Browsing by Subject "genomics"

Now showing 1 - 10 of 19
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    Cis‐acting allele specific expression (ASE) differences induced by alcohol and impacted by sex as well as parental genotype of origin
    (Wiley, 2018) Lo, Chiao-Ling; Lumeng, Lawrence; Bell, Richard L.; Liang, Tiebing; Lossie, Amy C.; Muir, Williams M.; Zhou, Feng C.; Anatomy and Cell Biology, School of Medicine
    Background Alcohol use disorders (AUDs) are influenced by complex interactions between the genetics of the individual and their environment. We have previously identified hundreds of polygenic genetic variants between the selectively bred high and low alcohol drinking (HAD and LAD) rat lines. Here we report allele specific expression (ASE) differences, between the HAD2 and LAD2 rat lines. Methods The HAD2 and LAD2 rats which have been sequenced were reciprocally crossed to generate 10 litters of F1 progeny. For 5 of these litters, the sire was HAD2; and, for the other 5 litters, the sire was a LAD2. From these 10 litters, two males and two females were picked from each F1 litter (N = 40 total). The F1‐pups were divided, with balancing for sex and direction of cross, into an alcohol (15%) vs a water control group. Alcohol‐drinking started in the middle of adolescence (~PND 35) and lasted 9 weeks. At the end of these treatments, rats were euthanized, the nucleus accumbens was dissected, and RNA was processed for RNA‐sequencing and ASE analyses. Results Analyses revealed that adolescent ethanol drinking, individual ethanol drinking levels, parentage, and sex‐of‐animal affected ASEs of about 300 genes. The identified genes included those associated with ethanol metabolism (e.g., Aldh2); neuromodulatory function [e.g., Cckbr, Slc6a7, and Slc1a1]; ion channel activity (e.g., Kcnc3); as well as other synaptic and epigenetic function. Conclusion These data indicate that ethanol drinking differentially amplified paternal vs maternal allelic contribution to the transcriptome. We hypothesize that this was due, at least in part, to ethanol‐induced changes in cis‐regulation of polymorphisms previously identified between the HAD2 and LAD2 rat lines. This report highlights the complexity of gene‐by‐environment interactions mediating a genetic predisposition for, and/or the active development of, alcohol use disorders.
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    Comparison of Multi-Sample Variant Calling Methods for Whole Genome Sequencing
    (Institute of Electrical and Electronics Engineers, 2014-10) Nho, Kwangsik; West, John D.; Li, Huian; Henschel, Robert; Bharthur, Apoorva; Tavares, Michel C.; Saykin, Andrew J.; Department of Medicine, IU School of Medicine
    Rapid advancement of next-generation sequencing (NGS) technologies has facilitated the search for genetic susceptibility factors that influence disease risk in the field of human genetics. In particular whole genome sequencing (WGS) has been used to obtain the most comprehensive genetic variation of an individual and perform detailed evaluation of all genetic variation. To this end, sophisticated methods to accurately call high-quality variants and genotypes simultaneously on a cohort of individuals from raw sequence data are required. On chromosome 22 of 818 WGS data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is the largest WGS related to a single disease, we compared two multi-sample variant calling methods for the detection of single nucleotide variants (SNVs) and short insertions and deletions (indels) in WGS: (1) reduce the analysis-ready reads (BAM) file to a manageable size by keeping only essential information for variant calling ("REDUCE") and (2) call variants individually on each sample and then perform a joint genotyping analysis of the variant files produced for all samples in a cohort ("JOINT"). JOINT identified 515,210 SNVs and 60,042 indels, while REDUCE identified 358,303 SNVs and 52,855 indels. JOINT identified many more SNVs and indels compared to REDUCE. Both methods had concordance rate of 99.60% for SNVs and 99.06% for indels. For SNVs, evaluation with HumanOmni 2.5M genotyping arrays revealed a concordance rate of 99.68% for JOINT and 99.50% for REDUCE. REDUCE needed more computational time and memory compared to JOINT. Our findings indicate that the multi-sample variant calling method using the JOINT process is a promising strategy for the variant detection, which should facilitate our understanding of the underlying pathogenesis of human diseases.
