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Genetic Phenomena Commons

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All Articles in Genetic Phenomena

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518 full-text articles. Page 6 of 17.

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline In Preclinical Alzheimer’S Disease, Tenielle Porter, Samantha C. Burnham, Greg Savage, Yen Ying Lim, Paul Maruff, Lidija Milicic, Madeline Peretti, David Ames, Colin L. Masters, Ralph N. Martins, Stephanie Rainey-Smith, Christopher C. Rowe, Olivier Salvado, Kevin Taddei, David Groth, Guiseppe Verdile, Victor L. Villemagne, Simon M. Laws 2018 Edith Cowan University

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline In Preclinical Alzheimer’S Disease, Tenielle Porter, Samantha C. Burnham, Greg Savage, Yen Ying Lim, Paul Maruff, Lidija Milicic, Madeline Peretti, David Ames, Colin L. Masters, Ralph N. Martins, Stephanie Rainey-Smith, Christopher C. Rowe, Olivier Salvado, Kevin Taddei, David Groth, Guiseppe Verdile, Victor L. Villemagne, Simon M. Laws

ECU Publications Post 2013

Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory ...


Nmd Monitors Translational Fidelity 24/7, Alper Celik, Feng He, Allan Jacobson 2017 University of Massachusetts Medical School

Nmd Monitors Translational Fidelity 24/7, Alper Celik, Feng He, Allan Jacobson

Open Access Articles

Nonsense-mediated mRNA decay (NMD) is generally thought to be a eukaryotic mRNA surveillance pathway tasked with the elimination of transcripts harboring an in-frame premature termination codon (PTC). As presently conceived, NMD acting in this manner minimizes the likelihood that potentially toxic polypeptide fragments would accumulate in the cytoplasm. This notion is to be contrasted to the results of systematic RNA-Seq and microarray analyses of NMD substrates in multiple model systems, two different experimental approaches which have shown that many mRNAs identified as NMD substrates fail to contain a PTC. Our recent results provide insight into, as well as a possible ...


Predicting Human Splicing Branchpoints By Combining Sequence-Derived Features And Multi-Label Learning Methods, Wen Zhang, Xiaopeng Zhu, Yu Fu, Junko Tsuji, Zhiping Weng 2017 Wuhan University

Predicting Human Splicing Branchpoints By Combining Sequence-Derived Features And Multi-Label Learning Methods, Wen Zhang, Xiaopeng Zhu, Yu Fu, Junko Tsuji, Zhiping Weng

Program in Bioinformatics and Integrative Biology Publications and Presentations

BACKGROUND: Alternative splicing is the critical process in a single gene coding, which removes introns and joins exons, and splicing branchpoints are indicators for the alternative splicing. Wet experiments have identified a great number of human splicing branchpoints, but many branchpoints are still unknown. In order to guide wet experiments, we develop computational methods to predict human splicing branchpoints.

RESULTS: Considering the fact that an intron may have multiple branchpoints, we transform the branchpoint prediction as the multi-label learning problem, and attempt to predict branchpoint sites from intron sequences. First, we investigate a variety of intron sequence-derived features, such as ...


Revealing A Non-Canonical Role Of Anti-Apoptotic Mcl-1 In Early Embryonic Development, Xue Yang 2017 University of Tennessee Health Science Center

Revealing A Non-Canonical Role Of Anti-Apoptotic Mcl-1 In Early Embryonic Development, Xue Yang

Theses and Dissertations (ETD)

MCL-1, a well-known pro-survival BCL-2 family member, is indispensable for the survival of various cellular lineages and is also among the most frequently amplified genes in a variety of human malignancies. Gene ablation studies previously revealed that Mcl-1 deficiency leads to embryonic lethality around E3.5 during peri-implantation stage. Strikingly, the study did not detect any increase in apoptotic cells of the blastocyst, indicating a function of MCL-1 beyond regulating apoptosis. Our previous studies revealed an unrecognized role of MCL-1 in promoting mitochondrial physiology, which is independent of its classical anti-apoptotic function and requires being imported into the mitochondrial matrix ...


