LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page i Aptara Genetics LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page ii Aptara LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page iii Aptara Genetics Ron W. Dudek PhD Full Professor East Carolina University Brody School of Medicine Department of Anatomy and Cell Biology Greenville, NC 27858 LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page iv Aptara Acquisitions Editor: Susan Rhyner Managing Editors: Stacey Sebring and Jennifer Verbiar Marketing Manager: Jennifer Kuklinski Design Coordination: Holly Reid McLaughlin Interior Designer: Karen Quigley Cover Designer: Larry Didona Compositor: Aptara Copyright © 2010 Lippincott Williams & Wilkins, a Wolters Kluwer business. 351 West Camden Street 530 Walnut Street Baltimore, MD 21201 Philadelphia, PA 19106 Printed in China. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or trans- mitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at 530 Walnut Street, Philadelphia, PA 19106, via email at [email protected], or via website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Dudek, Ronald W., 1950- Genetics / Ron W. Dudek. — 1st ed. p. ; cm. — (Board review series) Includes bibliographical references and index. ISBN 978-0-7817-9994-2 (alk. paper) 1. Genetics—Examinations, questions, etc. I. Title. II. Series: Board review series. [DNLM: 1. Genetic Phenomena—Examination Questions. 2. Genetic Diseases, Inborn—Examination Questions. QU 18.2 D845g 2009] QH440.3.D83 2009 576.5078—dc22 2009000283 DISCLAIMER Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omis- sions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publi- cation. Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publi- cation. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is par- ticularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: http://www.lww.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST. LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page v Aptara Acknowledgments I would like to express my thanks to Betty Sun for having the confidence in me so that I could write BRS Genetics. My working relationship with Betty Sun has extended over many years and many book projects. It was my pleasure and privilege to work with Betty Sun, who always brought wise counsel, keen insight, and common sense to the table. I would also like to thank all the LWW staff who played a role in BRS Genetics, includ- ing Kathleen Scogna, Stacey Sebring, Jen Clements, Jenn Verbiar, Jennifer Kuklinski, and Sally Glover. v LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page vi Aptara LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page vii Aptara Preface Since many US medical schools are unable to find adequate time in the curriculum for an in-depth genetics course, medical students find themselves in a less than advanta- geous position when reviewing genetics for the USMLE Step 1. A brief visit to any med- ical bookstore will reveal that there are about six excellent genetics textbooks that cover basic genetics and modern molecular genetic advancements. However good these books are, they are not designed for a review process under the time constraints that medical students face when preparing for the USMLE Step 1. Consequently, I wrote BRS Genetics with the goal of placing the student in a strategic position to review genetics in a reasonable time period and most importantly to answer all the Genetics questions that would likely appear on the USMLE Step 1. BRS Genetics expands many of the topics that have been included in High Yield Genetics for the stu- dent that needs a little more background and wants a little more depth. In addition, BRS Genetics has test questions after each chapter and a comprehensive exam that should serve the student well not only for USMLE Step 1 but also in their coursework. Discussions concerning the preparation for the USMLE Step 1 usually include mention of the “big three”: pathology, pharmacology, and physiology. For many USMLE Step 1 clinical case style of questions, these three disciplines coordinate very nicely to present a clinical case and then ask a mechanistic question as to WHY some- thing is observed or HOW a specific drug treatment works. The “big three” has become a perfect triad for USMLE Step 1 preparation. However, in the future, I think that a “new big three” will develop: embryology, genetics, and molecular biology. With the completion of the Human Genome Project and now the advancement of genome mapping for every individual, the future of medicine will revolve around the elucidation of the genetics of birth defects and other human diseases spearheaded by molecular biology techniques. Exactly when the “new big three” will have significant representation on the USMLE Step 1 is impossible for me to predict. However, when this does occur, the BRS series will be strategically placed to serve its customers with three superb publications: BRS Embryology, BRS Genetics, BRS Biochemistry and Molecular Biology (by Swanson, Kim, and Gluckman), and High Yield Cell and Molecular Biology. These books are well integrated, have min- imal overlap, and are updated with the latest information. More than any other field of medicine in the future, genetics and molecular biol- ogy will be the engines that drive new breakthroughs and new information that are rel- evant to clinical practice. This will require that BRS Embryology, BRS Genetics, BRS Biochemistry and Molecular Biology (by Swanson, Kim, and Gluckman), and High Yield Cell and Molecular Biology be routinely updated with new clinically relevant information. For this, I rely on my readers to e-mail me suggestions, comments, and new ideas for future editions. Please e-mail me at [email protected] Dr. Ron W. Dudek vii LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page viii Aptara LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page ix Aptara Contents Acknowledgments v Preface vii 1. THE HUMAN NUCLEAR GENOME 1 I. General Features 1 II. Protein-Coding Genes 2 III. RNA-Coding Genes 3 IV. Epigenetic Control 5 V. Noncoding DNA 6 Review Test 9 Answers and Explanations 11 2. DNA PACKAGING 12 I. The Biochemistry of Nucleic Acids 12 II. Levels of DNA Packaging 12 III. Centromere 13 IV. Heterochromatin and Euchromatin 13 Review Test 17 Answers and Explanations 18 3. CHROMOSOME REPLICATION 19 I. General Features 19 II. The Replication Process 19 III. The Telomere 20 IV. Types of DNA Damage and DNA Repair 20 V. Summary Table of DNA Machinery 21 Review Test 24 Answers and Explanations 25 4. MENDELIAN INHERITANCE 26 I. Autosomal Dominant Inheritance 26 II. Autosomal Recessive Inheritance 28 ix LWBK274-FM_i-xiv.qxd 06/02/2009 04:57 PM Page x Aptara x Contents III. X-Linked Dominant Inheritance 30 IV. X-Linked Recessive Inheritance 31 V. X Chromosome Inactivation and X-linked Inheritance 33 VI. The Family Pedigree in Various Mendelian Inherited Disorders 34 VII. Selected Photographs of Mendelian Inherited Disorders 34 Review Test 40 Answers and Explanations 43 5. UNIPARENTAL DISOMY AND REPEAT MUTATIONS 45 I. Uniparental Disomy (UPD) 45 II. Unstable Expanding Repeat Mutations (Dynamic Mutations) 45 III. Highly Expanded Repeats Outside the Gene 46 IV. Moderately Expanded CAG Repeats Inside the Gene 47 Review Test 51 Answers and Explanations 52 6. MITOCHONDRIAL INHERITANCE 53 I. Mitochondrial Function 53 II. The Human Mitochondrial Genome 53 III. The Protein-Coding Genes 54 IV. The RNA-Coding Genes 54 V. Other Mitochondrial Proteins 54 VI. Mutation Rate 54 VII. Mitochondrial Inheritance 55 VIII. Examples of Mitochondrial Disorders 55 IX. Selected Photographs of Mitochondrial Inherited Disorders 57 Review Test 61 Answers and Explanations 62 7. MULTIFACTORIAL INHERITED DISORDERS 63 I.