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MOLECULAR GENETIC PATHOLOGY
MOLECULAR GENETIC
PATHOLOGY

Edited by

LIANG CHENG, MD
Professor of Pathology and Urology
Director of Molecular Pathology Laboratory
Chief of Genitourinary Pathology Division
Department of Pathology and Laboratory Medicine
and Clarian Pathology Laboratory
Indiana University School of Medicine, Indianapolis, IN

DAVID Y. ZHANG, MD, PhD, MPH

Associate Professor of Pathology
Director, Molecular Pathology Laboratory
Department of Pathology
Mount Sinai School of Medicine
and the Mount Sinai Medical Center
New York, NY

,\1',
"'1\'
Humana Press
Preface

We have had the opportunity to witness both the beginning of clinical cytogenetics, diagnostic methodology and
and the subsequent growth of an exciting specialty that technology, tissue microarrays and biomarker validation,
combines both pathology and medical genetics, a field laser capture microdissection, clinical flow cytometry,
commonly referred to as molecular genetic pathology. The conceptual evolution in cancer biology, clinical genomics in
birth of this specialty took place in 1988 when Kari Mullis oncology, clinical proteomics, clinical pharmacogenomics,
developed a new DNA amplification technology called the clonality analysis in surgical pathology, fluorescence
polymerase chain reaction (PCR). Within a few years, this in situ hybridization (FISH), conventional cytogenetics for
technology was no longer being used exclusively in research hematology and oncology diagnosis, instrumentation, genetic
laboratories. The technique had found numerous new inheritance and population genetics, and genetic counseling .
applications in clinical medicine as a tool for diagnosis and Part II provides disease-based information, including prenatal
diseases monitoring. The use of PCR technology has greatly diagnosis, familial cancer syndromes, molecular testing for
expanded the specialties of anatomic and clinical pathology solid tumors, molecular pathology of the central nervous
and has increased the availability of genetic testing in the system, molecular virology, molecular bacteriology, mycology
clinical setting. We expect that such advances as the and parasitology, molecular testing for coagulopathies,
completion of the Human Genome Project, the maturation of molecular hemoglobinopathies, molecular diagnostics of
pharmacogenomics, the growth of proteomics, and the rapidly lymphoid malignancies, molecular diagnostics of myeloid
growing field of molecular genetic pathology will lead to a leukemias, HLA system and transfusion medicine (molecular
new era of personalized and customized patient care. approach), molecular forensic pathology, gene therapy, ethical
More recently, the American Board of Pathology (ABP), in and legal issues in molecular testing, and quality assurance and
conjunction with the American Board of Medical Genetics laboratory inspection. Each chapter begins with a detailed
(ABMG), established a new subspecialty, molecular genetic Table of Contents for easy reference.
pathology. Fellowship training for molecular genetic Assembling this diverse guidebook has truly been a team
pathology is approved by the Accreditation Council for effort, cutting across many traditional specialty boundaries .
Graduation Medical Education (ACGME). Many pathologists We are most grateful for all the contributors who made this
and medical geneticists are applying for advanced training project possible. Our special thanks go to Mr. Ryan P.
in this growing subspecialty. Training in molecular pathology Christy from the Multimedia Education Division of the
is also becoming a required element in pathology residency Department of Pathology at Indiana University, who has
curricula. To meet these demands, a team of more than edited the illustrations for the book. We would like to thank
50 leading experts has compiled this quick reference book the staff at Humana Press/Springer, including Ms. Mary Jo
for medical students, general practitioners, medical Casey, Mr. Paul Dolgert, Mr. Richard Hruska, and Mr. David
technologists, pathologists, and medical geneticists . We also Casey for their assistance in the development and editing of
hope that residents or fellows who are training in pathology this text, and in particular Ms. Amy Thau, without whose
and medical genetics will find this book helpful in their outstanding work this book would have been an impossible
preparation for board examinations . achievement.
Molecular Genetic Pathology contains two parts. Part I
covers general molecular genetic pathology and technology, Liang Cheng, MD
including principles of clinical molecular biology, principles David Y. Zhang, MD, PhD, MPH

v
 ...