Caenorhabditis Elegans Dbl-1/Bmp Regulates Lipid Accumulation Via Interaction With Insulin Signaling, James F. Clark, Michael Meade, Gehan Ranepura, David H. Hall, Cathy Savage-Dunn 2017 CUNY Queens College

Caenorhabditis Elegans Dbl-1/Bmp Regulates Lipid Accumulation Via Interaction With Insulin Signaling, James F. Clark, Michael Meade, Gehan Ranepura, David H. Hall, Cathy Savage-Dunn

Publications and Research

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively ...


Computational Investigation Of Homologous Recombination Dna Repair Deficiency In Sporadic Breast Cancer, Yue Wang, Matthew H. Ung, Sharon B. Cantor, Chao Cheng 2017 Huazhong University of Science and Technology

Computational Investigation Of Homologous Recombination Dna Repair Deficiency In Sporadic Breast Cancer, Yue Wang, Matthew H. Ung, Sharon B. Cantor, Chao Cheng

Open Access Articles

BRCAness has important implications in the management and treatment of patients with breast and ovarian cancer. In this study, we propose a computational framework to measure the BRCAness of breast and ovarian tumor samples based on their gene expression profiles. We define a characteristic profile for BRCAness by comparing gene expression differences between BRCA1/2 mutant familial tumors and sporadic breast cancer tumors while adjusting for relevant clinical factors. With this BRCAness profile, our framework calculates sample-specific BRCA scores, which indicates homologous recombination (HR)-mediated DNA repair pathway activity of samples. We found that in sporadic breast cancer high BRCAness ...


A Hyperthermophilic Phage Decoration Protein Suggests Common Evolutionary Origin With Herpesvirus Triplex Proteins And An Anti-Crispr Protein, Nicholas P. Stone, Brendan J. Hilbert, Daniel Hidalgo, Kevin T. Halloran, Brian A. Kelch 2017 University of Massachusetts Medical School

A Hyperthermophilic Phage Decoration Protein Suggests Common Evolutionary Origin With Herpesvirus Triplex Proteins And An Anti-Crispr Protein, Nicholas P. Stone, Brendan J. Hilbert, Daniel Hidalgo, Kevin T. Halloran, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

Virus capsid proteins reproducibly self-assemble into regularly-shaped, stable shells that protect the viral genome from external environmental assaults, while maintaining the high internal pressure of the tightly packaged viral genome. To elucidate how capsids maintain stability under harsh conditions, we investigated the capsid components of a hyperthermophilic virus, phage P74-26. We determined the structure of a capsid protein gp87 and show that it has the same fold as trimeric decoration proteins that enhance the structural stability of capsids in many other phage, despite lacking significant sequence homology. We also find that gp87 is significantly more stable than its mesophilic homologs ...


Rna Sequencing And Proteomics Approaches Reveal Novel Deficits In The Cortex Of Mecp2-Deficient Mice, A Model For Rett Syndrome, Natasha L. Pacheco, Michael R. Heaven, Leanne M. Holt, David K. Crossman, Kristin J. Boggio, Scott A. Shaffer, Daniel L. Flint, Michelle L. Olsen 2017 University of Alabama, Birmingham

Rna Sequencing And Proteomics Approaches Reveal Novel Deficits In The Cortex Of Mecp2-Deficient Mice, A Model For Rett Syndrome, Natasha L. Pacheco, Michael R. Heaven, Leanne M. Holt, David K. Crossman, Kristin J. Boggio, Scott A. Shaffer, Daniel L. Flint, Michelle L. Olsen

Open Access Articles

BACKGROUND: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. Much of our understanding of MeCP2 function is derived from transcriptomic studies with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression to better understand the biology between transcriptional and translational regulation.

METHODS: We therefore performed the first comprehensive transcriptome-proteome comparison in a RTT mouse model to elucidate RTT pathophysiology, identify potential therapeutic targets, and further our understanding of MeCP2 function. The whole cortex ...


