created2019
Description
In species with highly heteromorphic sex chromosomes, the degradation of one of the sex chromosomes can result in unequal gene expression between the sexes (e.g., between XX females and XY males) and between the sex chromosomes and the autosomes. Dosage compensation is a process whereby genes on the sex chromosomes achieve equal gene expression which prevents deleterious side effects from having too much or too little expression of genes on sex chromsomes. The green anole is part of a group of species that recently underwent an adaptive radiation. The green anole has XX/XY sex determination, but the content of the X chromosome and its evolution have not been described. Given its status as a model species, better understanding the green anole genome could reveal insights into other species. Genomic analyses are crucial for a comprehensive picture of sex chromosome differentiation and dosage compensation, in addition to understanding speciation.
In order to address this, multiple comparative genomics and bioinformatics analyses were conducted to elucidate patterns of evolution in the green anole and across multiple anole species. Comparative genomics analyses were used to infer additional X-linked loci in the green anole, RNAseq data from male and female samples were anayzed to quantify patterns of sex-biased gene expression across the genome, and the extent of dosage compensation on the anole X chromosome was characterized, providing evidence that the sex chromosomes in the green anole are dosage compensated.
In addition, X-linked genes have a lower ratio of nonsynonymous to synonymous substitution rates than the autosomes when compared to other Anolis species, and pairwise rates of evolution in genes across the anole genome were analyzed. To conduct this analysis a new pipeline was created for filtering alignments and performing batch calculations for whole genome coding sequences. This pipeline has been made publicly available.
In order to address this, multiple comparative genomics and bioinformatics analyses were conducted to elucidate patterns of evolution in the green anole and across multiple anole species. Comparative genomics analyses were used to infer additional X-linked loci in the green anole, RNAseq data from male and female samples were anayzed to quantify patterns of sex-biased gene expression across the genome, and the extent of dosage compensation on the anole X chromosome was characterized, providing evidence that the sex chromosomes in the green anole are dosage compensated.
In addition, X-linked genes have a lower ratio of nonsynonymous to synonymous substitution rates than the autosomes when compared to other Anolis species, and pairwise rates of evolution in genes across the anole genome were analyzed. To conduct this analysis a new pipeline was created for filtering alignments and performing batch calculations for whole genome coding sequences. This pipeline has been made publicly available.
ContributorsRupp, Shawn Michael (Author) / Wilson Sayres, Melissa A (Thesis advisor) / Kusumi, Kenro (Committee member) / DeNardo, Dale (Committee member) / Arizona State University (Publisher)
Created2016
Description
Mycobacterium leprae, the causative agent of Hansen’s disease (leprosy), has plagued humans and other animal species for millennia and remains of concern to public health throughout the world today. Recent research into the expanded use of medical tissues preserved as formalin-fixed, paraffin-embedded samples (FFPE), opened the door for the study of M. leprae DNA from preserved skin samples. However, problems persist with damage to the DNA including fragmentation and cross linkage. This study evaluated two methods commonly used for the recovery of host DNA from FFPE samples for their efficacy in extracting pathogen DNA (hot alkaline lysis protocol and QIAGEN QIAamp FFPE DNA kit). Twenty FFPE skin samples collected from 1995-2015 from human subjects in the Pacific Islands suffering from M. leprae infection, each exhibiting a range of bacillary loads, were analyzed to determine which extraction method was most successful in terms of ability to consistently yield reliable, robust traces of M. leprae infection. This study further examined these samples to understand the phylogeny of leprosy in the region, where gaps in the evolutionary history of M. leprae persist. DNA recovery from paired samples was similar using either method. However, by extending the incubation time of post-paraffin removal sample lysis, both protocols were more likely to yield positive traces of M. leprae, with this enhancement being especially evident in paucibacillary samples with low bacterial presence. The qPCR assay findings suggest that the hot alkaline procedure is most likely to yield positive identification of infection in these traditionally challenging samples.
ContributorsKing, Felicia Clarice (Author) / Stone, Anne (Thesis advisor) / Wilson, Melissa (Committee member) / Buetow, Ken (Committee member) / Arizona State University (Publisher)
Created2023
Pathways of Distinction Analysis of Liver Cancer Data: Genetic Differences Between Males and Females
Description
The Pathways of Distinction Analysis (PoDA) program calculates relationships between a given group of genes contained within a pathway, and a disease state. It was used here to investigate liver cancer, and to explore how genetic variability may contribute to the different rates of development of the disease in males and females. The goal of the study was to identify germline variation that differs by sex in hepatocellular carcinoma. Using the program, multiple pathways and genes were identified to have significant differences in their relationship to liver cancer in males and females. In animal studies, the genes which were identified using the PoDA analysis have been shown to impact liver cancer, often with different results for males and females. While these genes are often the focus in animal models, they are absent from current Genome Wide Association Studies (GWAS) catalogs for humans. By working to bridge the results of animal studies and human studies, the results help to identify the causes of liver cancer, and more specifically, the reason the disease affects males at much higher rates. The differences in pathways identified to be significant for the two sexes indicate the germline variance may play sex-specific roles in the development of hepatocellular carcinoma. Additionally, these results reinforce the capacity of the PoDA analysis to identify genes that may be missed by more traditional GWAS methods. This study lays the groundwork for further investigations into the identified genes and pathways, and how they behave differently within males and females.
ContributorsOlson, Erik Jon (Author) / Buetow, Kenneth (Thesis advisor) / Wilson, Melissa (Committee member) / Cartwright, Reed (Committee member) / Arizona State University (Publisher)
Created2021
DescriptionThis thesis summarizes the process of writing a children's book about achondroplasia directed at children without genetic disorders. The thesis also includes the children's book The Genetics of Little People that was created during the project.
ContributorsWatkins, Payton (Author) / Binsfeld, Allison (Co-author) / Wilson, Melissa (Thesis director) / Hunt-Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / Chemical Engineering Program (Contributor)
Created2022-05
Description
This thesis summarizes the process of writing a children's book about achondroplasia directed at children without genetic disorders. The thesis also includes the children's book The Genetics of Little People that was created during the project.
ContributorsWatkins, Payton (Author) / Binsfeld, Allison (Co-author) / Wilson, Melissa (Thesis director) / Hunt-Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / Chemical Engineering Program (Contributor)
Created2022-05
Description
This thesis summarizes the process of writing a children's book about achondroplasia directed at children without genetic disorders. The thesis also includes the children's book The Genetics of Little People that was created during the project.
ContributorsWatkins, Payton (Author) / Binsfeld, Allison (Co-author) / Wilson, Melissa (Thesis director) / Hunt-Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / Chemical Engineering Program (Contributor)
Created2022-05
Description
This thesis summarizes the process of writing a children's book about achondroplasia directed at children without genetic disorders. The thesis also includes the children's book The Genetics of Little People that was created during the project.
ContributorsBinsfeld, Allison (Author) / Watkins, Payton (Co-author) / Wilson, Melissa (Thesis director) / Hunt Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / School of Molecular Sciences (Contributor) / School of Human Evolution & Social Change (Contributor)
Created2022-05
ContributorsBinsfeld, Allison (Author) / Watkins, Payton (Co-author) / Wilson, Melissa (Thesis director) / Hunt Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / School of Molecular Sciences (Contributor)
Created2022-05
ContributorsBinsfeld, Allison (Author) / Watkins, Payton (Co-author) / Wilson, Melissa (Thesis director) / Hunt Brendish, Katherine (Committee member) / Barrett, The Honors College (Contributor) / School of Molecular Sciences (Contributor)
Created2022-05