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- All Subjects: Genetics
Description
As life expectancy increases worldwide, age related diseases are becoming greater health concerns. One of the most prevalent age-related diseases in the United States is dementia, with Alzheimer’s disease (AD) being the most common form, accounting for 60-80% of cases. Genetics plays a large role in a person’s risk of developing AD. Familial AD, which makes up less than 1% of all AD cases, is caused by autosomal dominant gene mutations and has almost 100% penetrance. Genetic risk factors are believed to make up about 49%-79% of the risk in sporadic cases. Many different genetic risk factors for both familial and sporadic AD have been identified, but there is still much work to be done in the field of AD, especially in non-Caucasian populations. This review summarizes the three major genes responsible for familial AD, namely APP, PSEN1 and PSEN2. Also discussed are seven identified genetic risk factors for sporadic AD, single nucleotide polymorphisms in the APOE, ABCA7, NEDD9, CASS4, PTK2B, CLU, and PICALM genes. An overview of the main function of the proteins associated with the genes is given, along with the supposed connection to AD pathology.
ContributorsRichey, Alexandra Emmeline (Author) / Brafman, David (Thesis director) / Raman, Sreedevi (Committee member) / School of International Letters and Cultures (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
With the rising data output and falling costs of Next Generation Sequencing technologies, research into data compression is crucial to maintaining storage efficiency and costs. High throughput sequencers such as the HiSeqX Ten can produce up to 1.8 terabases of data per run, and such large storage demands are even more important to consider for institutions that rely on their own servers rather than large data centers (cloud storage)1. Compression algorithms aim to reduce the amount of space taken up by large genomic datasets by encoding the most frequently occurring symbols with the shortest bit codewords and by changing the order of the data to make it easier to encode. Depending on the probability distribution of the symbols in the dataset or the structure of the data, choosing the wrong algorithm could result in a compressed file larger than the original or a poorly compressed file that results in a waste of time and space2. To test efficiency among compression algorithms for each file type, 37 open-source compression algorithms were used to compress six types of genomic datasets (FASTA, VCF, BCF, GFF, GTF, and SAM) and evaluated on compression speed, decompression speed, compression ratio, and file size using the benchmark test lzbench. Compressors that outpreformed the popular bioinformatics compressor Gzip (zlib -6) were evaluated against one another by ratio and speed for each file type and across the geometric means of all file types. Compressors that exhibited fast compression and decompression speeds were also evaluated by transmission time through variable speed internet pipes in scenarios where the file was compressed only once or compressed multiple times.
ContributorsHowell, Abigail (Author) / Cartwright, Reed (Thesis director) / Wilson Sayres, Melissa (Committee member) / Taylor, Jay (Committee member) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Mammary gland development in humans during puberty involves the enlargement of breast tissue, but this is not true in non-human primates. To identify potential causes of this difference, I examined variation in substitution rates across genes related to mammary development. Genes undergoing purifying selection show slower-than-average substitution rates, while genes undergoing positive selection show faster rates. These may be related to the difference between humans and other primates. Three genes were found to be accelerated were FOXF1, IGFBP5, and ATP2B2, but only the latter one was found in humans and it seems unlikely that it would be related to the differences between mammary gland development at puberty between humans and non-human primates.
ContributorsArroyo, Diana (Author) / Cartwright, Reed (Thesis director) / Wilson Sayres, Melissa (Committee member) / Schwartz, Rachel (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Intervertebral Disc Degeneration (IVDD) is a complex phenomenon characterizing the desiccation and structural compromise of the primary joint in the human spine. The intervertebral disc (IVD) serves to connect vertebral bodies, cushion shock, and allow for flexion and extension of the vertebral column. Often presenting in the 4th or 5th decades of life as low back pain, this disease was originally believed to be the result of natural “wear and tear” coupled with repetitive mechanical insult, and as such most studies focus on patients between 40 and 50 years of age. Research over the past two decades, however, has demonstrated that environmental factors have only a modest effect on disc degeneration, with genetic influences playing a much more substantial role. Extensive research has focused on this process, though definitive risk factors and a clear pathophysiology have proven elusive. The aim of this study was to assemble a cohort of patients exhibiting definitive signs of degeneration who were well below the average age of presentation, with minimal or no exposure to suspected environmental risk factors and to conduct a targeted genome analysis in an attempt to elucidate a common genetic component. Through whole genome sequencing and analysis, the results corroborated findings in a previous study, as well as demonstrated a potential connection and influence between mutations found in IVD structural or functional genes, and the provocation of IVDD. Though the sample size was limited in scale and age, these findings suggest that further IVDD research into the association of variants in collagen, aggrecan and the insulin-like growth factor receptor genes of young patients with an early presentation of disc degeneration and minimal exposure to suspected risk factors is merited.
ContributorsFulton, Travis (Author) / Liebig, Juergen (Thesis advisor) / Neisewander, Janet (Committee member) / Theodore, Nicholas (Committee member) / Arizona State University (Publisher)
Created2016
Description
Alzheimer’s disease (AD), despite over a century of research, does not have a clearly defined pathogenesis for the sporadic form that makes up the majority of disease incidence. A variety of correlative risk factors have been identified, including the three isoforms of apolipoprotein E (ApoE), a cholesterol transport protein in the central nervous system. ApoE ε3 is the wild-type variant with no effect on risk. ApoE ε2, the protective and most rare variant, reduces risk of developing AD by 40%. ApoE ε4, the risk variant, increases risk by 3.2-fold and 14.9-fold for heterozygous and homozygous representation respectively. Study of these isoforms has been historically complex, but the advent of human induced pluripotent stem cells (hiPSC) provides the means for highly controlled, longitudinal in vitro study. The effect of ApoE variants can be further elucidated using this platform by generating isogenic hiPSC lines through precise genetic modification, the objective of this research. As the difference between alleles is determined by two cytosine-thymine polymorphisms, a specialized CRISPR/Cas9 system for direct base conversion was able to be successfully employed. The base conversion method for transitioning from the ε3 to ε2 allele was first verified using the HEK293 cell line as a model with delivery via electroporation. Following this verification, the transfection method was optimized using two hiPSC lines derived from ε4/ε4 patients, with a lipofection technique ultimately resulting in successful base conversion at the same site verified in the HEK293 model. Additional research performed included characterization of the pre-modification genotype with respect to likely off-target sites and methods of isolating clonal variants.
ContributorsLakers, Mary Frances (Author) / Brafman, David (Thesis advisor) / Haynes, Karmella (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2017
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