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- All Subjects: Genomics
- All Subjects: Green anole--Evolution.
- All Subjects: MRP1
- Genre: Academic theses
- Creators: Huentelman, Matthew
- Status: Published
Description
Well-established model systems exist in four out of the seven major classes of vertebrates. These include the mouse, chicken, frog and zebrafish. Noticeably missing from this list is a reptilian model organism for comparative studies between the vertebrates and for studies of biological processes unique to reptiles. To help fill in this gap the green anole lizard, Anolis carolinensis, is being adapted as a model organism. Despite the recent release of the complete genomic sequence of the A. carolinensis, the lizard lacks some resources to aid researchers in their studies. Particularly, the lack of transcriptomic resources for lizard has made it difficult to identify genes complete with alternative splice forms and untranslated regions (UTRs). As part of this work the genome annotation for A. carolinensis was improved through next generation sequencing and assembly of the transcriptomes from 14 different adult and embryonic tissues. This revised annotation of the lizard will improve comparative studies between vertebrates, as well as studies within A. carolinensis itself, by providing more accurate gene models, which provide the bases for molecular studies. To demonstrate the utility of the improved annotations and reptilian model organism, the developmental process of somitogenesis in the lizard was analyzed and compared with other vertebrates. This study identified several key features both divergent and convergent between the vertebrates, which was not previously known before analysis of a reptilian model organism. The improved genome annotations have also allowed for molecular studies of tail regeneration in the lizard. With the annotation of 3' UTR sequences and next generation sequencing, it is now possible to do expressional studies of miRNA and predict their mRNA target transcripts at genomic scale. Through next generation small RNA sequencing and subsequent analysis, several differentially expressed miRNAs were identified in the regenerating tail, suggesting miRNA may play a key role in regulating this process in lizards. Through miRNA target prediction several key biological pathways were identified as potentially under the regulation of miRNAs during tail regeneration. In total, this work has both helped advance A. carolinensis as model system and displayed the utility of a reptilian model system.
ContributorsEckalbar, Walter L (Author) / Kusumi, Kenro (Thesis advisor) / Huentelman, Matthew (Committee member) / Rawls, Jeffery (Committee member) / Wilson-Rawls, Norma (Committee member) / Arizona State University (Publisher)
Created2012
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
Alzheimer’s disease (AD) is the world’s leading cause of dementia and is the sixthleading cause of death in the United States. While AD has been studied for over a century, little progress has been made in terms of treating or preventing disease progression; therefore, new therapeutic drug targets must be identified. Current clinical trials focus on inhibiting Beta- Secretase 1 (BACE1), the major enzyme involved in the formation of the amyloid beta (Abeta) peptide fragments that aggregate to form insoluble plaques in the brains of AD patients. However, many of these clinical trials have been halted due to neurological effects or organ damage with no substantial cognitive improvements. Because the current leading theory of AD is that the buildup of amyloid plaques leads to metabolic changes that result in the intraneuronal accumulation of hyperphosphorylated Microtubule Associated Protein Tau (TAU, encoded by the MAPT gene), which causes cell death resulting in brain atrophy and dementia (known as the Amyloid Cascade Hypothesis), identifying drug targets that modulate Amyloid Precursor Protein (APP) processing – without directly inhibiting BACE1 – may prove to be a viable treatment. In this work, the role of the Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) was studied in the context of AD. Rare mutations in ABCC1 were identified in a familial case of late-onset AD and in a sporadic case of early-onset AD, and previous laboratories have demonstrated that Abeta is a substrate for ABCC1-mediated export. Although the final experiments reveal no significant difference between the mutant and reference alleles, the data demonstrate that overexpression of ABCC1 modulates APP processing, resulting in decreased Abeta formation and increased alpha- secretase cleavage of the APP molecule, likely via transcriptional modulation of genes that are capable of altering APP metabolism. Therefore, pharmacological interventions that increase either ABCC1 expression or activity may be capable of halting, reversing, or preventing disease progression. Many cancer drug development pipelines have been employed to identify compounds that decrease ABCC1 expression or activity, and it is likely that compounds have been identified that have the opposite effect. These drugs should be studied in the context of Alzheimer’s disease.
ContributorsJepsen, Wayne Mathew (Author) / Huentelman, Matthew (Thesis advisor) / Kusumi, Kenro (Thesis advisor) / Jensen, Kendall (Committee member) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2021