Other Genetics and Genomics Commons^™

Charge Modulation Of Peptide/Nucleic Acid Complexes: An Anionic Additive Enhances Gene Silencing And Crispr/Cas9 Editing By Promoting Intracellular Nucleic Acid Release, Abdulelah Alhazza, Sorour Khayyatnejad Shoushtari, Hasan Uludag, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Introduction: Small interfering RNA (siRNA) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated Protein 9 (Cas9) complexes are effective approaches to temporarily downregulate protein expression via post-transcription RNA interference or permanently altering protein expression via editing genomic DNA, respectively. However, the efficient delivery of these mediators to targeted cells has been challenging, largely due to their anionic and hydrophilic nature, which hinders their interaction with the cell membrane and cellular internalization. Cell-penetrating peptides (CPPs) exhibit dual characteristics as a carrier for nucleic acid delivery, where positively charged components bind to the negatively charged nucleic acid, and the hydrophobic components …

Homocysteine Thiolactone From Translation Proofreading Is An Endogenous Ligand For Cell-Cell Signaling By The Receptor Sdia, Lorenzo Eugenio Leiva, Roberto A. Zúñiga, Gregory J. Phillips, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Several widespread mechanisms enable cellular communication and coordinate the behavior of bacterial populations. The modules responsible for cellular communication are often found in matching pairs: an enzyme that synthesizes a signal molecule and a specific receptor that decodes it. A notable exception is Escherichia coli SdiA, a homolog of known N-acyl-homoserine lactone (AHL) receptors, for which no corresponding AHL synthase exists. SdiA is an orphan receptor that enables cross-talk by sensing AHLs from other bacterial species. In this work, we investigated whether homocysteine thiolactone (HTL), an AHL-like molecule arising from a proofreading reaction of methionyl tRNA synthetase (MetRS) to correct …

Mobile Genetic Elements Shape Microbial Diversity And Functions In Thawing Permafrost Soils, Jiarong Guo, Samuel T. N. Aroney, Guillermo Domínguez-Huerta, Derek Smith, Dean Vik, Carlos Owusu-Ansah, Akbar Adjie Pratama, Sergei Solonenko, Funing Tian, Cristina Howard-Varona, Zhi-Ping Zhong, Aminata Fofana, Garrett J. Smith, Suzanne B. Hodgkins, Dylan Cronin, Isogenie Field Teams 2010–2017, 2019, Emerge Coordinators, Ben J. Woodcroft, Gene W. Tyson, Virginia I. Rich, Matthew B. Sullivan, Simon Roux, Sarah C. Bagby, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Ecosystems are shaped by communities of microorganisms whose niches and impacts depend on functional profiles influenced by gene gains and losses. Culture-based experiments demonstrate that mobile genetic elements (MGEs) can mediate gene flux, but quantitative understanding of these dynamics in natural systems remains limited. Here we develop and apply a systematic, meta-omic framework to investigate MGEs in a complex natural system using an 8-year soil time series collected at Stordalen Mire, in Sweden’s thawing permafrost margin. In this climate-critical peatland, we identify ~2.1 million MGE recombinases across 89 microbial phyla and assess ecological distributions, affected functions, past mobility and current …

The Competition Between Splicing And 3′ Processing Shapes The Human Transcriptome, Lindsey V. Soles, Shuangyu Li, Liang Liu, Kristianna S.K. Sarkan, Erik G. Alvstad, Lusong Tian, Yoseop Yoon, Marielle Valdez, Ivan Marazzi, Yongsheng Shi

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Eukaryotic pre-mRNA processing steps, including splicing and 3′ processing, are tightly coordinated, yet the underlying mechanisms remain incompletely understood. U1 snRNP has been proposed to inhibit 3′ processing at intronic polyadenylation (IPA) sites through a splicing-independent mechanism termed telescripting. In contrast, we discovered that disrupting splicing by using six different methods—targeting various key components such as U1 snRNP, U2 snRNP, U2AF, and SF3b—activates 3′ processing at thousands of IPA sites. Notably, splicing inhibition, especially of U1 snRNP, induced widespread premature transcription termination within gene bodies through both IPA-coupled and IPA-independent mechanisms. Inhibition of different splicing factors activated overlapping and distinct …

Reverse Micelles Produce Hydroxyapatite Nanoparticles As More Efficient Gene Delivery Carriers Than Regular Micelles, Vuk Uskoković