Contents

Preface v 10 Clinical Pharmacogenomics

Catalina Lopez-Correa
Contributors ix and LawrenceM. Gelbert 241

Part I General Sections 11 Clonality Analysis in Modem Oncology

and Surgical Pathology
Liang Cheng, Shaobo Zhang,
1 Principles of Clinical Molecular Biology Timothy D. Jones,
Shaobo Zhang, Darrell D. Davidson, and Deborah E. Blue 261
David Y. Zhang, Jodi A. Parks,
and Liang Cheng 1
12 Fluorescence In Situ Hybridization
(FISH) and Conventional
2 Principles of Clinical Cytogenetics
Stuart Schwartz 33 Cytogenetics for Hematology
and Oncology Diagnosis
3 Diagnostic Methodology and Technology Vesna Najfeld 303
Josephine Wu, Tao Feng, Ruliang Xu, Fei fe,
Bruce E. Petersen, Liang Cheng, 13 Instrumentation
and David Y. Zhang 65 Bruce E. Petersen, Josephine Wu,
Liang Cheng, and David Y. Zhang 365
4 Tissue Microarrays
and Biomarker Validation 14 Genetic Inheritance and Population
Martina Storz and Holger Moch 133 Genetics
Tatiana Foroudand Daniel L. Koller 393
5 Laser Capture Microdissection
Matthew Kuhar and Liang Cheng 141
15 Genetic Counseling
Kimberly A. Quaid and
6 Clinical Flow Cytometry Lisa J. Cushman 405
Magdalena Czader 155

7 Conceptual Evolution in Cancer Biology Part II Disease-Based Sections

Shaobo Zhang, Darrell D. Davidson,
and Liang Cheng 185 16 Molecular Medical Genetics
Lisa Edelmann, Stuart Scott,
8 Clinical Genomics in Oncology and Ruth Kornreich 415
Hugo M. Horlings and
Marc van de Vijver 209 17 Prenatal Diagnosis
Nataline Kardon and Lisa Edelmann 441
9 Clinical Proteomics
David H. Geho, Virginia Espina, 18 Familial Cancer Syndromes
Lance A. Liotta, Emanuel F. Petricoin, Michelle P. Eliefj, Antonio Lopez-Beltran,
and Julia D. Wulfkuhle 231 Rodolfo Montironi, and Liang Cheng ..... 449

vii
Contents
llIiJltEii

19 Molecular Testing for Solid Tumors 26 Molecular Diagnostics of Myeloid

Neal I. Lindeman and Paola Dal Cin 467 Leukemias
C. Cameron Yin and Dan M. Jones 675
20 Molecular Pathology of the Central
Nervous System 27 The HLA System and Transfusion
Eyas M. Hattab and Brent T. Harris 497 Medicine: Molecular Approach
S. Yoon Choo 689
21 Molecular Virology
Josephine Wu, Mona Sharaan, 28 Molecular Forensic Pathology
and David Y. Zhang 533 P. Michael Conneally and
Stephen R. Dlouhy 703
22 Molecular Bacteriology, Mycology
and Parasitology 29 Gene Therapy: Vector Technology
Mona Sharaan, Josephine Wu, and Clinical Applications
Bruce E. Petersen, and Kenneth Cornetta 717
David Y. Zhang 581
30 Ethical and Legal Issues
23 Molecular Testing for Coagulopathies in Molecular Testing
Veshana Ramiah and Thomas L. Ortel 623 Kimberly A. Quaid 731