Crispr-Based Dna Imaging In Living Cells Reveals Cell Cycle-Dependent Chromosome Dynamics, Hanhui Ma, Li-Chun Tu, University of Central Florida, Yu-Chieh Chung, David Grünwald, Shaojie Zhang, Thoru Pederson 2017 University of Massachusetts Medical School

Crispr-Based Dna Imaging In Living Cells Reveals Cell Cycle-Dependent Chromosome Dynamics, Hanhui Ma, Li-Chun Tu, University Of Central Florida, Yu-Chieh Chung, David Grünwald, Shaojie Zhang, Thoru Pederson

University of Massachusetts Medical School Faculty Publications

In contrast to the well-studied condensation and folding of chromosomes during mitosis, their dynamics in interphase are less understood. We developed a sensitive, multicolor system, CRISPR-Sirius, allowing the real-time tracking of the dynamics of chromosomal loci. We tracked loci kilobases to megabases apart and found significant variation in the inter-locus distances of each pair, indicating differing degrees of DNA contortion. We resolved two distinct modes of dynamics of loci: saltatory local movements as well as translational movements of the domain. The magnitude of both of these modes of movements increased from early to late G1, whereas the translational movements were ...


Unexpected Crispr Off-Target Mutation Pattern In Vivo Are Not Typically Germline-Like, Zhiting Wei, Funan He, Guohui Chuai, Hanhui Ma, Zhixi Su, Qi Liu 2017 Tongji University

Unexpected Crispr Off-Target Mutation Pattern In Vivo Are Not Typically Germline-Like, Zhiting Wei, Funan He, Guohui Chuai, Hanhui Ma, Zhixi Su, Qi Liu

University of Massachusetts Medical School Faculty Publications

A computationally evolutionary investigation was performed to re-analyze the WGS data of the two studies published in Nature Methods (2015, 2017) with opposite conclusions on CRISPR off-target mutations. Our analysis concluded that the so-called unexpected SNVs pattern obtained by the study of Schaefer et al. are not typically germline-like. Some of unusual and unidentified mutations may arise, but the real reasons remain to be explored. Based on the available data and a direct comparison of the two studies, we presented two possible reasons and future re-analysis directions that may contribute to such different conclusions. To characterize the authentic CRISPR-mediated mutations ...


Alterations In Mrna 3' Utr Isoform Abundance Accompany Gene Expression Changes In Human Huntington's Disease Brains, Lindsay S. Romo, Ami Ashar-Patel, Edith L. Pfister, Neil Aronin 2017 University of Massachusetts Medical School

Alterations In Mrna 3' Utr Isoform Abundance Accompany Gene Expression Changes In Human Huntington's Disease Brains, Lindsay S. Romo, Ami Ashar-Patel, Edith L. Pfister, Neil Aronin

Open Access Articles

The huntingtin gene has two mRNA isoforms that differ in their 3' UTR length. The relationship of these isoforms with Huntington's disease is not established. We provide evidence that the abundance of huntingtin 3' UTR isoforms differs between patient and control neural stem cells, fibroblasts, motor cortex, and cerebellum. Huntingtin 3' UTR isoforms, including a mid-3' UTR isoform, have different localizations, half-lives, polyA tail lengths, microRNA sites, and RNA-binding protein sites. Isoform shifts in Huntington's disease motor cortex are not limited to huntingtin; 11% of alternatively polyadenylated genes change the abundance of their 3' UTR isoforms. Altered expression ...


A Role For Tau Protein In Maintaining Ribosomal Dna Stability And Cytidine Deaminase-Deficient Cell Survival, Elias Bou Samra, Geraldine Buhagiar-Labarchede, Christelle Machon, Jerome Guitton, Rosine Onclercq-Delic, Michael R. Green, Olivier Alibert, Claude Gazin, Xavier Veaute, Mounira Amor-Gueret 2017 PSL Research University

A Role For Tau Protein In Maintaining Ribosomal Dna Stability And Cytidine Deaminase-Deficient Cell Survival, Elias Bou Samra, Geraldine Buhagiar-Labarchede, Christelle Machon, Jerome Guitton, Rosine Onclercq-Delic, Michael R. Green, Olivier Alibert, Claude Gazin, Xavier Veaute, Mounira Amor-Gueret

Open Access Articles

Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis ...


