DOCSLIB.ORG

A Brief History of Human Disease Genetics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Brief History of Human Disease Genetics Review A brief history of human disease genetics https://doi.org/10.1038/s41586-019-1879-7 Melina Claussnitzer1,2,3, Judy H. Cho4,5,6, Rory Collins7,8, Nancy J. Cox9, Emmanouil T. Dermitzakis10,11, Matthew E. Hurles12, Sekar Kathiresan2,13,14, Eimear E. Kenny4,6,15, Received: 16 July 2019 Cecilia M. Lindgren2,16,17, Daniel G. MacArthur2,13,18, Kathryn N. North19,20, Sharon E. Plon21,22, Accepted: 13 November 2019 Heidi L. Rehm2,13,18,23, Neil Risch24, Charles N. Rotimi25, Jay Shendure26,27,28, Nicole Soranzo12,29 & Mark I. McCarthy17,30,31,32* Published online: 8 January 2020 A primary goal of human genetics is to identify DNA sequence variants that infuence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. medicine, which was previously restricted to a few specific clinical Anniversary indications, is poised to go mainstream. collection: This Review charts recent milestones in the history of human disease go.nature.com/ genetics and provides an opportunity to reflect on lessons learned by nature150 the human genetics community. We focus first on the long-standing division between genetic discovery efforts targeting rare variants with large effects and those seeking alleles that influence predispo- sition to common diseases. We describe how this division, with its For almost all human diseases, individual susceptibility is, to some echoes of the century-old debate between Mendelian and biometric degree, influenced by genetic variation. Consequently, characterizing views of human genetics, has obscured the continuous spectrum of the relationship between sequence variation and disease predisposi- disease risk alleles—across the range of frequencies and effect sizes— tion provides a powerful tool for identifying processes fundamental observed in the population, and outline how genome-wide analyses to disease pathogenesis and highlighting novel strategies for preven- in large biobanks are transforming genetic research by enabling a tion and treatment. comprehensive perspective on genotype–phenotype relationships. Over the past 25 years, advances in technology and analytical We describe how the expansion in the scale and scope of strategies approaches, often building on major community projects—such as for enumerating the functional consequences of genetic variation those that generated the human genome sequence1 and elaborated is transforming the torrent of genetic discoveries from the past dec- on that reference to capture sites of genetic variation2–6—have enabled ade into mechanistic insights, and the ways in which this knowledge many of the genes and variants that are causal for rare diseases to be increasingly underpins advances in clinical care. Finally, we reflect on identified and enabled a systematic dissection of the genetic basis of some of the challenges and opportunities that confront the field, and common multifactorial traits. There is growing momentum behind the principles that will, over the coming decade, drive the application the application of this knowledge to drive innovation in clinical care, of human genetics to enhance understanding of health and disease most obviously through developments in precision medicine. Genomic and maximize clinical benefit. 1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 2Broad Institute of MIT and Harvard Cambridge, Cambridge, MA, USA. 3Institute of Nutritional Science, University of Hohenheim, Stuttgart, Germany. 4Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 7Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK. 8UK Biobank, Stockport, UK. 9Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 10Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. 11Health 2030 Genome Center, Geneva, Switzerland. 12Wellcome Sanger Institute, Hinxton, UK. 13Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 14Verve Therapeutics, Cambridge, MA, USA. 15Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 16Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. 17Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 18Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 19Murdoch Children’s Research Institute, Parkville, Victoria, Australia. 20University of Melbourne, Parkville, Victoria, Australia. 21Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 22Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX, USA. 23Department of Pathology, Harvard Medical School, Boston, MA, USA. 24Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. 25Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA. 26Department of Genome Sciences, University of Washington, Seattle, WA, USA. 27Brotman Baty Institute for Precision Medicine, Magnuson Health Sciences Building, Seattle, WA, USA. 28Howard Hughes Medical Institute, Seattle, WA, USA. 29Department of Haematology, University of Cambridge, Cambridge, UK. 30Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK. 31Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. 