24 Molecular Hemoglobinopathies 31 Quality Assurance and Laboratory

Jodi A. Parks, Tina Y. Fodrie, Inspection
Shaobo Zhang, and Carol L. Johns and Liang Cheng 737
Liang Cheng 637
Appendix
25 Molecular Diagnostics of Lymphoid Liang Cheng and Shaobo Zhang 751
Malignancies
Francisco Vega and
Dan M. Jones 655 Index 767

lU l U 21M I rr m1ttt lllTJrr_wn

viii
 -
Contributors

DEBORAH E . BLUE, MD MAGDALENA CZADER, MD, PhD

Assistant Professor of Pathology Assistant Professor of Pathology
Associate Director, Molecular Pathology Laboratory Director of Clinical Flow Cytometry Laboratory
Department of Pathology and Laboratory Medicine Department of Pathology and Laboratory Medicine
and Clarian Pathology Laboratory Indiana University School of Medicine
Indiana University School ofMedicine Indianapolis, IN
Indianapolis, IN
PAOLA DAL ON, PhD
LIANG CHENG, MD Associate Professor of Pathology
Professor of Pathology and Urology Cytogenetics Laboratory
Director ofMolecular Pathology Laboratory Department of Pathology
Chief, Genitourinary Pathology Division Brigham and Women's Hospital
Department of Pathology and Laboratory Medicine and Harvard Medical School
and Clarian Pathology Laboratory Boston, MA
Indiana University School of Medicine
Indianapolis, IN DARRELL D . DAVIDSON, MD, PhD
Assistant Professor of Pathology
S. Yo ON CHOO, MD Department of Pathology and Laboratory Medicine
Associate Professor of Pathology and Medicine Indiana University School of Medicine
Director of HLA Laboratory, Associate Medical Director Indianapolis, IN
of Blood Bank
Departments of Pathology and Medicine STEPHEN R. DLOUHY, PhD
Mount Sinai School of Medicine and the Mount Sinai Associate Research Professor
Medical Center Department ofMedical and Molecular Genetics
New York, NY Indiana University School of Medicine
Indianapolis, IN
P. MICHAEL CONNEALLY, PhD
Distinguished Professor Emeritus, Medical and LISA EDELMANN, PhD
Molecular Genetics and Neurology Assistant Professor
Department of Medical and Molecular Genetics Department of Genetics and Genomic Sciences
Indiana University School of Medicine Director, Molecular Cytogenetics
Indianapolis, IN Co-Director, Genetic Testing Laboratory
Mount Sinai School of Medicine and the Mount Sinai
KENNETH CORNETIA, MD Medical Center
Joe C. Christian Professor and Chairman New York, NY
Department ofMedical and Molecular Genetics
Indiana University School ofMedicine MICHELLE P. EUEFF, MD
Indianapolis, IN Staff Pathologist
Diagnostic Pathology Services, Inc.
LISA 1. CUSHMAN, PhD Nampa, ID
Certified Genetic Counselor
Department of Medical and Molecular Genetics
Indiana University School of Medicine
Indianapolis, IN