Administration and Staff Articles and Research

Hydroxyapatite (HAp) is an effective inorganic gene delivery carrier due to its ability to transport genetic cargo across cell membranes, protect it from proteolysis, and enable escape from late endosomes via pH-controlled dissolution. However, its transfection efficiency remains lower than that of viral agents, prompting studies of hybrids with cationic molecules or phases to enhance the gene delivery performance. This study reports on the synthesis of HAp in regular and reverse micellar regions of a ternary microemulsion system composed of cetyltrimethylammonium bromide (CTAB), 1-hexanol and water. Spectroscopic characterization revealed that CTAB headgroups adopted more ordered supramolecular conformations in reverse micelles …

Immunological Surveillance Against Cancer Across Mammals, Orsolya Vincze, Piotr Minias, Alexandre Corthay, Fernando Colchero, Jean-François Lemaître, Louise Maille, Tamás Malkócs, Justus Hagemann, Dalia A. Conde, Samuel Pavard, Antoine M. Dujon, Beata Ujvari, Frédéric Thomas, Amy M. Boddy, Carlo C. Maley, Damien Chevallier, Tuul Sepp, Thomas Pradeu, Mathieu Giraudeau

Presidential Fellows Articles and Research

Contrary to expectations based on their higher cell numbers, larger and longer-lived species do not face dramatically increased risk of cancer. This strongly suggests that evolution has fashioned natural cancer resistance mechanisms, yet our knowledge remains limited on what these mechanisms might be. The cancer immunological surveillance hypothesis, proposed by Burnet and Thomas in the 1950s, highlights immunity as a key factor determining species-specific cancer resistance. Here we address the original, evolutionary interpretation of this hypothesis by investigating the relationship between cancer mortality risk and markers of efficient antigen presentation. Our results show that the expansion of the MHC class …

Utilizing Pharmacogenomics To Improve Students' Self-Perception On The Interprofessional Competencies Of Roles And Responsibilities, And Teams And Teamwork, Amanda Brown, Moom R. Roosan, Robert Goldsteen, Scott D. Ochs, Reza Taheri

Pharmacy Faculty Articles and Research

Introduction

Pharmacogenomics (PGx) is an emerging discipline with the potential to revolutionize personalized medicine, but its successful implementation requires interprofessional collaboration. To address this need, a virtual interprofessional education (IPE) session was designed for student pharmacists and medical students to engage in a case-based learning experience.

Objective

The primary objective was to develop and implement an IPE activity focused on a patient case requiring PGx-guided dual antiplatelet therapy and to assess students' perceptions of two Interprofessional Education Collaborative (IPEC) Version 3 Core Competencies. A secondary objective was to identify key lessons from the session.

Methods

Pharmacist and physician faculty collaboratively …

Highly Targeted Metabolomics Coupled With Gene Expression Analysis By Rt–Qpcr Improves Beef Separation Based On Grass, Grain, Or Grape Supplemented Diet, Lucas Krusinski, Chloe Castanon, Rosalee S. Hellberg, Isabella C. F. Maciel, Muhammad Ahsin, Stephan Van Vliet, Jason E. Rowntree, Jennifer I. Fenton

Food Science Faculty Articles and Research

The objective of this study was to use a multi-omics (i.e., gene expression quantification, metabolomics, and fatty acid [FA] profiling) approach to separate and authenticate beef from three different dietary groups. In this 2-year study, Red Angus steers (n = 54) were randomly allocated to one of three treatments: (1) complex biodiverse pasture (GRASS), (2) total mixed ration (TMR) in feedlot (GRAIN), or (3) TMR in feedlot supplemented with 5% (dry matter) grapeseed extract for the last 30 days (GRAPE). FAs were measured by gas chromatography-mass spectrometry (GC–MS), secondary metabolites were identified using ultra-high-performance liquid chromatography tandem mass spectrometry …

Use Of A Novel Combination Of Multiplex Pcr And Dna Barcoding In Assessing Authenticity Of Ginseng Products, Diane Y. Kim, Donna Miranda-Romo, Adriana R. Ten Cate, Rosalee S. Hellberg

Food Science Faculty Articles and Research

Ginseng (Panax sp.) is a medicinal plant used for its purported health benefits, primarily in East Asian countries. The COVID-19 pandemic led to a significant increase in sales of dietary supplements, including ginseng supplements, to purportedly support immune health and provide other health benefits. However, this heightened demand has subsequently increased the risk of adulteration in these dietary supplements. This study aimed to determine the efficacy of a novel combination of DNA barcoding and multiplex PCR to identify species in ginseng supplements. A total of 50 commercial ginseng supplements containing Panax ginseng, Panax quinquefolius, or Panax notoginseng were obtained …

