Browsing by Subject "genes"

Now showing 1 - 10 of 11
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    AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia
    (Oxford University Press, 2015-09-15) Virts, Elizabeth L.; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F.; Wiek, Constanze; Kelich, Stephanie L.; Lottmann, Nadine; Kennedy, Felicia M.; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E.; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L.; Foroud, Tatiana M.; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C.; Vance, Gail H.; Pruss, Dmitry; Timms, Kirsten M.; Lanchbury, Jerry S.; Alpi, Arno F.; Hanenberg, Helmut; Department of Pediatrics, IU School of Medicine
    Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2–6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2–6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2–6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.
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    Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction
    (Elsevier, 2016) Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.; Department of Psychiatry, IU School of Medicine
    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission in human addiction. Overall, C. elegans can be used to model aspects of drug addiction and identify systems and molecular mechanisms that mediate drug effects. The findings are surprisingly consistent with analogous findings in higher-level organisms. Further, model refinement is warranted to improve model validity and increase utility for medications development.
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    Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation
    (Oxford, 2019-08) Rhodes, Steven D.; He, Yongzheng; Smith, Abbi; Jiang, Li; Lu, Qingbo; Mund, Julie; Li, Xiaohong; Bessler, Waylan; Qian, Shaomin; Dyer, William; Sandusky, George E.; Horvai, Andrew E.; Armstrong, Amy E.; Clapp, D. Wade; Pediatrics, School of Medicine
    Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1−/− SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
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    A closer look at the mysterious HSD17B131
    (Elsevier, 2020-11) Dong, X. Charlie; Biochemistry and Molecular Biology, School of Medicine
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    Gene-based GWAS and -biological pathway analysis of the resilience of executive functioning
    (Springer US, 2014-03) Mukherjee, Shubhabrata; Kim, Sungeun; Ramanan, Vijay K.; Gibbons, Laura E.; Nho, Kwangsik; Glymour, M. Maria; Ertekin-Taner, Nilüfer; Montine, Thomas J.; Saykin, Andrew J.; Crane, Paul K.; Alzheimer’s Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, School of Medicine
    Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123=2.8×10−6) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p=1.33×10−7). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density etc. were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.
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    Impulsivity and Alcohol Drinking in an Animal Model of Alcoholism
    (Office of the Vice Chancellor for Research, 2010-04-09) Grahame, N.J.; Oberlin, B.O.; Bristow, R.E.; Heighton, M.E.
    Alcoholism is a widespread problem, and although we are beginning to characterize genes that mediate its heritable nature, we still do not understand how a family history of alcoholism places individuals at risk for this disorder. One trait that is consistently elevated, both in alcoholics and those who suffer from a variety of addictive disorders, is impulsivity. Impulsivity can be defined as a self-defeating tendency to choose immediate, but small rewards over large rewards given at following a delay. Normally, instituting a delay to a reward decreases its subjective value, a phenomenon called delay discounting. In alcoholics, the slope of this decline in value as a function of time is steeper than in non-drinkers, but it has been difficult to demonstrate in humans whether this results from a lifetime of drinking, or causes problem drinking in the first place. In the present studies we utilized an animal model of alcoholism, the selectively bred High Alcohol Preferring (HAP) mouse, comparing them to Low Alcohol Preferring (LAP) mice as well as non-selected, outbred mice using the translational measure of impulsivity, delay discounting. By using alcohol naïve mice, we were able to assess whether genes promoting alcohol drinking increase impulsivity without the potential confound of a history of alcohol exposure. In follow-up studies, we assessed whether pharmacotherapies for alcoholism decrease impulsivity as well as alcohol consumption in HAP mice. Alcohol naïve HAP, LAP, and HS/Ibg mice were subjected to a saccharin-motivated delay discounting procedure in which the value of an immediate reward was titrated until it was subjectively equivalent to a delayed reward. As expected, time to the delayed reward decreased its value, and did so more steeply in HAP mice than in LAP and unselected HS/Ibg mice, supporting the hypothesis that impulsivity plays a causal role in initiating high drinking behavior. In related studies, we assessed whether two pharmacotherapies for alcoholism, memantine (an NMDA antagonist) and naltrexone (an opioid antagonist), altered delay discounting behavior and (in separate mice) alcohol drinking. Although these two drugs decreased free-choice drinking in HAP mice, consistent with their beneficial effects on alcoholism, they did not alter impulsivity. Amphetamine, a general dopamine agonist with known anti-impulsive actions, decreased impulsivity in HAP mice, but did not alter alcohol consumption in a behaviorally selective manner. These findings support a role for impulsivity in the development of alcoholism, but leave unanswered the question of which neural systems would serve as the best pharmacological targets for the development of medications aimed at treating those with, or at a high risk for, alcoholism.