JltW

ix
Contributors
mUI

VIRGINIA ESPINA, MS HUGO M. HORLINGS, MD

Research Professor Department of Pathology
The Center for Applied Proteomics The Netherlands Cancer Institute/Antoni van
and Molecular Medicine Leeuwenhoek Hospital
George Mason University Amsterdam, The Netherlands
Manassas, VA
CAROL L. JOHNS, PhD
TAO FENG, MS, MP (ASCP) Supervisor and Technical Coordinator
Research Assistant Clarian Molecular Pathology Laboratory
Department of Pathology Indiana University School of Medicine
Mount Sinai School of Medicine Indianapolis, IN
and the Mount Sinai Medical Center
New York, NY DAN M . JONES, MD, PhD
Professor of Pathology
TINA Y. FODRIE, BS, MT, MP (ASCP) Department of Hematopathology
Supervisor, Department of Molecular Pathology Medical Director, Molecular Diagnostics Laboratory
Indiana University School of Medicine The University of Texas M. D. Anderson Cancer Center
and VA Medical Center Houston, TX
Indianapolis, IN
TIMOTHY D . JONES, MD
TATIANA FOROUD, PhD Staff Pathologist
Professor ofMedical and Molecular Genetics Department of Pathology
Department of Medical and Molecular Genetics Floyd Memorial Hospital and Health Services
Indiana University School of Medicine New Albany, IN
Indianapolis, IN
NATALINE KARDON, MD
DAVID H. GEHO, MD, PhD Associate Professor
Associate Director of Imaging Director of Prenatal Cytogeneti cs Laboratory
Merck and Company, Inc. Department of Genetics and Genomic Science s
West Point, PA Mount Sinai School of Medicine and the Mount Sinai
Medical Center
LAWRENCE M. GELBERT, PhD New York, NY
Research Advisor
Eli Lilly and Company DANIEL L. KOLLER, PhD
Indianapolis, IN Research Assistant Professor
Department of Medical and Molecular Genetics
BRENT T. HARRIS, MD, PhD Indiana University School of Medicine
Assistant Professor of Pathology Indianapolis, IN
Department of Pathology
Dartmouth Medical School RUTH KORNREICH, PhD
Lebanon, NH Research Assistant Professor ofHuman Genetics
Co-Director Genetic Testing Laboratory
EYAS M. HATIAB, MD Department of Human Genetics
Associate Professor of Pathology Mount Sinai School of Medicine and the Mount Sinai
Department of Pathology and Laboratory Medicine Medical Center
and Clarian Pathology Laboratory New York, NY
Indiana University School of Medicine
Indianapolis, IN MATIHEW KUHAR, MD
Resident
Department of Pathology and Laboratory Medicine and
Clarian Pathology Laboratory
Indiana University School of Medicine
Indianapolis, IN

_ _ _ _ _..... ...
Jjl...
J'M"iG.~~ll!il"'_1f:Jrn!1
~ • If'l!!W1!¥_M'''RW'''' ··. ·.,.
...
.t tti''''
·~ f _
IU!

x
 Contributors

NEAL I. LINDEMAN, MD JODI A. PARKS, MD

Associate Pathologist, Clinical Chemistry Visiting Lecturer, Clinical Chemistry
Associate Pathologist, Molecular Diagnostics Department of Pathology and Laboratory Medicine
Brigham and Women 's Hospital and Clarian Pathology Laboratory
Assistant Professor of Pathology Indiana University School of Medicine
Harvard Medical School Indianapolis, IN
Boston , MA
BRUCE E. PETERSEN, MD
LANCE A. LIOTIA, MD, PhD Molecular Genetic Pathology Fellow
Director, The Center for Applied Proteomics Department of Pathology
and Mole cular Medicine Mount Sinai School of Medicine and the Mount Sinai
Professor of Life Scien ces Medical Center
George Mason University New York, NY
Manassas, VA
EMANUEL F. PETRICOIN, PhD
ANTONIO LOPEZ-BELTRAN, MD, PhD Professor of Life Sciences
Professor of Pathology Director, The Center for Applied Proteomics
Department of Pathology and Surgery and Molecular Medicine
Cordoba University Medical School Chair, Department of Molecular and Microbiolog y
Cordoba, Spain George Mason University
Manassas, VA
CATALINA LOPEZ-CORREA, MD, PhD
Principal Research Scientist KIMBERLY A. QUAID, PhD
Eli Lilly and Company Professor of Medical and Molecular Genetics
Indianapolis, IN Department of Medical and Molecular Genetics
Indiana University School of Medicine
HOLGER MOCH, MD Indianapolis, IN
Professor and Chairman
Institute of Surgical Pathology VESHANA RAMIAH, MD
Department of Pathology Hematology/Oncology Fellow
University Hospital Zurich Duke University Medical Center
Zurich, Switzerland Durham, NC