32Human Genetics, Genentech, South San Francisco, CA, USA. *e-mail: [email protected] Nature | Vol 577 | 9 January 2020 | 179 Review Rare (monogenic) disease Common (complex) disease Genes harbouring variants causal for monogenic disease Genome-wide signicant association signals Type of discovery Resources Technologies Key ndings 0 1,000 2,000 3,000 4,000 80,000 60,000 40,000 20,000 0 1994 1994 1996 1996: DeCODE Genetics founded71,72 1996: Power of association vs linkage37 1996 1998 1998 2000 2000: Draft human genome1 2000 2001: NOD2 linkage for Crohn’s disease34,35 2002 2002 2003: Clinical microarray testing10 2003: HapMap resource2 2004 2004: Open data sharing (DECIPHER)17 2004 2005: Next-generation sequencing12 2005: First GWAS38,39 2006 2006: UKBiobank recruitment started74 2006 2007: Wellcome Trust Case-Control Consortium40 2008 2008: GWAS results catalogue initiated44 2008 2009: Clinical exome sequencing11 2009: Polygenic architecture of complex disease43 2010 2010: 1000 Genomes resource3 2010 2011: Exome-based diagnosis in trios13 2012 2012 2013: Launch of ClinVar, ClinGen and Matchmaker Exchange18,22,23 2014 2014: Genotype-driven 2014 disease discovery15,16 2015: Imputation servers accessible4 2016 2016: Population frequency 2016: Integration of GWAS and 2016 variant database (ExAC)5 sequence data for complex traits45 2017: UKBiobank GWAS completed74 2018: GWAS sample exceeding 1 million90 2018 2018 2018: Polygenic contribution to rare diseases93 Fig. 1 | Growth in the discovery of disease-associated genetic variation. The GWAS and sequencing studies, have supported identification of more than cumulative numbers of genes harbouring variants causal for rare, monogenic 60,000 genetic associations across thousands of human diseases and traits. diseases and traits and of significant GWAS associations implicated in Centre, more recent developments have brought a synthesis of the rare- and common, complex diseases and traits are shown. Left, the advent of high- common-variant approaches based around the combination of sequence- throughput sequencing technologies and availability of reference genomes informed analyses in large cohorts. Key events contributing to these themes from diverse populations has supported a fourfold increase in the discovery of are depicted in the timeline. GA4GH, Global Alliance for Genomics and rare disease-causing genes between 1999 and 2019. Right, international efforts Health160; ExAC, Exome Aggregation Consortium5. such as the Human Genome Project and the HapMap Project, combined with Completion of the draft human genome sequence1 reduced many Rare diseases, rare variants of the obstacles to disease-gene mapping and propelled a fourfold During the 1980s and 1990s, efforts to map disease genes were focused increase in the genes implicated as causal for rare, single-gene dis- on rare, monogenic and syndromic diseases and were mostly driven orders (Fig. 1). Microarray-based detection of structural variation10 by linkage analysis and fine mapping within large multiplex pedi- and exome- and genome-wide sequencing11,12 have been pivotal, bol- grees. Localization of genetic
Load more

Recommended publications
  • Genomics and Its Impact on Science and Society: the Human Genome Project and Beyond
    DOE/SC-0083 Genomics and Its Impact on Science and Society The Human Genome Project and Beyond U.S. Department of Energy Genome Research Programs: genomics.energy.gov A Primer ells are the fundamental working units of every living system. All the instructions Cneeded to direct their activities are contained within the chemical DNA (deoxyribonucleic acid). DNA from all organisms is made up of the same chemical and physical components. The DNA sequence is the particular side-by-side arrangement of bases along the DNA strand (e.g., ATTCCGGA). This order spells out the exact instruc- tions required to create a particular organism with protein complex its own unique traits. The genome is an organism’s complete set of DNA. Genomes vary widely in size: The smallest known genome for a free-living organism (a bac- terium) contains about 600,000 DNA base pairs, while human and mouse genomes have some From Genes to Proteins 3 billion (see p. 3). Except for mature red blood cells, all human cells contain a complete genome. Although genes get a lot of attention, the proteins DNA in each human cell is packaged into 46 chro- perform most life functions and even comprise the mosomes arranged into 23 pairs. Each chromosome is majority of cellular structures. Proteins are large, complex a physically separate molecule of DNA that ranges in molecules made up of chains of small chemical com- length from about 50 million to 250 million base pairs. pounds called amino acids. Chemical properties that A few types of major chromosomal abnormalities, distinguish the 20 different amino acids cause the including missing or extra copies or gross breaks and protein chains to fold up into specific three-dimensional rejoinings (translocations), can be detected by micro- structures that define their particular functions in the cell.
