GENETICS AND GENOMICS

Transcription

1 GENETICS AND GENOMICS Editor: Csaba Szalai, PhD, university professor Authors: Chapter 1: Valéria László Chapter 2, 3, 4, 6, 7: Sára Tóth Chapter 5: Erna Pap Chapter 8, 9, 10, 11, 12, 13, 14: Csaba Szalai Chapter 15: András Falus and Ferenc Oberfrank Keywords: Mitosis, meiosis, mutations, cytogenetics, epigenetics, Mendelian inheritance, genetics of sex, developmental genetics, stem cell biology, oncogenetics, immunogenetics, human genomics, genomics of complex diseases, genomic methods, population genetics, evolution genetics, pharmacogenomics, nutrigenetics, gene environmental interaction, systems biology, bioethics. Summary The book contains the substance of the lectures and partly of the practices of the subject of Genetics and Genomics held in Semmelweis University for medical, pharmacological and dental students. The book does not contain basic genetics and molecular biology, but rather topics from human genetics mainly from medical point of views. Some of the 15 chapters deal with medical genetics, but the chapters also introduce to the basic knowledge of cell division, cytogenetics, epigenetics, developmental genetics, stem cell biology, oncogenetics, immunogenetics, population genetics, evolution genetics, nutrigenetics, and to a relative new subject, the human genomics and its applications for the study of the genomic background of complex diseases, pharmacogenomics and for the investigation of the genome environmental interactions. As genomics belongs to sytems biology, a chapter introduces to basic terms of systems biology, and concentrating on diseases, some examples of the application and utilization of this scientific field are also be shown. The modern human genetics can also be associated with several ethical, social and legal issues. The last chapter of this book deals with these issues. At the end of each chapter there are questions, with which the readers can ascertain whether they understood and/or learned the chapter. Because it is an e-book, some terms and definitions has a hyperlink for more detailed explanations in the World Wide Web. Besides university students, the book is also recommended to all those who are interested in modern medical genetics and genomics and want to be up-to date in these subjects. Typotex Kiadó 2013

2 COPYRIGHT: András Falus, Valéria László, Ferenc Oberfrank, Erna Pap, Dr. Csaba Szalai, Sára Tóth, Budapest University of Technology and Economics Creative Commons NonCommercial-NoDerivs 3.0 (CC BY-NC-ND 3.0) This work can be reproduced, circulated, published and performed for non-commercial purposes without restriction by indicating the author's name, but it cannot be modified. Lector: Viktor Molnár, MD, head of Csertex Research Laboratory ISBN Prepared under the editorship of Typotex Kiadó Responsible manager: Votisky Zsuzsa Made within the framework of the project Nr. TÁMOP-4.1.2/A/1-11/ , entitled Konzorcium a biotechnológia és bioinformatika aktív tanulásáért.

3 Content 1. Transmission of genetic information Cell cycle and regulation of cell cycle G0 - G1 transition G1 S transition, S-phase G2 M transition M-phase Chromosome structure Disappearance and re-formation of nuclear envelope Structure and role of mitotic spindle Metaphase anaphase transition Cytokinesis Operation of cell cycle checkpoints Meiosis Phases of meiosis Oogenesis Spermatogenesis Regulation of meiosis Mutations and polymorphisms The classification of mutations Gene mutations DNA repair Mutagenicity tests Useful web-sites: Questions Cytogenetics. Chromosome mutations Structural chromosome aberrations Deletions Duplications Translocations Reciprocal translocations Inversions Ring (ring) chromosome Isochromosome Dicentric chromosome Acentric fragment Numerical chromosome aberrations Euploid chromosome mutations Aneuploid chromosomal aberrations The most common numerical chromosomal abnormalities Trisomy Csaba Szalai

4 4 Genetics and genomics Trisomy Trisomy Numerical sex chromosome aberrations Turner syndrome Klinefelter syndrome Triple X syndrome Double-Y syndrome, "superman" or Jacobs syndrome Uniparental disomy (UPD) Mixoploid mutations Mosaicism Chimerism Useful web-sites: Questions: Epigenetics Epigenetic changes - molecular modifications DNA methylation CpG as mutation hot spot Histone modifications Non-coding RNAs Epigenetic phenomena X-chromosome inactivation Genomic imprinting Imprinting related diseases Evolutionary causes of imprinting The significance of epigenetic effects Useful web-sites Questions Mendelian Inheritance: autosomal inheritance Introduction Interpretation of some basic genetic terms Phenomena that fine-tune classical monogenic inheritance Autosomal dominant inheritance General characteristics of autosomal dominant (AD) inheritance Diseases due to the mutation of structural genes Marfan syndrome Osteogenesis imperfecta Diseases due to mutations of receptor genes Achondroplasia Familial hypercholesterolemia Polycystic kidney disease Mutations of the gene of a protein with a yet unknown function Huntington Chorea Mutation of Protooncogenes Pharmacogenetic diseases Porfiria Malignant hyperthermia Autosomal recessive inheritance General characteristics of autosomal recessive (AR) inheritance Enzymopathies Csaba Szalai