RODOLFO MONTIRONI, MD, FRCPath STUART SCHWARTZ, PhD, FACMG

Professor of Pathology Professor of Human Genetics
Institute of Pathological Anatomy and Histopathology Department of Human Genetics
Polytechnic University of the Marche Region (Ancona) University of Chicago
School of Medicine Chicago,IL
United Hospitals
Ancona, Italy STUART SCOTT, PhD
Clinical Molecular Genetics Fellow
VESNA NAJFELD, PhD Department of Human Genetics
Professor of Pathology and Medicine Mount Sinai School of Medicine and the Mount Sinai
Director, Tumor Cytogenetics, and Oncology, Molecular Medical Center
and Cellular Tumor Markers New York, NY
Mount Sinai School of Medicine and the Mount Sinai
Medical Center MONA SHARAAN, MD
New York, NY Molecular Genetic Pathology Fellow
Department of Pathology
THOMAS L. ORTEL, MD, PhD Mount Sinai School of Medi cine and the Mount Sinai
Associate Professor of Medicine and Pathology Medical Center
Hemostasis and Thrombosis Center New York, NY
Duke University Medical Center
Durham , NC
AU
""'
XI
Contributors

MARTINA STORZ, BS RULIANG XU, MD, PhD

Directorof TMA Core Facility Associate Professor of Pathology
Institute ofSurgical Pathology Departmentof Pathology
Departmentof Pathology New York University School of Medicine
University Hospital Zurich New York, NY
Zurich, Switzerland
FEI YE, PhD
MARC VAN DE VIJVER, MD, PhD Assistant Professor
Professor of Pathology Departmentof Pathology
Department of Pathology Mount Sinai School of Medicine and the Mount Sinai
The Netherlands Cancer Institute/Antoni van Medical Center
Leeuwenhoek Hospital New York, NY
Amsterdam, The Netherlands
C. CAMERON YIN, MD, PhD
FRANCISCO VEGA, MD, PhD Assistant Professor of Pathology
Assistant Professor of Pathology Departmentof Hematopathology
Departmentof Hematopathology The University of Texas M. D. Anderson Cancer Center
The University of Texas M. D. Anderson Cancer Center Houston, TX
Houston, TX
DAVID Y. ZHANG, MD, PhD, MPH
JOSEPHINE WU, DDS, CLSp(MB), CLDir Associate Professorof Pathology
Assistant Professor Director, Molecular Pathology Laboratory
Departmentof Pathology Departmentof Pathology
Mount Sinai School of Medicine and the Mount Sinai Mount Sinai School of Medicine and the Mount Sinai
Medical Center Medical Center
New York, NY New York, NY

JULIA D. WULFKUHLE, PhD SHAOBO ZHANG, MD

Research Professor Associate Research Professor
The Centerfor Applied Proteomics and Molecular Departmentof Pathology and LaboratoryMedicine
Medicine Indiana University School ofMedicine
George Mason University Indianapolis, IN
Manassas, VA

xii
RID sr.
- we w I.
Part I
General Sections
1

Principles of Clinical Molecular Biology

Shaobo Zhang, MD, Darrell D. Davidson, MD, PhD, David Y. Zhang, MD, PhD, MPH,
Jodi A. Parks, MD, and Liang Cheng, MD

CONTENTS

I. Deoxyribonucleic Acid (DNA) 1-4 Chromosomes 1-19

Overv iew 1-4
Types of DNAs 1-5
IV. RNA and Proteins 1-22
Overview 1-22
DNA Repli cation 1-7
Types of RNA 1-23
DNA Mutation 1-8
Ribosome and Ribozyme 1-23
DNA Mutation and Disease 1-9
mRNA Processing 1-24
Factors Related to DNA Aberrations 1-9
DNA Repair Mechanisms 1-12 Protein Translation 1-27

II . Genes 1-13 V. Mitochondrial DNA 1-28

Overview 1-13 Overview 1-28
Gene Components 1-13 mtDNA Inheritance 1-28
Functional Categories of Genes 1-13 Characteristics of mtDNA 1-28
Cancer- Related Genes 1-14 Mitochondrial Genes and Gene Expression 1-28
Regulation of Gene Expression 1-14 mtDNA Replication 1-29
Signal Tran sduction 1-19 mtDNA Damage, Mutations,
and Repair 1-30
III. Chromosomes 1-19 Mitochondrial Disease 1-31
Overview 1-19
Chromatin 1-19 VI. Suggested Reading 1-32

3
 1-4 Molecular Genetic Pathology

DEOXYRIBONUCLEIC ACID (DNA)