Flt1 And Transcriptome-Wide Polyadenylation Site (Pas) Analysis In Preeclampsia, Ami Ashar-Patel, Yasin Kaymaz, Augustine Rajakumar, Jeffrey A. Bailey, S. Ananth Karumanchi, Melissa J. Moore 2017 University of Massachusetts Medical School

Flt1 And Transcriptome-Wide Polyadenylation Site (Pas) Analysis In Preeclampsia, Ami Ashar-Patel, Yasin Kaymaz, Augustine Rajakumar, Jeffrey A. Bailey, S. Ananth Karumanchi, Melissa J. Moore

Open Access Articles

Maternal symptoms of preeclampsia (PE) are primarily driven by excess anti-angiogenic factors originating from the placenta. Chief among these are soluble Flt1 proteins (sFlt1s) produced from alternatively polyadenylated mRNA isoforms. Here we used polyadenylation site sequencing (PAS-Seq) of RNA from normal and PE human placentae to interrogate transcriptome-wide gene expression and alternative polyadenylation signatures associated with early-onset PE (EO-PE; symptom onset < 34 weeks) and late-onset PE (LO-PE; symptom onset > 34 weeks) cohorts. While we observed no general shift in alternative polyadenylation associated with PE, the EO-PE and LO-PE cohorts do exhibit gene expression profiles distinct from both each other and from normal placentae. The only two genes upregulated ...


A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Yuanyuan Chen, Vineeta Bajaj, Caitlin M. Connolly, Hsin-Jung Chou, Upasna Sharma, Hsiuyi V. Chen, Daniel N. Bolon, Oliver J. Rando, Paul D. Kaufman 2017 University of Massachusetts Medical School

A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Yuanyuan Chen, Vineeta Bajaj, Caitlin M. Connolly, Hsin-Jung Chou, Upasna Sharma, Hsiuyi V. Chen, Daniel N. Bolon, Oliver J. Rando, Paul D. Kaufman

University of Massachusetts Medical School Faculty Publications

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this ...


Fundamental Limits On Dynamic Inference From Single Cell Snapshots, Caleb Weinreb, Samuel Wolock, Betsabeh K. Tusi, Merav Socolovsky, Allon M. Klein 2017 Harvard Medical School

Fundamental Limits On Dynamic Inference From Single Cell Snapshots, Caleb Weinreb, Samuel Wolock, Betsabeh K. Tusi, Merav Socolovsky, Allon M. Klein

University of Massachusetts Medical School Faculty Publications

Single cell expression profiling reveals the molecular states of individual cells with unprecedented detail. However, because these methods destroy cells in the process of analysis, they cannot measure how gene expression changes over time. But some information on dynamics is present in the data: the continuum of molecular states in the population can reflect the trajectory of a typical cell. Many methods for extracting single cell dynamics from population data have been proposed. However, all such attempts face a common limitation: for any measured distribution of cell states, there are multiple dynamics that could give rise to it, and by ...


Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch 2017 University of Nebraska Medical Center

Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch

Theses & Dissertations

DNA methyltransferase 3A (DNMT3A) is a master epigenetic regulator of benign and malignant hematopoiesis. To dissect the biological consequences of homozygous and heterozygous Dnmt3a inactivation in malignant hematopoiesis, we generated Dnmt3a homozygous null (Dnmt3aΔ/Δ) and Dnmt3a heterozygous (Dnmt3a+/) mice and compared the presentations of hematologic malignancies between cohorts. Bi-allelic inactivation of Dnmt3a results in the presentation of mature lymphoid neoplasms resembling chronic lymphocytic leukemia (CLL; B220+CD19+CD5+; 88% penetrance (37/42)) and CD8+ peripheral T-cell lymphoma (PTCL; TCRβ+CD3+CD8+CD4; 40% penetrance (17/42)). In contrast, mono-allelic inactivation of Dnmt3a results in the presentation of CLL ...