    [Show full text]
  • Genetics and Genomics of Human Population Structure 20
    Genetics and Genomics of Human Population Structure 20 Sohini Ramachandran , Hua Tang , Ryan N. Gutenkunst , and Carlos D. Bustamante Abstract Recent developments in sequencing technology have created a fl ood of new data on human genetic variation, and this data has yielded new insights into human popu- lation structure. Here we review what both early and more recent studies have taught us about human population structure and history. Early studies showed that most human genetic variation occurs within populations rather than between them, and that genetically related populations often cluster geographically. Recent studies based on much larger data sets have recapitulated these observations, but have also demonstrated that high-density genotyping allows individuals to be reliably assigned to their population of origin. In fact, for admixed individuals, even the ancestry of particular genomic regions can often be reli- ably inferred. Recent studies have also offered detailed information about the composition of specifi c populations from around the world, revealing how history has shaped their genetic makeup. We also briefl y review quantitative models of human genetic history, including the role natural selection has played in shaping human genetic variation. Contents 20.2.3 Characterizing Locus-Specifi c Ancestry ...................................................... 594 20.1 Introduction ............................................................... 590 20.3 Global Patterns of Human Population Structure ....... 595 20.1.1 Evolutionary Forces Shaping 20.3.1 The Apportionment of Human Human Genetic Variation ........................... 590 Diversity ..................................................... 595 20.2 Quantifying Population Structure ............................. 592 20.3.2 The History and Geography of Human Genes ......................................... 596 20.2.1 FST and Genetic Distance ............................ 592 20.2.2 Model-Based Clustering 20.3.3 Genetic Structure of Human Populations ..
    [Show full text]
  • What Is the Human Genome Project?
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Supervised Undergraduate Student Research Chancellor’s Honors Program Projects and Creative Work Spring 4-2000 What is the Human Genome Project? Lauren Leigh Taylor University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_chanhonoproj Recommended Citation Taylor, Lauren Leigh, "What is the Human Genome Project?" (2000). Chancellor’s Honors Program Projects. https://trace.tennessee.edu/utk_chanhonoproj/434 This is brought to you for free and open access by the Supervised Undergraduate Student Research and Creative Work at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Chancellor’s Honors Program Projects by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Lauren Taylor Senior Project- (very partial) Dr.Koontz, mentor Dr. Broadhead- I should have this ready to tum in by next Tuesday or Wednesday. Thanks for your grace-- Intro As part of the University of Tennessee Honors Program, I am required to submit a senior project, consisting of research and creative analysis supervised by a faculty mentor. Although these project topics may cover any subject, most students choose a topic that falls within their undergraduate course of study. I have chosen to do this as well. As a Biology major, I have undergone ample preparation to enter a highly advanced field of modern science and medicine. One of the "hot topics" of science today is the international collaboration of scientists working to map the human genome, known as the Human Genome Project.
    [Show full text]
  • The Economic Impact and Functional Applications of Human Genetics and Genomics
    The Economic Impact and Functional Applications of Human Genetics and Genomics Commissioned by the American Society of Human Genetics Produced by TEConomy Partners, LLC. Report Authors: Simon Tripp and Martin Grueber May 2021 TEConomy Partners, LLC (TEConomy) endeavors at all times to produce work of the highest quality, consistent with our contract commitments. However, because of the research and/or experimental nature of this work, the client undertakes the sole responsibility for the consequence of any use or misuse of, or inability to use, any information or result obtained from TEConomy, and TEConomy, its partners, or employees have no legal liability for the accuracy, adequacy, or efficacy thereof. Acknowledgements ASHG and the project authors wish to thank the following organizations for their generous support of this study. Invitae Corporation, San Francisco, CA Regeneron Pharmaceuticals, Inc., Tarrytown, NY The project authors express their sincere appreciation to the following indi- viduals who provided their advice and input to this project. ASHG Government and Public Advocacy Committee Lynn B. Jorde, PhD ASHG Government and Public Advocacy Committee (GPAC) Chair, President (2011) Professor and Chair of Human Genetics George and Dolores Eccles Institute of Human Genetics University of Utah School of Medicine Katrina Goddard, PhD ASHG GPAC Incoming Chair, Board of Directors (2018-2020) Distinguished Investigator, Associate Director, Science Programs Kaiser Permanente Northwest Melinda Aldrich, PhD, MPH Associate Professor, Department of Medicine, Division of Genetic Medicine Vanderbilt University Medical Center Wendy Chung, MD, PhD Professor of Pediatrics in Medicine and Director, Clinical Cancer Genetics Columbia University Mira Irons, MD Chief Health and Science Officer American Medical Association Peng Jin, PhD Professor and Chair, Department of Human Genetics Emory University Allison McCague, PhD Science Policy Analyst, Policy and Program Analysis Branch National Human Genome Research Institute Rebecca Meyer-Schuman, MS Human Genetics Ph.D.