Overview - Nucleotide is made up of a phosphate group, a

pentose sugar (deoxyribose), and a nitrogenous base
• Definition
(Figure 1)
- DNA is a large nucleic acid polymer arranged in
• The phosphodiester bond
chromosomes for storage, expression and transmission
of genetic information • The phosphate group is bond to the nucleoside
- The genetic information is encoded by a sequence of at the hydroxyl group of the 5' carbon atom of
nucleotides deoxyribose

• Components of DNA • Phosphodiester bonds are strong covalent bonds

between phosphate groups connecting the 5'
- Bases are molecules containing carbon-nitrogen rings carbon of one deoxyribose to the 3' carbon of
in DNA the next deoxyribose of the adjacent nucleotide
• Purines: adenine (A) and guanine (G) have two nucleotide (Figure 2)
joined carbon-nitrogen rings • The phosphodiester bond determines DNA
• Pyrimidines: thymine (T) and cytosine (C) have one chain polarity (ends designated as either 5'
carbon-nitrogen ring or 3')
- Nucleoside is made up of a five-carbon sugar • DNA sequence refers to the order of the nucleotides
(deoxyribose) and a base in a DNA strand, which code for unique sets of
- Deoxyribose is the same sugar found in RNA, but with genetic information, both proteins and regulatory
oxygen removed from the 2' carbon position segments

Adenine Guanine Cytosine Thymine

N
NH2

j'N=C
~)
'\ N
I

N
HOf>°""I HOf> 0",,1
~H ~H
HO H HO H

2-Deoxyribose Cytidine Adenosine

I
Nucleoside
Fig. 1. There are four bases in DNA: Adenine (A), guanine (G), thymine (T), and cytosine (C). Adenine and guanine are purines
and thymine and cytosine are pyrimidines. Deoxyribose is the sugar in DNA. The carbon atoms are numbered as indicated. Note
there is no oxygen on site 2 of deoxyribose. A nucleoside molecule is composed of a base and deoxyribose. When a phosphate
group is added to nucleoside, the complex becomes a nucleotide . Nucleotides are the basic building blocks of DNA.

4
Principles of Clinical Molecular Biology 1-5

5 CH2 Base

l /o~ 1
4C C
I\HI
H HI'
I H
3'--1
o H
2

I
O=p-O-
I
o
I
5 CH2
o Base

c/~l
'\ H
H\1 HI'
1 H
C--C
I
o H
I

Fig . 2. 3'5' Phosphodiester bonds joint by the unit of the repetitive sugar-phosphate chain. Each nucleotide is linked by the
3' carbon atom of upstream ribose to the 5' carbon of the downstream ribose. Phosphodiester bonds are central to all life on
earth, as they make up the backbone of DNA and RNA strands in every organism.

- The deoxyribonucleotides in DNA differ only in the • A DNA fragment appears to have a unique
bases they carry, so the DNA sequence is denoted by a function, either structural , regulatory, or coding
base sequence (e.g., -ATTGCAT-)
- Base sequence is presented from 5' to 3'
Types of DNAs
- DNA strands are pairs of complementary molecules,
which entwine each other in an antiparallel direction • Single copy DNA is a specific DNA sequence that is
present only once in the genome
- Two strands of DNA wind around each other to form a
double helix (Figure 3) • Repetitive DNA is a DNA segment with a specific
DNA sequence that is repeated multiple times in the
• Deoxyribose-phosphate backbone is on the exterior
genome
of the DNA double helix
• Moderately repetitive DNA refers to 10-10 5 copies of the
• The interior of the DNA is formed by paired bases
sequence per genome
attached to each other by hydrogen bounds.
G (Guanine) pairs with C (Cytosine) via three - Moderate repeated DNA is found primarily in non-
hydrogen bonds, and A (Adenine) pairs with coding sequences
T (Thymine) via two hydrogen bonds inside the • Highly repetitive DNA describes DNA sequence present
double helix. Note that the three hydrogen bonds in greater than 105 copies per genome
joining G to C (GC bond) are stronger than the two - Highly repeated DNA is found primarily in
hydrogen bonds joining A to T (AT bond) (Figure 4) centromere and telomere regions as tandem repeats
- DNA has two DNA chains; one is oriented 5' ~3' while • Tandem repeat DNA contains a variable number of short
the other strand is oriented 3' ~5' direction (antiparallel) DNA sequences repeated many times in series . The
• Sense is a DNA strand that could be transcribed. number of repeats is unique to each individual , and can
Sense strand has a sequence similar to its RNA be used for relationship testing
transcript - The tandem repeat pattern may vary from one base
• Antisense is the complimentary strand of sense. repeats (mononucleotide repeat) to several IOOO-bp
Antisense works as template for the RNA transcript repeat sequences