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    Draft Whole-Genome Sequence of Haemophilus ducreyi Strain AUSPNG1, Isolated from a Cutaneous Ulcer of a Child from Papua New Guinea.
    (ASM, 2016-02) Gangaiah, Dharanesh; Marinov, Georgi K.; Roberts, Sally A.; Robson, Jenny; Spinola, Stanley M.; Department of Microbiology & Immunology, IU School of Medicine
    Haemophilus ducreyi has recently emerged as a leading cause of cutaneous ulcers in the yaws-endemic areas of Papua New Guinea and other South Pacific islands. Here, we report the draft genome sequence of the H. ducreyi strain AUSPNG1, isolated from a cutaneous ulcer of a child from Papua New Guinea.
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    Eugenomics: eugenics and ethics in the 21st century
    (2006-08) Aultman, Julie
    Re-examines eugenic issues in the light of modern-day genomics.
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    Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)
    (Future Medicine Ltd., 2012-12) Lahiri, Debomoy K.; Maloney, Bryan; Department of Psychiatry, School of Medicine
    The goal of genome-wide association studies is to identify SNPs unique to disease. It usually involves a single sampling from subjects' lifetimes. While primary DNA sequence variation influences gene-expression levels, expression is also influenced by epigenetics, including the ‘somatic epitype’ (GSE), an epigenotype acquired postnatally. While genes are inherited, and novel polymorphisms do not routinely appear, GSE is fluid. Furthermore, GSE could respond to environmental factors (such as heavy metals) and to differences in exercise, maternal care and dietary supplements – all of which postnatally modify oxidation or methylation of DNA, leading to altered gene expression. Change in epigenetic status may be critical for the development of many diseases. We propose a ‘longitudinal epigenome-wide association study’, wherein GSE are measured at multiple time points along with subjects' histories. This Longitudinal epigenome-wide association study, based on the ‘dynamic’ somatic epitype over the ‘static’ genotype, merits further investigation.
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    Genetic and genomic selection in insects as food and feed
    (Wageningen Academic, 2021) Eriksson, T.; Picard, Christine J.; Biology, School of Science
    This review will summarise existing tools and resources and highlight areas of focus for the insects as food and feed industry for the production of insects as alternative protein sources. By applying knowledge gained from other agricultural organisms coupled with the ease of insect population growth and rearing capabilities, and the increase in biotechnological advances, strains optimised for various economic and biological traits should be one of the most attainable goals for researchers and insect farmers alike. We have reviewed strengths (and weaknesses) of various genetic and genomic approaches, and consider the future of insect farming in the context of genetic and genomic selection of insects.
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    The genomic landscape of retinoblastoma: a review
    (Wiley Blackwell (Blackwell Publishing), 2014-01) Thériault, Brigitte L.; Dimaras, Helen; Gallie, Brenda L.; Corson, Timothy W.; Department of Ophthalmology, IU School of Medicine
    Retinoblastoma is a paediatric ocular tumour that continues to reveal much about the genetic basis of cancer development. Study of genomic aberrations in retinoblastoma tumours has exposed important mechanisms of cancer development and identified oncogenes and tumour suppressors that offer potential points of therapeutic intervention. The recent development of next-generation genomic technologies has allowed further refinement of the genomic landscape of retinoblastoma at high resolution. In a relatively short period of time, a wealth of genetic and epigenetic data has emerged on a small number of tumour samples. These data highlight the inherent molecular complexity of this cancer despite the fact that most retinoblastomas are initiated by the inactivation of a single tumour suppressor gene. This review outlines the current understanding of the genomic, genetic and epigenetic changes in retinoblastoma, highlighting recent genome-wide analyses that have identified exciting candidate genes worthy of further validation as potential prognostic and therapeutic targets.
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    Genomics of Osteoporosis
    (2004-08) Krishnan, Subha; Econs, Michael J.