    [Show full text]
  • Determining De Novo Mutation Rates Knowing the Human De Novo Mutation Rate Is Important for Understanding Our Evolution and the Origins of Genetic Diseases
    RESEARCH HIGHLIGHTS IN BRIEF GENE THERAPY Single-stranded RNAs for potent RNAi In the development of gene-based therapies, delivery of ssRNAs is simpler than it is for dsRNAs (as this requires lipid formulation, for example). However, ssRNAs have previously been found to be far less potent for gene silencing. Lima et al. have now overcome this limitation by chemical modifications of ssRNAs that increase their stability. They show that these modified ssRNAs act through the RNAi pathway as guide strands for Argonaute 2 to induce specific gene silencing. Yu et al. demonstrate the therapeutic potential of these RNAs in a mouse model of Huntington’s disease using ssRNAs that target the mutant HTT allele. The gene-silencing efficiency for the ssRNAs seems to be similar to equivalent dsRNAs. ORIGINAL RESEARCH PAPERS Lima, W. F. et al. Single-stranded siRNAs activate RNAi in animals. Cell 150, 883–894 (2012) | Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012) CLINICAL GENOMICS Sequencing to track bacterial infection outbreaks The use of genome sequencing to research disease outbreaks retrospectively has been demonstrated by high-profile cases, such as the recent cholera outbreak in Haiti. But can whole-genome sequencing be used to provide information that can be used in clinical decision making during an outbreak? Two recent studies suggest that it can. Köser et al. investigated a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in a neonatal unit and identified transmission events, using data from the Illumina MiSeq platform. The authors note that the timescale (1.5 days from DNA extraction to sequence) and cost of their study demonstrates that such information can be obtained on a clinically relevant time frame.
    [Show full text]
  • Genetic Variation and Human Evolution
    | NSW Department of Education Genetic Variation and Human Evolution. This article is referenced in the Module 5 and 6 guide, IQ6-1: Can population genetic patterns be predicted with any accuracy? The article is no longer available online. It is archived at the American Society of Human Genetics www.ashg.org. The article provides background information about the use of mitochondrial DNA and Y- chromosome DNA studies to determine a possible path for human evolution. Students could carry out their own research after reading this article. Genetic Variation and Human Evolution Lynn B. Jorde, Ph.D. Department of Human Genetics University of Utah School of Medicine. The past two decades have witnessed an explosion of human genetic data. Innumerable DNA sequences and genotypes have been generated, and they have led to significant biomedical advances. In addition, these data have greatly increased our understanding of patterns of genetic diversity among individuals and populations. The purpose of this brief review is to show how our knowledge of genetic variation can contribute to an understanding of our similarities and differences, our origins, and our evolutionary history. Patterns of genetic diversity inform us about population history because each major demographic event leaves an imprint on a population's collective genomic diversity. A reduction in population size reduces genetic diversity, and an increase in population size eventually increases diversity. The exchange of migrants between populations inevitably results in greater genetic similarity, while isolation preserves genetic uniqueness. These demographic signatures are passed from generation to generation, such that the genomes of modern individuals reflect their demographic history.
    [Show full text]
  • Evolutionary Genetics
    Evolutionary Genetics Ruben C. Arslan & Lars Penke Institute of Psychology Georg August University Göttingen Forthcoming in D. M. Buss (Ed.), Handbook of Evolutionary Psychology (2nd ed.). New York: Wiley. September 17, 2014 Corresponding author: Ruben C. Arslan Georg August University Göttingen Biological Personality Psychology and Psychological Assessment Georg Elias Müller Institute of Psychology Goßlerstr. 14 37073 Göttingen, Germany Tel.: +49 551 3920704 Email: [email protected] 1 Introduction When Charles Darwin developed the theory of evolution, he knew nothing about genetics. Hence, one of its biggest weaknesses was that Darwin had to base it on crude ideas of inheritance. Around the same time, Gregor Mendel discovered the laws of inheritance, but the scientific community initially failed to appreciate his work’s importance. It was only in the 1930’s that Dobzhansky, Fisher, Haldane, Wright, Mayr and others unified genetics and the theory of evolution in the ‘modern synthesis’. Still, the modern synthesis was built on a basic understanding of genetics, with genes merely being particulate inherited information. The basics of molecular genetics, like the structure of DNA, were not discovered until the 1950’s. When modern evolutionary psychology emerged from ethology and sociobiology in the late 1980’s, it had a strong emphasis on human universals, borne from both the assumption that complex adaptations are monomorphic (or sexually dimorphic) and have to go back to at least the last common ancestor of all humans, and the methodological proximity to experimental cognitive psychology, which tends to treat individual differences as statistical noise. As a consequence, genetic differences between people were marginalized in evolutionary psychology (Tooby & Cosmides, 1990).
