Page 31 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 1

ANATOMY AND PHYSIOLOGY OF THE GENE

Andrew J. Wagner, Nancy Berliner, and Edward J. Benz, Jr.

Normal blood cells have limited life spans; they must be replenished universally applicable to the study of all living entities. Indeed, the
in precise numbers by a continuously renewing population of pro- power of the molecular genetic approach lies in the universality of its
genitor cells. Homeostasis of the blood requires that proliferation utility.
of these cells be efficient yet strictly constrained. Many distinctive One exception to the central dogma of molecular biology that is
types of mature blood cells must arise from these progenitors by a especially relevant to hematologists is the storage of genetic informa-
controlled process of commitment to, and execution of, complex tion in RNA molecules in certain viruses, notably the retroviruses
programs of differentiation. Thus, developing red blood cells must associated with T-cell leukemia and lymphoma, and the human
produce large quantities of hemoglobin but not the myeloperoxidase immunodeficiency virus. When retroviruses enter the cell, the RNA
characteristic of granulocytes, the immunoglobulins characteristic of genome is copied into a DNA replica by an enzyme called reverse
lymphocytes, or the fibrinogen receptors characteristic of platelets. transcriptase. This DNA representation of the viral genome is then
Similarly, the maintenance of normal amounts of coagulant and expressed according to the rules of the central dogma. Retroviruses
anticoagulant proteins in the circulation requires exquisitely regu- thus represent a variation on the theme rather than a true exception
lated production, destruction, and interaction of the components. to or violation of the rules.
Understanding the basic biologic principles underlying cell growth,
differentiation, and protein biosynthesis requires a thorough knowl-
edge of the structure and regulated expression of genes because the ANATOMY AND PHYSIOLOGY OF GENES
gene is now known to be the fundamental unit by which biologic
information is stored, transmitted, and expressed in a regulated DNA Structure
fashion.
Genes were originally characterized as mathematical units of DNA molecules are extremely long, unbranched polymers of
inheritance. They are now known to consist of molecules of deoxy- nucleotide subunits. Each nucleotide contains a sugar moiety called
ribonucleic acid (DNA). By virtue of their ability to store information deoxyribose, a phosphate group attached to the 5′ carbon position,
in the form of nucleotide sequences, to transmit it by means of and a purine or pyrimidine base attached to the 1′ position (Fig.
semiconservative replication to daughter cells during mitosis and 1.1). The linkages in the chain are formed by phosphodiester bonds
meiosis, and to express it by directing the incorporation of amino between the 5′ position of each sugar residue and the 3′ position of
acids into proteins, DNA molecules are the chemical transducers of the adjacent residue in the chain (see Fig. 1.1). The sugar–phosphate
genetic information flow. Efforts to understand the biochemical links form the backbone of the polymer, from which the purine or
means by which this transduction is accomplished have given rise to pyrimidine bases project perpendicularly.
the discipline of molecular genetics. The haploid human genome consists of 23 long, double-stranded
DNA molecules tightly complexed with histones and other nuclear
THE GENETIC VIEW OF THE BIOSPHERE: THE CENTRAL proteins to form compact linear structures called chromosomes.
The genome contains 3 billion nucleotides; each chromosome is
DOGMA OF MOLECULAR BIOLOGY thus 50 to 200 million bases in length. The individual genes are
aligned along each chromosome. The human genome contains about
The fundamental premise of the molecular biologist is that the 30,000 genes. Blood cells, similar to most somatic cells, are diploid.
magnificent diversity encountered in nature is ultimately governed That is, each chromosome is present in two copies, so there are 46
by genes. The capacity of genes to exert this control is in turn chromosomes consisting of approximately 6 billion base pairs (bp)
determined by relatively simple stereochemical rules, first appreciated of DNA.
by Watson and Crick in the 1950s. These rules constrain the types The four nucleotide bases in DNA are the purines (adenosine
of interactions that can occur between two molecules of DNA or and guanosine) and the pyrimidines (thymine and cytosine).
ribonucleic acid (RNA). The basic chemical configuration of the other nucleic acid found
DNA and RNA are linear polymers consisting of four types of in cells, RNA, is quite similar, except that the sugar is ribose
nucleotide subunits. Proteins are linear unbranched polymers consist- (having a hydroxyl group attached to the 2′ carbon rather than
ing of 21 types of amino acid subunits. Each amino acid is distin- the hydrogen found in deoxyribose) and the pyrimidine base uracil
guished from the others by the chemical nature of its side chain, the is used in place of thymine. The bases are commonly referred to
moiety not involved in forming the peptide bond links of the chain. by a shorthand notation: the letters A, C, T, G, and U are used
The properties of cells, tissues, and organisms depend largely on the to refer to adenosine, cytosine, thymine, guanosine, and uracil,
aggregate structures and properties of their proteins. The central respectively.
dogma of molecular biology states that genes control these properties The ends of DNA and RNA strands are chemically distinct
by controlling the structures of proteins, the timing and amount of because of the 3′ → 5′ phosphodiester bond linkage that ties adjacent
their production, and the coordination of their synthesis with that of bases together (see Fig. 1.1). One end of the strand (the 3′ end) has
other proteins. The information needed to achieve these ends is an unlinked (free at the 3′ carbon) sugar position and the other (the
transmitted by a class of nucleic acid molecules called RNA. Genetic 5′ end) has a free 5′ position. There is thus a polarity to the sequence
information thus flows in the direction DNA → RNA → protein. of bases in a DNA strand: the same sequence of bases read in a 3′ →
This central dogma provides, in principle, a universal approach for 5′ direction carries a different meaning than if read in a 5′ → 3′
investigating the biologic properties and behavior of any given cell, direction. Cellular enzymes can thus distinguish one end of a nucleic
tissue, or organism by study of the controlling genes. Methods per- acid from the other; most enzymes that “read” the DNA sequence
mitting direct manipulation of DNA sequences should then be tend to do so only in one direction (3′ → 5′ or 5′ → 3′ but not

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