Molecular Genetics
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21632
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Browsing Molecular Genetics by Author "Silzer, Talisa K."
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Item Mito-nuclear compatibility in risk for cognitive decline in admixed populations(2019-03-05) Pathak, Gita; Barber, Robert C.; Phillips, Nicole R.; Silzer, Talisa K.Background. The issue of missing heritability has vexed the study of many complex diseases, Alzheimer’s disease (AD) not excluded. Only ~35% of the heritability of AD has been accounted for, the majority of which lies in APOE allele e4, which has a less-pronounced effect in certain admixed populations. There are few genetic and/or mitochondrial studies of admixed populations, and our understanding of mitochondrially-related cognitive decline has largely been based on studies of highly homogenous populations (by design). The concept of mito-nuclear compatibility states that optimization of mitochondrial DNA (mtDNA) with nuclear genetic background is a source of significant selective evolutionary pressure. Evidence for this phenomenon in human populations is emerging (Zaidi and Makova, 2019), and opens the door for studies in the context of human disease. Purpose. The purpose of this study is to determine whether divergent nuclear and mitochondrial genomes confer risk for cognitive impairment and decline in admixed populations. Methods. Participants in the Texas Alzheimer’s Research and Care Consortium (TARCC) were used for this study. DNA extracts from peripheral blood buffy coat were genotyped on the Multi-Ethnic Genotyping Array (Illumina) which types 1.7 million SNPs and includes ancestry specific genetic variation. The top 10 eigenvectors (smartpca via Eigensoft) were generated via principle component analysis of nuclear DNA (nDNA) and used to cluster subjects with the 1000 Genomes population data in order to ascertain global, ancestral nDNA background. Mitochondrial DNA variants from the array were analyzed using HaploGrep/MitoTool for mtDNA haplotype assignment. Non-concordance of mtDNA:nDNA ancestry will be identified and scored as in Zaidi and Makova, 2019 and tested for association with cognitive state (normal, mild cognitive impairment, or Alzheimer’s disease) as well as cognitive decline between time points. Results. Preliminary studies indicate that cognitive decline is associated with mitochondrial phenotypes in Caucasian subjects; these results were dependent on sex. Mitochondrial copy number was a main driver in the predictive model in both males and females, but to a differing degree. Conclusion. Discrepancy between mtDNA and nDNA genomic backgrounds has been previously correlated with mtDNA copy number (Zaidi and Makova, 2019); similar discrepancy may explain health disparities in complex diseases that are more prevalent in particular admixed populations.Item Mitochondrial RNA Sequencing Variation in Age-Related Pathologies(2019-03-05) Phillips, Nicole; Silzer, Talisa K.Background. Mitochondrial function has been implicated in a number of age-related disease pathologies, and post-transcriptional sequence modifications in mitochondrial RNA (mtRNA) have been correlated with variation in the mitochondrial function. One of the most significant modifications is methylation of mitochondrial transfer RNAs (tRNA) at their 9th position (termed “p9 sites”). Post-transcriptional modifications to these tRNAs are known to alter efficiency of translation and protein synthesis, affecting downstream mitochondrial function. The impact that these modifications to the mitochondrial transcriptome have on risk for age-related disease has not been previously explored. Purpose. The purpose of this study was to determine if altered post-transcriptional modification rates to mitochondrial p9 tRNA sites is associated with risk for age-related disease pathologies. Methods. RNA sequencing and genotyping data was analyzed from cerebellar tissue of 275 Caucasian subjects consisting of elderly controls, and individuals with diagnosed AD, progressive supranuclear palsy or pathological aging. Data were obtained through the Synapse data repository and were collected by the Mayo RNAseq study, led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Heteroplasmy in mtRNA was measured using the VarScan software tool. Variants in the nuclear-encoded gene MRPP3 were analyzed for association with altered p9 methylation rates. Results. Average number and rate of heteroplasmy at the 13 sites were compared across control and case groups. A higher rate of heteroplasmy was observed at the p9 sites, indicating the presence of methylation within these tRNAs. Concluding Remarks. Post-transcriptional modification of mtRNA occurs under normal, non-pathologic states; alteration of methylation rate at the p9 site of mitochondrial tRNAs may be associated with aging pathology. The rate of p9 methylation has been associated with genetic factors encoded in the nuclear DNA (Hodgkinson et al., 2014). Targeting methylation of mitochondrial tRNA could prove to be a viable therapeutic approach for deficits in mitochondrial function.