5 Content Phenylketonuria (PKU) Classical albinism Congenital adrenal hyperplasia (CAH) Xeroderma pigmentosum Cystic fibrosis Haemoglobinopathies Sickle cell anemia Thalassemia Genes and Tumors Genes and Drugs Conclusion Questions The role of sex in heredity X-linked inheritance X-linked dominant (XD) Inheritance X-linked recessive (XR) Inheritance Y-linked (holandric) Inheritance Sex influenced inheritance Sex limited inheritance Genomic imprinting Cytoplasmic inheritance Maternal genetic effect Mitochondrial inheritance The X chromosome inactivation Questions Genetics of biological processes Developmental genetics Morphogens Homeobox genes The genetics of sex Male sex determination in mammals Development of female sex in mammals Stem cell biology Oncogenetics Oncogenes Tumor suppressor genes Anti-apoptotic genes Telomerase Immunogenetics Useful web-sites Questions: Introduction to genomics Genomics Human Genome Project DNA sequencing Participants in the Human Genome Project Some results of the HGP Variations in the human genome Junk DNA in the human genome Csaba Szalai

6 6 Genetics and genomics 8.8. Comparative genomics Literature Questions Genomic approach to complex diseases General features of the complex diseases Environmental factors Why is it important to study the genomic background of the complex diseases? Heritability of the complex diseases Calculating heritability Difficulties in the studies of the genomic background of complex diseases Development of genomic methods, problems Problems of the rare variants Epigenetics of the complex disease The random behavior of the genome Statistical problems Possible solutions Why are the complex diseases more frequent in our days? Thrifty gene hypothesis Hygiene hypothesis Additional theories Literature Questions Genomic methods for complex diseases Genetic markers Methods for the genomic backgrounds of diseases Study of genetic variants GWAS Evaluation of GWAS results Partial genome screenings Positional cloning Personal genomics New generation sequencing (NGS) Measurement of gene expression Additional microarray-based methods Animal models The advantages of the animal models Shortcomings of animal models Experimental disease models Literature Questions Population and evolution genetics Population genetics Types of sample collection Selection of populations for genetic studies Hardy Weinberg equilibrium Linkage and haplotype Founder populations Association studies Csaba Szalai

7 Content Risk calculation Evolutionary genetics Gene environmental interactions and the human genome Natural selection Role of infections in formation of the genome Genetic drift Why are some lethal mutations frequent? Examples for effects forming the genome Literature Questions Gene environmental interaction Penetrance of the mutations Interactions between highly penetrant mutations and the environment Examples for interactions between low penetrant mutations and environment Smoking-genome interaction Genomic background of smoking Smoking-gene interaction in disease susceptibilities Smoking-gene interactions in complex diseases Examples for gene-environmental interactions Genomic investigations of the gene-environmental interaction Nutrigenetics and nutrigenomics The future of gene-environmental interaction Literature Questions Pharmacogenomics Goals of pharmacogenomics Drug development Adverse drug response Genomic background of adverse effects Difficulties of the pharmacogenomic researches Genetic variants influencing pharmacokinetics Genes influencing pharmacodynamics Examples of pharmacogenetic studies Pharmacogenetics of statins Clopidogrel Pharmacotherapy of asthma Interaction between genetic variations and β2-agonists Interaction between genetic variations and leukotriene antagonists The future of pharmacogenomics Literature Questions Systems biologic approach of diseases Introduction Displaying interactions Human interactome Disease genes in the networks Nodes and edges in diseases Human Diseasome Csaba Szalai

8 8 Genetics and genomics Shared gene hypothesis Shared metabolic pathway hypothesis Shared microrna hypothesis Phenotypic Disease Network (PDNs) Application of systems biological approaches Literature Questions Bioethical and research ethical issues in genetic research Background The ethically challenging areas and of genetic research, the "border" issues The biobanks Some general ethics-related issues The specific genetic research bioethics and research ethics The ethics issues of commercialization of genetic information The genetic research, biobanks, data management and ethics legislation Conclusion Bibliography Csaba Szalai