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    Large-scale genomics unveil polygenic architecture of human cortical surface area
    (Nature Publishing Group, 2015-07-20) Chen, Chi-Hua; Peng, Qian; Schork, Andrew J.; Lo, Min-Tzu; Fan, Chun-Chieh; Wang, Yunpeng; Desikan, Rahul S.; Bettella, Francesco; Hagler, Donald J.; Westlye, Lars T.; Kremen, William S.; Jernigan, Terry L.; Hellard, Stephanie Le; Steen, Vidar M.; Espeseth, Thomas; Huentelman, Matt; Håberg, Asta K.; Agartz, Ingrid; Djurovic, Srdjan; Andreassen, Ole A.; Schork, Nicholas; Dale, Anders M.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ~2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2~0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N=466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.
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    Mitochondrial DNA Deletions and ROS Scavengers
    (Office of the Vice Chancellor for Research, 2015-04-17) Kennedy, John; Watkins, Keltsey; Tinkey, Michaela; Croslyn, Corinne; McDougall, Scott
    The purpose of this experiment is to observe how deletion of genes that are involved in the electron transport chain cause mitochondrial damage and an increase in reactive oxygen species and if antioxidants could minimize the effects of oxidation. Saccharomyces cerevisiae is ideal for this study as it is used for research with chronological aging. Chronological aging is the survival during the stationary phase after nutrients and space becomes limited and has been used to study neurons in the central nervous system, oxidative stress, and changes in morphology. Deletions of mitochondrial DNA and the increase of reactive oxygen species over time has been linked to a decline in the production of ROS scavengers. ROS scavengers serve as a defense against the oxidation of various cells by neutralizing the reactive oxygen species. These include antioxidants such as Vitamin-C, Vitamin-E, and flavonoids. For this experiment, genes from the yeast Saccharomyces cerevisiae will be removed using gene knockout, which will inactivate the genes of interest. The genes of interest are Cox 1, 2, 3, 5a, 12, 23 and SOD 1 (Superoxide Dismutase) and 2, OPA 1, and Atg32. These genes are important in the electron transport chain, fission, fusion, and mitophagy. The mutated yeast will then be placed into a ROS scavenger media containing Vitamin-C and incubated overnight. Assays that will be used include Rhodamine 123 which determines membrane potential and proton flow from the inner membrane to the matrix, Janus Green which reveals alterations in the electron transport chain and amount of oxygen available, Cytochrome c Oxidase assay which can determine cytochrome c activity and outer membrane stress, and dihydrorhodamine to indicate ROS levels. Using fluorescent dyes such as Rhodamine 123 will allow the cells to be observe through a microscope and observe the amount of damage and fission that has been produced by the mutations and the effects of the antioxidants on the destruction of the mutated cells.
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    New analyses provide supportive evidence for specific genes related to bipolar disorder
    (Wiley, 2021-05) Nurnberger, John I.; Psychiatry, School of Medicine
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    Rare coding variants and X-linked loci associated with age at menarche
    (Nature Publishing Group, 2015-08-04) Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Tõnu; Elks, Cathy E.; Altmaier, Elisabeth; He, Chunyan; Huffman, Jennifer E.; Mihailov, Evelin; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Stolk, Lisette; Teumer, Alexander; Thompson, Deborah J.; Traglia, Michela; Wang, Carol A.; Yerges-Armstrong, Laura M.; Antoniou, Antonis C.; Barbieri, Caterina; Coviello, Andrea D.; Cucca, Francesco; Demerath, Ellen W.; Dunning, Alison M.; Gandin, Ilaria; Grove, Megan L.; Gudbjartsson, Daniel F.; Hocking, Lynne J.; Hofman, Albert; Huang, Jinyan; Jackson, Rebecca D.; Karasik, David; Kriebel, Jennifer; Lange, Ethan M.; Lange, Leslie A.; Langenberg, Claudia; Li, Xin; Luan, Jian'an; Mägi, Reedik; Morrison, Alanna C.; Padmanabhan, Sandosh; Pirie, Ailith; Polasek, Ozren; Porteous, David; Reiner, Alex P.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia F.; Schlessinger, David; Scott, Robert A.; Stöckl, Doris; Visser, Jenny A.; Völker, Uwe; Vozzi, Diego; Wilson, James G.; Zygmunt, Marek; Boerwinkle, Eric; Buring, Julie E.; Crisponi, Laura; Easton, Douglas F.; Hayward, Caroline; Hu, Frank B.; Liu, Simin; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Strauch, Konstantin; Streeten, Elizabeth A.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Wellons, Melissa; Franceschini, Nora; Chasman, Daniel I.; Thorsteinsdottir, Unnur; Murray, Anna; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.; Perry, John R. B.; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ~3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ~0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.