    [Show full text]
  • Ethical Issues in Human Genetics and Genomics
    ETHICAL ISSUES Fact sheet 19 IN HUMAN GENETICS AND GENOMICS This fact sheet talks about some of the ethical issues to think about when we have a DNA test. Therefore, a person has the right to choose. Genetic counselling is important both before and after IN SUMMARY genetic testing so that all the implications of having • The type of results from a genetic a test can be understood. test may raise ethical issues in a Limitations of genetic testing different way to other types of health information While sometimes, genetic tests provide reliable and accurate information for people to make decisions, • Laboratories undertaking the testing at other times it may not be possible to get a result should be accredited (approved or that is certain. certified). We are each much more than the sum of our genes: our environment can influence our health and development and many health factors are not WHY IS GENETIC INFORMATION DIFFERENT? genetic. For a number of reasons, genetic information is often considered different when compared to other The discovery of a variation in a particular gene medical information about an individual. may provide some information about the nature of a health condition that a person has, will develop, The shared nature and ownership of genetic or for which they may be at increased risk. Rarely information can it predict how severe the condition will be, or the age at which symptoms will first start. Genetic conditions are family health problems. A diagnosis or an increased chance of developing How our health or development shows up (called a health condition because of an inherited DNA the phenotype) and whether this links with our change has implications for a person and their genetic make-up (called the genotype) can help family.
    [Show full text]
  • The Fundamentals of Human Genetics and Genomics
    THE FUNDAMENTALS OF HUMAN GENETICS AND GENOMICS Duration 5 days of face-to-face teaching plus self-directed learning Cost: £1250. If you are an NHS employee, full funding is available through Health Education England Tutors: Dr Kate Everett – St George’s University of London Genetics Research Centre, Reader in Human Genetics Prof Guy Tear – King’s College London, Prof of Molecular Neurobiology Location: St George’s University of London This module will cover the key elements of human molecular genomics which students need as standalone knowledge and to provide a foundation for further modules within Genomic Medicine. Students will learn about the structure of the genome and genes, how genetic information is transferred from DNA to protein, about different patterns of inheritance and different types of genetic variation, and how scientists and clinicians try to identify disease genes and mutations. AIMS • Prepare students to understand the role of genetics in disease and how genomic information can be utilised to elucidate disease mechanism and biology, and its role in personalised medicine. • Serve as a foundation for those wishing to advance their careers within the NHS in genomic medicine. LEARNING OUTCOMES By the end of this module the student will be able to: • Explain core elements of genome architecture, including the properties of DNA and chromatin structure • Critically evaluate the regulation of gene expression, transcription and translation • Interpret variation in genome structure and sequence in the context of physiological function and disease, and across human populations • Describe the correlation between genotype and phenotype ENTRY REQUIREMENTS Applicants should have a minimum of a lower second class degree (2:2) in a subject that offers an appropriate grounding in science, genetics or healthcare.