    Osteoporosis is the most common bone disease in United States and developed countries and a major public health threat for an estimated 44 million Americans. It is characterized by low bone mineral density and micro architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture, especially of hip, spine and wrist. Osteoporosis is multifactorial disease influenced by large number of environmental and genetic factors. Though a number of FDA approved drugs are available for treating this complex disease, a medication, which could specifically and effectively reverse symptoms of it is lackin. As the initial step for approaching disease treatment my current research focuses on locatin candidate genes on linkage regions for BMD on human chromosomes, which potentially can be used for developing novel targets and strategies for therapeutic interventions. We will also define the mouse homologs in the syntenic regions as basis for future studies involving animal models of disturbed BMD. An automated interface which will give information on human - mouse synteny between human marker intervals of interest was developed which will expedite future synteny studies.
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    Harnessing Compensatory Pathways and Acquired Resistance in Treating Triple-Negative Breast Cancer
    (2024-08) Solzak, Jeffrey Peter; Schneider, Bryan P.; Radovich, Milan; Nephew, Kenneth P.; Palkowitz, Alan; Herbert, Brittney-Shea
    Triple-negative breast cancer (TNBC) is defined by the absence of estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth factor receptor 2 (HER2) over-expression. While TNBC comprises a minority of breast cancer cases, about 15%, it results in a disproportionally higher rate of mortality compared to hormone positive breast cancers. Compared to individuals with ER and HER2 positive disease, individuals with TNBC will have a higher incidence of visceral metastasis, a higher likelihood of relapse within the first three years after chemotherapy and surgery, and a shorter overall survival after the onset of metastatic disease. Despite the recent approvals of targeted agents, including: immune checkpoint inhibition using pembrolizumab, the TROP2 antibody drug conjugate (ADC) sacituzumab govitecan, and PARP inhibitors for germline BRCA-mutated tumors, cytotoxic chemotherapy remains the mainstay treatment for metastatic TNBC. To identify novel targets that could potentially be harnessed for therapeutic combinations, we utilized a strategic method by analyzing compensatory genomic and transcriptomic responses to targeted therapy. We demonstrate this herein, by identifying a novel combination targeting the PI3K & Wnt pathways that elicited clinical efficacy in a Phase I clinical trial. We further build on our hypothesis by also studying real-world evidence to identify novel resistance mechanisms in TNBC patients treated with the TROP2 ADC Sacituzumab govitecan. Our data suggest that the comparison of compensatory mechanisms before and after treatment can potentially inform efficacious therapeutic decision-making. In summation, with these data presented, we provide opportunities for furthering the therapeutic landscape to give patients with this dreadful disease more options in the clinical setting.
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    Identification of FDA-approved Drugs Targeting Breast Cancer Stem Cells Along With Biomarkers of Sensitivity
    (Nature Research, 2013-08-28) Bhat-Nakshatri, Poornima; Goswami, Chirayu P.; Badve, Sunil; Sledge, George W.; Nakshatri, Harikrishna
    Recently developed genomics-based tools are allowing repositioning of Food and Drug Administration (FDA)-approved drugs as cancer treatments, which were employed to identify drugs that target cancer stem cells (CSCs) of breast cancer. Gene expression datasets of CSCs from six studies were subjected to connectivity map to identify drugs that may ameliorate gene expression patterns unique to CSCs. All-trans retinoic acid (ATRA) was negatively connected with gene expression in CSCs. ATRA reduced mammosphere-forming ability of a subset of breast cancer cells, which correlated with induction of apoptosis, reduced expression of SOX2 but elevated expression of its antagonist CDX2. SOX2/CDX2 ratio had prognostic relevance in CSC-enriched breast cancers. K-ras mutant breast cancer cell line enriched for CSCs was resistant to ATRA, which was reversed by MAP kinase inhibitors. Thus, ATRA alone or in combination can be tested for efficacy using SOX2, CDX2, and K-ras mutation/MAPK activation status as biomarkers of response.