5
1-6 Molecular Genetic Pathology

3'end
5' 3'

3' 5'

3' end 5'end

Fig. 3. Human genomic DNA contains two polynucleotide chains wound around each other to form a double-stranded helix . The
two chains are "antiparallel,' one running 5'-3' and the other running 3'-5' direction . The DNA strands are synthesized and read
out by RNA polymerase in the 5'-3' direction . The purine or pyrimidine attached to each deoxyribose project s into the center of
the helix. Base A pairs with T and a G pairs with C through hydrogen bonds in the central axis.

- These segments of DNA are satellite DNA because of - Microsatellite DNAs are sequences <15 bp in length
the experimental observation that they often form that repeat 10-100 times without interruption. There
a minor satellite band near the major centrifugation are approx 200,000 microsatellite loci in the human
fraction when DNA is separated by density gradient genome (Table 1)
- Clusters of such repeats are scattered on many • Loss of heterozygosity (LOH) in a cell represents
chromosomes. Each variant is an allele that is the loss of one parent's contribution of DNA to a
inherited co-dominantly cell 's genome, often in microsatellite regions
- Megasatellite DNAs are tandem repeat DNA segments • It often indicates the presence of tumor-suppressor
with a length greater than 1000 bp (1 kbp) repeated gene loss around the microsatellite locus
50-400 times
• LOH can arise through deletion, nonreciprocal
- Satellite DNAs comprise about 15% of human DNA. DNA transfer, mitotic recombination, or
The repeated sequence ranges from 5 to 170 bp and chromosome loss
the complex is about 100 kbp in length
• LOH is often used to analyze the clonal origin
- Minisatellite DNAs are repeated sequence s ranging
of cancer-associated loci
from 14 to 500 bp in length . The repeat complex is
0.1-20 kbp in length. Minisatellite DNA is present in • Microsatellite DNA loci are useful markers for
telomere region the detection of LOH

6
Principles of Clinical Molecular Biology 1-7

• When parents' contributions of certain

microsatellite loci are of different size, these
microsatellite loci are informative
- Microsatellite instability at critical loci is a marker for
malignancy or premalignant genetic change
(see details in Chapter 7)
• Mitochondrial DNA (mtDNA) (see Mitochondrial DNA)

DNA Replication
• Double-stranded DNA (dsDNA) is exactly duplicated
prior to cell division so that each daughter cell is
endowed with an exact replica of the parent cell DNA
• DNA replication occurs during S (synthesis) phase of the
H cell cycle
I
-:?C......... / ..... H - - - - O
N - Cell cycle refers to a cycle of events in a eukaryotic
HC C II cell from one cell division to the next; it consists of
I IN---H - N /C<, C __ N\ . Go' G I' S, G 2, and M phases (Figure 5)