Aars Online: A Collaborative Database On The Structure, Function, And Evolution Of The Aminoacyl-Trna Synthetases, Jordan Douglas, Haissi Cui, John J. Perona, Oscar Vargas-Rodriguez, Henna Tyynismaa, Claudia Alvarez Carreño, Jiqiang Ling, Lluís Ribas De Pouplana, Xiang-Lei Yang, Michael Ibba, Hubert Becker, Frédéric Fischer, Marie Sissler, Charles W. Carter Jr., Peter Wills

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various translational and non-translational activities beyond aminoacylation, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the 22 coded amino acids are handled by 16 evolutionary families of Class I aaRS and 21 families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like …

The Effect Of Acute Social Isolation On Neural Molecular Responses In Components Of The Social Decision-Making Network, Patricia C. Lopes, Madeleine Chang, Faith Holloway, Biola Fatusin, Sachin Patel, Chandler Siemonsma, Morgan Kindel

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Prolonged or chronic social isolation has pronounced effects on animals, ranging from altered stress responses, increased anxiety and aggressive behaviour, and even increased mortality. The effects of shorter periods of isolation are much less well researched; however, short periods of isolation are used routinely for testing animal behaviour and physiology. Here, we studied how a 3 h period of isolation from a cagemate affected neural gene expression in three brain regions that contain important components of the social decision-making network, the hypothalamus, the nucleus taeniae of the amygdala, and the bed nucleus of the stria terminalis, using a gregarious bird …

Multi-Omics Reveals Largely Distinct Transcript- And Protein-Level Responses To The Environment In An Intertidal Mussel, Lani U. Gleason, Florian J. Fekete, Richelle L. Tanner, W. Wesley Dowd

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Organismal responses to stressful environments are influenced by numerous transcript- and protein-level mechanisms, and the relationships between expression changes at these levels are not always straightforward. Here, we used paired transcriptomic and proteomic datasets from two previous studies from gill of the California mussel, Mytilus californianus, to explore how simultaneous transcript and protein abundance patterns may diverge under different environmental scenarios. Field-acclimatized mussels were sampled from two disparate intertidal sites; individuals from one site were subjected to three further treatments (common garden, low-intertidal or high-intertidal outplant) that vary in temperature and feeding time. Assessing 1519 genes shared between …

Multiple Light Signaling Pathways Control Solar Tracking In Sunflowers, Christopher J. Brooks, Hagop S. Atamian, Stacey L. Harmer

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Sunflowers are famous for their ability to track the sun throughout the day and then reorient at night to face east the following morning. This occurs by differential growth patterns, with the east sides of stems growing more during the day and the west sides of stems growing more at night. This process, termed heliotropism, is generally believed to be a specialized form of phototropism; however, the underlying mechanism is unknown. To better understand heliotropism, we compared gene expression patterns in plants undergoing phototropism in a controlled environment and in plants initiating and maintaining heliotropic growth in the field. We …

The Pros Of Changing Trna Identity, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The notion that errors in protein synthesis are universally harmful to the cell has been questioned by findings that suggest such mistakes may sometimes be beneficial. However, how often these beneficial mistakes arise from programmed changes in gene expression as opposed to reduced accuracy of the translation machinery is still unclear. A new study published in JBC shows that some bacteria have beneficially evolved the ability to mistranslate specific parts of the genetic code, a trait that allows improved antibiotic resistance.

Physiological And Transcriptomic Responses Of Two Artemisia Californica Populations To Drought: Implications For Restoring Drought-Resilient Native Communities, Hagop S. Atamian Dr., Jennifer L. Funk

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

As climate change brings drier and more variable rainfall patterns to many arid and semi-arid regions, land managers must re-assemble appropriate plant communities for these conditions. Transcriptome sequencing can elucidate the molecular mechanisms underlying plant responses to changing environmental conditions, potentially enhancing our ability to screen suitable genotypes and species for restoration. We examined physiological and morphological traits and transcriptome sequences of coastal and inland populations of California sagebrush (Artemisia californica), a critical shrub used to restore coastal sage scrub vegetation communities, grown under low and high rainfall environments. The populations are located approximately 36 km apart but …