Overexpressed Somatic Alleles Are Enriched In Functional Elements In Breast Cancer, Paula Restrepo, Mercedeh Movassagh, Nawaf Alomran, Christian Miller, Muzi Li, Chris Trenkov, Yulian Manchev, Sonali Bahl, Stephanie Warnken, Liam Spurr, Tatiyana Apanasovich, Keith Crandall, Nathan Edwards, Anelia Horvath 2017 George Washington University

Overexpressed Somatic Alleles Are Enriched In Functional Elements In Breast Cancer, Paula Restrepo, Mercedeh Movassagh, Nawaf Alomran, Christian Miller, Muzi Li, Chris Trenkov, Yulian Manchev, Sonali Bahl, Stephanie Warnken, Liam Spurr, Tatiyana Apanasovich, Keith Crandall, Nathan Edwards, Anelia Horvath

Open Access Articles

Asymmetric allele content in the transcriptome can be indicative of functional and selective features of the underlying genetic variants. Yet, imbalanced alleles, especially from diploid genome regions, are poorly explored in cancer. Here we systematically quantify and integrate the variant allele fraction from corresponding RNA and DNA sequence data from patients with breast cancer acquired through The Cancer Genome Atlas (TCGA). We test for correlation between allele prevalence and functionality in known cancer-implicated genes from the Cancer Gene Census (CGC). We document significant allele-preferential expression of functional variants in CGC genes and across the entire dataset. Notably, we find frequent ...


Replication Fork Slowing And Stalling Are Distinct, Checkpoint-Independent Consequences Of Replicating Damaged Dna, Divya Ramalingam Iyer, Nicholas R. Rhind 2017 University of Massachusetts Medical School

Replication Fork Slowing And Stalling Are Distinct, Checkpoint-Independent Consequences Of Replicating Damaged Dna, Divya Ramalingam Iyer, Nicholas R. Rhind

Open Access Articles

In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions ...


Heterogeneity And Intrinsic Variation In Spatial Genome Organization, Elizabeth Finn, Gianluca Pegoraro, Hugo B. Brandao, Anne-Laure Valton, Marlies E. Oomen, Job Dekker, Leonid Mirny, Tom Misteli 2017 National Cancer Institute

Heterogeneity And Intrinsic Variation In Spatial Genome Organization, Elizabeth Finn, Gianluca Pegoraro, Hugo B. Brandao, Anne-Laure Valton, Marlies E. Oomen, Job Dekker, Leonid Mirny, Tom Misteli

University of Massachusetts Medical School Faculty Publications

The genome is hierarchically organized in 3D space and its architecture is altered in differentiation, development and disease. Some of the general principles that determine global 3D genome organization have been established. However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are poorly characterized. Here, we systematically probe the heterogeneity in genome organization in human fibroblasts by combining high-resolution Hi-C datasets and high-throughput genome imaging. Optical mapping of several hundred genome interaction pairs at the single cell level demonstrates low steady-state frequencies of colocalization in the population and independent behavior of individual alleles in single nuclei ...


Hereditary Renal Amyloidosis Associated With A Novel Apolipoprotein A-Ii Variant, Tatiana Prokaeva, Harun Akar, Brian Spencer, Andrea Havasi, Haili Cui, Carl J. O'Hara, Olga Gursky, John D. Leszyk, Martin Steffen, Sabrina Browning, Allison Rosenberg, Lawreen H. Connors 2017 Boston University

Hereditary Renal Amyloidosis Associated With A Novel Apolipoprotein A-Ii Variant, Tatiana Prokaeva, Harun Akar, Brian Spencer, Andrea Havasi, Haili Cui, Carl J. O'Hara, Olga Gursky, John D. Leszyk, Martin Steffen, Sabrina Browning, Allison Rosenberg, Lawreen H. Connors

Open Access Articles

Here, we report a family with renal amyloidosis associated with a novel stop codon mutation in APOA2 and the apoA-II variant, 78Leuext21.


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