Su~
N",
r
O----H- N
.....
I ...... C__
C~
I ;CH
""N...... N
- Semiconservative replication means that each DNA
molecule consists of one original and one newly
synthesized chain (Figure 6)
I \
H Sugar • DNA Polymerases
- DNA polymerases are enzymes involved in DNA
replication. Eukaryotic cells have five different DNA
Fig. 4. The double helical structure of DNA is largely due to
polymerases
hydrogen bonding between the base pairs linking one
complementary strand to the other. Hydrogen bonds are non- • DNA polymerase a and 8 replicate nuclear DNA
covalent, weak bonds between electron donors and recipients. • DNA polymerase ~ and E are involved in DNA
There are two hydrogen bonds between A and T and three repair
hydrogen bonds between G and C, thus the bonds between G • DNA polymerase y replicates mitochondria DNA
and C are stronger than between A and T. (mtDNA)
• Multiple replications means that replication begin s at
multiple sites within a DNA strand and proceeds
bidirectionally from each origin (Figure 7)
- The replication apparatus at each origin forms a
bubble and extends toward both ends of the DNA
Table 1. Major Characteristics of Repetitive molecule until it meets another bubble
DNA - The leading strand is the DNA chain that is
synthesized continuously in the 5'-3' direction
Number of • Synthesis of the leading strand is catalyzed by
DNA polymerase 8
Form of DNA Length (bpJ repeats
- The lagging strand is the DNA chain that is
synthesized as a series of short fragments, known as
Single copy Vary Single copy
Okazaki fragments, polymerized in the 5' ~3'
Moderately repetitive Vary 10-105 direction also (Figure 8)
Highly repetitive Vary >105 • The newly synthesized DNA fragments will
eventually meet and ligate to create an intact
Tandem repeat
strand
Megasatellite >1000 50-400 • The lagging strand is synthesized by DNA
Satellite 5-170 500-2000 polymerase a
Minisatellite 14-500 7-40 • The lagging strand polymerizes from 5' to 3'
at the nucleotide level but overall growth by
Microsatellite <15 10-100 ligation of Okazaki fragments is in the 3' ~5'
direction

7
1-8 Molecular Genetic Pathology

M PHASE
mitosis
(nuclear
division)

S PHASE
(DNA replication)

Fig. 5. The cell cycle, or cell-divi sion cycle, is the series of events in a eukaryotic cell between one cell division and the next. The
cell cycle consists of four phases , G I' S, Go' and M phase. Go is a period in which cells exist in a quiescent state. Go' G l' G2, and
S phase are collectively known as interpha se. Cells in Go phase are resting cells unable to divide without a signal to re-enter the
cell cycle. DNA synthesis occurs during S phase, which is followed by a short G 2 phase . Mitosi s and cytokinesis together are
defined as the M (mitotic) phase, during which the mother cell divides into two daughter cells .

DNA Mutation - Deletion is an irreversible mutation in which one or

more nucleotides are removed from the DNA
• DNA mutation is a permanent change in the genetic sequence
material sequence
• The deletion will cause a shift of the reading frame
• Most mutations are found in noncoding sequences
• A one base deletion, for example, will shift all
• Single base pair substitution (point mutation) involves a codons left, altering the amino acids for which
single nucleotide, which is replaced with another nucleotide they code
- Point mutation is the most common form of mutation • Insertion is a mutation that adds one or more nucleotides
- It happens most commonly in non-coding sequences to the DNA sequence
- It is also the most frequent type of mutation associated - An insertion in the coding region of a gene may cause
with tumor suppressor gene mutation a shift in the reading frame
• Transitions are the mutations that substitute a different - An insertion alters splicing of messenger RNA
purine for a purine or a pyrimidine for a pyrimidine (mRNA) (splice site mutation)
• Transversions are mutations that substitute a different • Amplification increases the dosage of genes located
purine for a pyrimidine or a pyrimidine for a purine within a locus by inserting multiple copies of the
• Synonymous (silent) mutation is a single base pair chromosomal region or by promulgating fragments of
substitution yielding a different codon that still DNA containing the locus outside the chromo somes.
codes for the same amino acid Proteins produced from amplified genes are generally
• Missense mutation is a single base pair substitution increased
that results in a different codon and a different • Loss of heterozygosity (LOH) is a DNA alteration in
amino acid which one allele from one parent's contribution is lost,
either by deletion or a recombination event
• Nonsense mutation is a single base pair substitution
that converts a codon specifying an amino acid into • The most frequently observed gene associated with LOH
a stop codon in sporadic cancer is p53

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