Identification And Characterization Of Epicuticular Proteins Of Nematodes Sharing Motifs With Cuticular Proteins Of Arthropods, Bruno Betschart, Marco Bisoffi, Ferial Alaeddine

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Specific collagens and insoluble proteins called cuticlins are major constituents of the nematode cuticles. The epicuticle, which forms the outermost electron-dense layer of the cuticle, is composed of another category of insoluble proteins called epicuticlins. It is distinct from the insoluble cuticlins localized in the cortical layer and the fibrous ribbon underneath lateral alae. Our objective was to identify and characterize genes and their encoded proteins forming the epicuticle. The combination between previously obtained laboratory results and recently made available data through the whole-genome shotgun contigs (WGS) and the transcriptome Shotgun Assembly (TSA) sequencing projects of Ascaris suum allowed us …

The Effect Of Infection Risk On Female Blood Transcriptomics, Brenna M. G. Gormally, Patricia C. Lopes

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Defenses against pathogens can take on many forms. For instance, behavioral avoidance of diseased conspecifics is widely documented. Interactions with these infectious conspecifics can also, however, lead to physiological changes in uninfected animals, an effect that is much less well understood. These changes in behavior and physiology are particularly important to study in a reproductive context, where they can impact reproductive decisions and offspring quality. Here, we studied how an acute (3 h) exposure to an immune-challenged male affected female blood transcriptomics and behavior. We predicted that females paired with immune-challenged males would reduce eating and drinking behaviors (as avoidance …

Induction Of Il19 Expression Through Jnk And Cgas-Sting Modulates Dna Damage–Induced Cytokine Production, Sara H. Small, E. Jessica Tang, Ryan L. Ragland, Yaroslava Ruzankina, David W. Schoppy, Rahul S. Mandal, M. Rebecca Glineburg, Zgjim Ustelenca, Daniel J. Powell, Fiona Simpkins, F. Bradley Johnson, Eric J. Brown

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was …

Role Of A Cryptic Trna Gene Operon In Survival Under Translational Stress, Javier Santamaría-Gómez, Miguel Ángel Rubio, Rocío López-Igual, Ana B. Romero-Losada, Fernando M. Delgado-Chaves, Roque Bru-Martínez, Francisco J. Romero-Campero, Antonio Herrero, Michael Ibba, Jesús A. G. Ochoa De Alda, Ignacio Luque

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

As compared to eukaryotes, bacteria have a reduced tRNA gene set encoding between 30 and 220 tRNAs. Although in most bacterial phyla tRNA genes are dispersed in the genome, many species from distinct phyla also show genes forming arrays. Here, we show that two types of arrays with distinct evolutionary origins exist. This work focuses on long tRNA gene arrays (L-arrays) that encompass up to 43 genes, which disseminate by horizontal gene transfer and contribute supernumerary tRNA genes to the host. Although in the few cases previously studied these arrays were reported to be poorly transcribed, here we show that …

Enhanced Detection Of Expanded Repeat Mrna Foci With Hybridization Chain Reaction, M. Rebecca Glineburg, Yuan Zhang, Amy Krans, Elizabeth M. Tank, Sami J. Barmada, Peter K. Todd

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Transcribed nucleotide repeat expansions form detectable RNA foci in patient cells that contribute to disease pathogenesis. The most widely used method for detecting RNA foci, fluorescence in situ hybridization (FISH), is powerful but can suffer from issues related to signal above background. Here we developed a repeat-specific form of hybridization chain reaction (R-HCR) as an alternative method for detection of repeat RNA foci in two neurodegenerative disorders: C9orf72 associated ALS and frontotemporal dementia (C9 ALS/FTD) and Fragile X-associated tremor/ataxia syndrome. R-HCR to both G₄C₂ and CGG repeats exhibited comparable specificity but > 40 × sensitivity compared to FISH, …

Wild Mice With Different Social Network Sizes Vary In Brain Gene Expression, Patricia C. Lopes, Barbara König

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background

Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution …

A "Choose-Your-Own" Classroom-Based Activity That Promotes Scientific Inquiry About Rna Interference, Jeremy L. Hsu

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

RNA interference (RNAi), the process that results in the degradation of a target gene’s mRNA, is a fundamental part of eukaryotic gene regulation and is also an important molecular technique that allows for experimental manipulation of gene expression without altering DNA sequences. Despite the importance of RNAi, there have been relatively few lecture-based activities designed to teach about the consequences of this process and counter common misconceptions. I present here an inquiry-based activity that is centered around a “choose your own experiment” design where students generate hypotheses and critically evaluate their ideas by choosing several simulated experiments. The activity presents …