    [Show full text]
  • Anthropological Genetics Wednesdays 6.10- 8 Pm, Purple Seminar Room, 6Th Floor Science & Engineering Hall Fall 2015
    ANTH 6491: Anthropological Genetics Wednesdays 6.10- 8 pm, Purple Seminar Room, 6th floor Science & Engineering Hall Fall 2015 Brief Summary: A detailed examination of molecular approaches to understanding human evolution and diversity. Emphasize will be on current research findings and new methodologies exploring topics such as: human origins and hominin evolution, population genomics, molecular adaptations, epigenetics and gene-culture interactions. We will also consider relevant social and ethical issues, including commercial DNA testing and ownership of biological samples. Instructor: Brenda Bradley Office: SEH 6820 Telephone: (203) 710.9698 Email: bradleyjbrenda@ gmail.com Office Hours: Wednesdays 1-3, or by appointment Lab website: gwprimategenomicslab.org Course website: via blackboard Human Evolutionary Genetics blog: http://gwheg.blogspot.com Course Description: This seminar course explores current research and methodologies in human genomics and evolutionary genetics. The first sequence and analysis of the human genome was published in 2001. Our understanding of human genetic variation and molecular evolution has accelerated dramatically in the ~15 years since. This course will examine, from an anthropological perspective, our current understanding of the structure and evolution of the human genome, transcriptome and microbiome. We will discuss how advancements in paleogenetics (e.g. sequencing of the Neanderthal and other hominin genomes) influence and confound our understanding of human origins and migrations. We will consider human genomic diversity within the context of local selective pressures related to biogeography, environment and culture (e.g. altitude, UV- exposure, diet). With the rapid advancement of genomic tools, particularly in medical genetics, have also come important ethical and social implications, and this course will consider some of these issues, such as personal genomics, sample ownership and privacy.
    [Show full text]
  • Chapter 9 What Molecules Can't Tell Us About the Spread of Languages
    What Molecules Can’t Tell Us Chapter 9 What Molecules Can’t Tell Us about the Spread of Languages and the Neolithic Hans-Jürgen Bandelt, Vincent Macaulay & Martin Richards A wealth of molecular sequence data seems to have hapless hunter-gatherers as it flooded in. Curiously revolutionized our knowledge about the distant past, though, for us (being familiar with our Dennell, so what can molecular geneticists tell us about the Barker and Whittle), the initial interest lay in the spread of languages and the Neolithic? How does discovery that there were some Neolithic immigrants inference proceed — from data to tales? Is the ge- after all. It even seemed that an estimate of ~20 per netic approach the key to a new synthesis? We will cent Near Eastern Neolithic ancestry in Europe might retell some stories of past and recent publications, actually be taken as rather strongly confirming (at briefly comment on them and discuss the potential least one interpretation of) the Cavalli-Sforza et al. of the future and the limits of the genetic programme. picture, viz. the colonization model of farming ori- gins. The ‘archaeogenetic’ enterprise It soon became clear, though, that there might be more mileage in taking on the demic-diffusionists Following Amorim (1999), and echoing the ‘geneti- rather than the indigenists, especially as it seemed cal archaeology’ of von Haeseler et al. (1996), Ren- that a certain dogmatism had set in amongst the frew (2000) coined the term ‘archaeogenetics’ for ‘the former camp. But it was not clear that such a low newly-emerged discipline which applies molecular Neolithic input was incompatible with demic diffu- genetics to the study of the human past’.
    [Show full text]
  • Human Genetics Lecture #1 March 31, 2016
    Bio 5491 - Advanced Genetics Human Genetics Lecture #1 March 31, 2016 Cristina de Guzman Strong, Ph.D. Department of Medicine Dermatology/Pharmacogenomics Center for the Study of Itch McDonnell Basic Sciences 770 [email protected] 362-7695 Human Genetics • Karyotype • Mutations in Regulatory • Genetic Variants Elements • Mendelian Diseases • Copy number variation • Penetrance/Expressivity diseases • Human Genome Project • Mitochondrial genetics • GWAS/Next-Gen • Human-specific variation sequencing (Exome) • Future • Undiagnosed Diseases • Epigenetics/ENCODE What is Human Genetics? The relationship between natural DNA sequence variation(s) and human phenotypic traits What is different about Human Genetics? • Imprinting……..uniquely mammalian. • Trinucleotide repeat diseases…….anticipation. • One can study complex behaviours and cognition. • Extensive sequence variation leads to common/ complex disease 1. Common disease – common variant hypothesis 2. Large # of small-effect variants 3. Large # of large-effect rare variants 4. Combo of genotypic, environmental, epigenetic interactions Greg Gibson, Nature Review Gen 2012 Human Genome (Karyotype) 22 autosomes/ XY sex chromosomes 02_13.jpg Human genome is ~41% GC, but that is non-randomly distributed. Dark G-bands are lower GC (and lower gene content) Genetic variation: Single Base Pair C T – SNP (single nucleotide polymorphism) - Freq > 0.01 – Can also be 1 insertion or 1 deletion, “indel” – Alleles with Freq < 0.01 – called rare variants OR SNVs – Mutations: usually, really RARE. Alter
    [Show full text]