Deletion Of Uls1 Confers Damage Tolerance In Sgs1 Mutants Through A Top3-Dependent D-Loop Mediated Fork Restart Pathway, M. Rebecca Glineburg, Eleanor Johns, F. Brad Johnson

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Homologous recombination (HR)-based repair during DNA replication can apparently utilize several partially overlapping repair pathways in response to any given lesion. A key player in HR repair is the Sgs1-Top3-Rmi1 (STR) complex, which is critical for resolving X-shaped recombination intermediates formed following bypass of methyl methanesulfonate (MMS)-induced damage. STR mutants are also sensitive to the ribonucleotide reductase inhibitor, hydroxyurea (HU), but unlike MMS treatment, HU treatment is not accompanied by X-structure accumulation, and it is thus unclear how STR functions in this context. Here we provide evidence that HU-induced fork stalling enlists Top3 prior to recombination intermediate formation. The resistance …

Hnrnpa2 Mediated Acetylation Reduces Telomere Length In Response To Mitochondrial Dysfunction, Manti Guha, Satish Srinivasan, F. Bradley Johnson, Gordon Ruthel, Kip Guja, Miguel Garcia-Diaz, Brett A. Kaufman, M. Rebecca Glineburg, Jikang Fang, Hiroshi Nakagawa, Jeelan Basha, Tapas Kundu, Narayan G. Avadhani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner’s syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria …

Repeat-Associated Non-Aug (Ran) Translation And Other Molecular Mechanisms In Fragile X Tremor Ataxia Syndrome, M. Rebecca Glineburg, Peter K. Todd, Nicolas Charlet-Berguerand, Chantal Sellier

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5′UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA …

Ran Translation At C9orf72-Associated Repeat Expansions Is Selectively Enhanced By The Integrated Stress Response, Katelyn M. Green, M. Rebecca Glineburg, Michael G. Kearse, Brittany N. Flores, Alexander E. Linsalata, Stephen J. Fedak, Aaron C. Goldstrohm, Sami J. Barmada, Peter K. Todd

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G₄C₂ repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an …

Genomic Data Reveal A Loss Of Diversity In Two Species Of Tuco-Tucos (Genus Ctenomys) Following A Volcanic Eruption, Jeremy L. Hsu, Jeremy Chase Crawford, Mauro N. Tammone, Uma Ramakrishnan, Eileen A. Lacey, Elizabeth A. Hadly

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Marked reductions in population size can trigger corresponding declines in genetic variation. Understanding the precise genetic consequences of such reductions, however, is often challenging due to the absence of robust pre- and post-reduction datasets. Here, we use heterochronous genomic data from samples obtained before and immediately after the 2011 eruption of the Puyehue-Cordón Caulle volcanic complex in Patagonia to explore the genetic impacts of this event on two parapatric species of rodents, the colonial tuco-tuco (Ctenomys sociabilis) and the Patagonian tuco-tuco (C. haigi). Previous analyses using microsatellites revealed no post-eruption changes in genetic variation in C. …

Exploring Molecular Mechanisms Of Paradoxical Activation In The Braf Kinase Dimers: Atomistic Simulations Of Conformational Dynamics And Modeling Of Allosteric Communication Networks And Signaling Pathways, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach. Using this theoretical framework, we have combined molecular dynamics simulations with coevolutionary analysis and modeling of the residue interaction networks to determine molecular determinants of paradoxical activation. We …

Genetic Analysis Reveals A Hierarchy Of Interactions Between Polycystin-Encoding Genes And Genes Controlling Cilia Function During Left-Right Determination, Daniel T. Grimes, Jennifer L. Keynton, Maria T. Buenavista, Xingjian Jin, Saloni H. Patel, Shinohara Kyosuke, Jennifer Vibert, Debbie J. Williams, Hiroshi Hamada, Rohana Hussain, Surya M. Nauli, Dominic P. Norris

Pharmacy Faculty Articles and Research

During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This ‘nodal flow’ is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca²⁺ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we …

The Genetic Ancestry Of African Americans, Latinos, And European Americans Across The United States, Katarzyna Bryc, Eric Y. Durand, J. Michael Macpherson, David Reich, Joanna Mountain

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical …