Ch03.pdf

CHAPTER

Genetic Control

of Cell Function

Genetic Control of Cell Function

Gene Structure

Genetic Code

Protein Synthesis

Messenger RNA

Transfer RNA

Ribosomal RNA

Regulation of Gene Expression

Gene Mutations

Chromosomes

Cell Division

Chromosome Structure

Patterns of Inheritance

Deﬁnitions

Genetic Imprinting

Mendel’s Laws

Pedigree

Gene Mapping and Technology

Genomic Mapping

Linkage Studies

Dosage Studies

Hybridization Studies

Recombinant DNA Technology

Gene Therapy

DNA Fingerprinting

The term gene is used to describe a part of the DNA mole-

cule that contains the information needed to code for the types

of proteins and enzymes needed for the day-to-day function of

the cells in the body. In addition, a gene is the unit of heredity

passed from generation to generation. For example, genes con-

trol the type and quantity of hormones that a cell produces, the

antigens and receptors that are present on the cell membrane,

and the synthesis of enzymes needed for metabolism. Of the

estimated 35,000 to 140,000 genes that humans possess, more

than 5000 have been identiﬁed and more than 2300 have been

localized to a particular chromosome. With few exceptions,

each gene provides the instructions for the synthesis of a single

protein. This chapter includes discussions of genetic regulation

of cell function, chromosomal structure, patterns of inheri-

tance, and gene technology.

GENETIC CONTROL OF CELL FUNCTION

The genetic information needed for protein synthesis is en-

coded in the DNA contained in the cell nucleus. A second type

of nucleic acid, ribonucleic acid (RNA), is involved in the actual

synthesis of cellular enzymes and proteins. Cells contain sev-

eral types of RNA: messenger RNA, transfer RNA, and ribo-

somal RNA. Messenger RNA (mRNA) contains the transcribed

instructions for protein synthesis obtained from the DNA mol-

ecule and carries them into the cytoplasm. Transcription is fol-

lowed by translation, the synthesis of proteins according to the

instructions carried by mRNA. Ribosomal RNA (rRNA) pro-

vides the machinery needed for protein synthesis. Transfer

RNA (tRNA) reads the instructions and delivers the appropri-

ate amino acids to the ribosome, where they are incorporated

into the protein being synthesized.

The mechanism for genetic control of cell function is illus-

trated in Figure 3-1. The nuclei of all the cells in an organism

contain the same accumulation of genes derived from the ga-

metes of the two parents. This means that liver cells contain the

same genetic information as skin and muscle cells. For this to

be true, the molecular code must be duplicated before each suc-

ceeding cell division, or mitosis. In theory, although this has

not yet been achieved in humans, any of the highly differenti-

ated cells of an organism could be used to produce a complete,

genetically identical organism, or clone. Each particular cell type

bonucleic acid (DNA). DNA is an extremely stable macro-

molecule found in the nucleus of each cell. Because of

the stable structure of DNA, the genetic information can sur-

vive the many processes of reduction division, in which the ga-

metes ( i.e., ovum and sperm) are formed, and the fertilization

process. This stability is also maintained throughout the many

mitotic cell divisions involved in the formation of a new or-

ganism from the single-celled fertilized ovum called the zygote.

G enetic information is stored in the structure of deoxyri-

Chapter 3: Genetic Control of Cell Function

KEY CONCEPTS

FUNCTION OF DNA IN CONTROLLING

CELL FUNCTION

genetic disorders are attributed to defects in mitochondrial

DNA. Leber’s hereditary optic neuropathy was the ﬁrst human

disease attributed to mutation in mitochondrial DNA.

■

The information needed for the control of cell struc-

ture and function is embedded in the genetic infor-

mation encoded in the stable DNA molecule.

Gene Structure

The structure that stores the genetic information in the nucleus

is a long, double-stranded, helical molecule of DNA. DNA is

composed of nucleotides, which consist of phosphoric acid, a

ﬁve-carbon sugar called deoxyribose, and one of four nitroge-

nous bases. These nitrogenous bases carry the genetic informa-

tion and are divided into two groups: the purine bases , adenine

and guanine, which have two nitrogen ring structures, and the

pyrimidine bases, thymine and cytosine, which have one ring.

The backbone of DNA consists of alternating groups of sugar

and phosphoric acid; the paired bases project inward from the

sides of the sugar molecule. DNA resembles a spiral staircase,

with the paired bases representing the steps (Fig. 3-2). A precise

complementary pairing of purine and pyrimidine bases occurs

in the double-stranded DNA molecule. Adenine is paired with

thymine, and guanine is paired with cytosine. Each nucleotide

in a pair is on one strand of the DNA molecule, with the bases

on opposite DNA strands bound together by hydrogen bonds

that are extremely stable under normal conditions. Enzymes

called DNA helicases separate the two strands so that the genetic

information can be duplicated or transcribed.

Several hundred to almost one million base pairs can rep-

resent a gene; the size is proportional to the protein product

it encodes. Of the two DNA strands, only one is used in tran-

scribing the information for the cell’s polypeptide-building

machinery. The genetic information of one strand is mean-

ingful and is used as a template for transcription; the com-

plementary code of the other strand does not make sense and

is ignored. However, both strands are involved in DNA du-

plication. Before cell division, the two strands of the helix sep-

arate and a complementary molecule is duplicated next to

each original strand. Two strands become four strands. During

cell division, the newly duplicated double-stranded mole-

cules are separated and placed in each daughter cell by the

mechanics of mitosis. As a result, each of the daughter cells

again contains the meaningful strand and the complementary

strand joined in the form of a double helix. This type of DNA

replication has been termed semiconservative as opposed to

conservative (Fig. 3-3).

The DNA molecule is combined with several types of pro-

tein and small amounts of RNA into a complex known as chro-

matin. Chromatin is the readily stainable portion of the cell nu-

cleus. Some DNA proteins form binding sites for repressor

molecules and hormones that regulate genetic transcription;

others may block genetic transcription by preventing access of

nucleotides to the surface of the DNA molecule. A speciﬁc

group of proteins called histones are thought to control the fold-

ing of the DNA strands.

■

Although every cell in the body contains the same

genetic information, each cell type uses only a por-

tion of the information, depending on its structure

and function.

■

The production of the proteins that control cell func-

tion is accomplished by (1) the transcription of the

DNA code for assembly of the protein onto messen-

ger RNA, (2) the translation of the code from mes-

senger RNA and assembly of the protein by riboso-

mal RNA in the cytoplasm, and (3) the delivery of

the amino acids needed for protein synthesis to

ribosomal RNA by transfer RNA.

in a tissue uses only part of the information stored in the ge-

netic code. Although information required for the develop-

ment and differentiation of the other cell types is still present,

it is repressed.

Besides nuclear DNA, part of the DNA of a cell resides in

the mitochondria. Mitochondrial DNA is inherited from the

mother by her offspring ( i.e., matrilineal inheritance). Several

Deoxyribonucleic acid (DNA)

Messenger ribonucleic acid (mRNA)

Transfer ribonucleic acid (tRNA)

Ribosomal ribonucleic acid (rRNA)

Protein synthesis

Control of cellular activity

Genetic Code

The four bases—guanine, adenine, cytosine, and thymine (ura-

cil is substituted for thymine in RNA)—make up the alphabet

of the genetic code. A sequence of three of these bases forms the

fundamental triplet code used in transmitting the genetic infor-

mation needed for protein synthesis. This triplet code is called

■ FIGURE 3-1 ■ DNA-directed control of cellular activity through

synthesis of cellular proteins. Messenger RNA carries the tran-

scribed message, which directs protein synthesis, from the nucleus

to the cytoplasm. Transfer RNA selects the appropriate amino

acids and carries them to ribosomal RNA where assembly of the

proteins takes place.

Unit One: Mechanisms of Disease

Sugar-phosphate backbone

Bases

Hydrogen bonds

Transcription

■ FIGURE 3-2 ■ The DNA double helix

and transcription of messenger RNA

(mRNA). The top panel ( A ) shows the se-

quence of four bases (adenine [A], cyto-

sine [C], guanine [G], and thymine [T]),

which determines the speciﬁcity of ge-

netic information. The bases face inward

from the sugar-phosphate backbone and

form pairs ( dashed lines ) with complemen-

tary bases on the opposing strand. In the

bottom panel ( B ), transcription creates a

complementary mRNA copy from one of

the DNA strands in the double helix.

mRNA

A A

a codon (Table 3-1). An example is the nucleotide sequence

GCU (guanine, cytosine, and uracil), which is the triplet RNA

code for the amino acid alanine. The genetic code is a univer-

sal language used by most living cells ( i.e., the code for the

amino acid tryptophan is the same in a bacterium, a plant, and

a human being). Stop codes, which signal the end of a protein

molecule, are also present. Mathematically, the four bases can

be arranged in 64 different combinations. Sixty-one of the

triplets correspond to particular amino acids, and three are stop

signals. Only 20 amino acids are used in protein synthesis in

humans. Several triplets code for the same amino acid; there-

fore, the genetic code is said to be redundant or degenerate. For

example, AUG is a part of the initiation or start signal and the

codon for the amino acid methionine. Codons that specify the

same amino acid are called synonyms. Synonyms usually have

the same ﬁrst two bases but differ in the third base.

Semiconservative Model

Conservative Model

Protein Synthesis

Although DNA determines the type of biochemical product

that the cell synthesizes, the transmission and decoding of in-

formation needed for protein synthesis are carried out by RNA,

the formation of which is directed by DNA. The general struc-

ture of RNA differs from DNA in three respects: RNA is a

single-stranded, rather than a double-stranded, molecule; the

sugar in each nucleotide of RNA is ribose, instead of deoxyri-

bose; and the pyrimidine base thymine in DNA is replaced by

uracil in RNA. Three types of RNA are known: mRNA, tRNA,

and rRNA. All three types are synthesized in the nucleus by

RNA polymerase enzymes that take directions from DNA. Be-

cause the ribose sugars found in RNA are more susceptible to

degradation than the sugars in DNA, the types of RNA mole-

cules in the cytoplasm can be altered rapidly in response to

extracellular signals.

original strand of DNA

newly synthesized strand of DNA

■ FIGURE 3-3 ■ Semiconservative vs conservative models of DNA

replication as proposed by Meselson and Stahl in 1958. In semi-

conservative DNA replication, the two original strands of DNA un-

wind and a complementary strand is formed along each original

strand.

Messenger RNA

Messenger RNA is the template for protein synthesis. It is a long

molecule containing several hundred to several thousand nu-

cleotides. Each group of three nucleotides forms a codon that

Chapter 3: Genetic Control of Cell Function

TABLE 3-1

Triplet Codes for

expressed from a single gene and reduces how much DNA must

be contained in the genome.

Amino Acids

Transfer RNA

The clover-shaped tRNA molecule contains only 80 nucleo-

tides, making it the smallest RNA molecule. Its function is to

deliver the activated form of amino acids to protein molecules

in the ribosomes. At least 20 different types of tRNA are known,

each of which recognizes and binds to only one type of amino

acid. Each tRNA molecule has two recognition sites: the first

is complementary for the mRNA codon and the second is for

the amino acid itself. Each type of tRNA carries its own spe-

cific amino acid to the ribosomes, where protein synthesis is

taking place; there it recognizes the appropriate codon on the

mRNA and delivers the amino acid to the newly forming pro-

tein molecule.

Amino Acid RNA Codons

Alanine GCU GCC GCA GCG

Arginine CGU CGC CGA CGG AGA AGG

Asparagine AAU AAC

Aspartic acid GAU GAC

Cysteine UGU UGC

Glutamic acid GAA

GAG

Glutamine

CAA

CAG

Glycine

GGU GGC GGA GGG

Histidine

CAU

CAC

Isoleucine

AUU

AUC

AUA

Leucine

CUU CUC CUA CUG UUA UUG

Lysine

AAA

AAG

Methionine AUG

Phenylalanine UUU UUC

Proline

CCU CCC CCA CCG

Ribosomal RNA

The ribosome is the physical structure in the cytoplasm where

protein synthesis takes place. Ribosomal RNA forms 60% of

the ribosome, with the remainder of the ribosome composed

of the structural proteins and enzymes needed for protein syn-

thesis. As with the other types of RNA, rRNA is synthesized in

the nucleus. Unlike other RNAs, ribosomal RNA is produced in

a specialized nuclear structure called the nucleolus. The formed

rRNA combines with ribosomal proteins in the nucleus to pro-

duce the ribosome, which is then transported into the cyto-

plasm. On reaching the cytoplasm, most ribosomes become at-

tached to the endoplasmic reticulum and begin the task of

protein synthesis.

Proteins are made from a standard set of amino acids, which

are joined end to end to form the long polypeptide chains of

protein molecules. Each polypeptide chain may have as many

as 100 to more than 300 amino acids in it. The process of

protein synthesis is called translation because the genetic code

is translated into the production language needed for protein

assembly. Besides rRNA, translation requires the coordinated

actions of mRNA and tRNA. Each of the 20 different tRNA mol-

ecules transports its speciﬁc amino acid to the ribosome for in-

corporation into the developing protein molecule. Messenger

RNA provides the information needed for placing the amino

acids in their proper order for each speciﬁc type of protein.

During protein synthesis, mRNA contacts and passes through

the ribosome, which “reads” the directions for protein synthe-

sis in much the same way that a tape is read as it passes through

a tape player (Fig. 3-4). As mRNA passes through the ribosome,

tRNA delivers the appropriate amino acids for attachment to

the growing polypeptide chain. The long mRNA molecule usu-

ally travels through and directs protein synthesis in more than

one ribosome at a time. After the ﬁrst part of the mRNA is read

by the ﬁrst ribosome, it moves onto a second and a third. As a

result, ribosomes that are actively involved in protein synthe-

sis are often found in clusters called polyribosomes.

Serine

UCU UCC UCA UCG AGC AGU

Threonine

ACU

ACC

ACA

ACG

Tryptophan

UGG

Tyrosine

UAU

UAC

Valine

GUU GUC GUA GUG

Start (CI)

AUG

Stop (CT)

UAA

UAG

UGA

(Guyton A. [2000]. Textbook of medical physiology [10th ed., p. 28].

Philadelphia: W.B. Saunders)

is exactly complementary to the triplet of nucleotides of the

DNA molecule. Messenger RNA is formed by a process called

transcription, in which the weak hydrogen bonds of the DNA are

broken so that free RNA nucleotides can pair with their exposed

DNA counterparts on the meaningful strand of the DNA mol-

ecule (see Fig. 3-2). As with the base pairing of the DNA

strands, complementary RNA bases pair with the DNA bases.

In RNA, uracil replaces thymine and pairs with adenine.

During transcription, a specialized nuclear enzyme, called

RNA polymerase, recognizes the beginning or start sequence of

a gene. The RNA polymerase attaches to the double-stranded

DNA and proceeds to copy the meaningful strand into a single

strand of RNA as it travels along the length of the gene. On

reaching the stop signal, the enzyme leaves the gene and re-

leases the RNA strand. The RNA strand then is processed.

Processing involves the addition of certain nucleic acids at

the ends of the RNA strand and cutting and splicing of certain

internal sequences. Splicing often involves the removal of

stretches of RNA. Because of the splicing process, the ﬁnal

mRNA sequence is different from the original DNA template.

RNA sequences that are retained are called exons, and those ex-

cised are called introns. The functions of the introns are un-

known. They are thought to be involved in the activation or

deactivation of genes during various stages of development.

Splicing permits a cell to produce a variety of mRNA mole-

cules from a single gene. By varying the splicing segments of the

initial mRNA, different mRNA molecules are formed. For ex-

ample, in a muscle cell, the original tropomyosin mRNA is

spliced in as many as 10 different ways, yielding distinctly dif-

ferent protein products. This permits different proteins to be

Regulation of Gene Expression

Although all cells contain the same genes, not all genes are ac-

tive all of the time, nor are the same genes active in all cell

types. On the contrary, only a small, select group of genes is

active in directing protein synthesis in the cell, and this group

varies from one cell type to another. For the differentiation

Unit One: Mechanisms of Disease

Forming

protein

Peptide bond

Amino acid

Transfer RNA

"head" bearing anticodon

Ribosome

■ FIGURE 3-4 ■ Protein synthesis.

A messenger RNA strand is moving

through a small ribosomal RNA

subunit in the cytoplasm. Transfer

RNA transports amino acids to the

mRNA strand and recognizes the

RNA codon calling for the amino

acid by base pairing (through its

anticodon). The ribosome then

adds the amino acid to the grow-

ing polypeptide chain. The ribo-

some moves along the mRNA

strand and is read sequently. As

each amino acid is bound to the

next by a peptide bond, its tRNA is

released.

G G

G A

C C

U U

G G

Messenger RNA

Direction of

messenger RNA

advance

Codon

process of cells to occur in the various organs and tissues of the

body, protein synthesis in some cells must be different from

that in others. To adapt to an ever-changing environment, cer-

tain cells may need to produce varying amounts and types of

proteins. Certain enzymes, such as carbonic anhydrase, are syn-

thesized by all cells for the fundamental metabolic processes

on which life depends.

The degree to which a gene or particular group of genes is

active is called gene expression. A phenomenon termed induction

is an important process by which gene expression is increased.

Except in early embryonic development, induction is pro-

moted by some external inﬂuence. Gene repression is a process

whereby a regulatory gene acts to reduce or prevent gene ex-

pression. Some genes are normally dormant but can be acti-

vated by inducer substances; other genes are naturally active

and can be inhibited by repressor substances. Genetic me-

chanisms for the control of protein synthesis are better under-

stood in microorganisms than in humans. However, it can be

assumed that the same general principles apply.

The mechanism that has been most extensively studied is

the one by which the synthesis of particular proteins can be

turned on and off. For example, in the bacterium Escherichia coli

grown in a nutrient medium containing the disaccharide lac-

tose, the enzyme galactosidase can be isolated. The galactosi-

dase catalyzes the splitting of lactose into a molecule of glucose

and a molecule of galactose. This is necessary if lactose is to be

metabolized by E. coli . However, if the E. coli is grown in a

medium that does not contain lactose, very little of the enzyme

is produced. From these and other studies, it is theorized that

the synthesis of a particular protein, such as galactosidase, re-

quires a series of reactions, each of which is catalyzed by a spe-

ciﬁc enzyme.

At least two types of genes control protein synthesis: struc-

tural genes that specify the amino acid sequence of a polypep-

tide chain and regulator genes that serve a regulatory function

without stipulating the structure of protein molecules. The reg-

ulation of protein synthesis is controlled by a sequence of

genes, called an operon, on adjacent sites on the same chromo-

some (Fig. 3-5). An operon consists of a set of structural genes

that code for enzymes used in the synthesis of a particular prod-

uct and a promoter site that binds RNA polymerase and initi-

ates transcription of the structural genes. The function of the

operon is further regulated by activator and repressor opera-

Activator

operator

Repressor

operator

Operon

Promoter

Structural

Gene A

Structural

Gene B

Structural

Gene C

Inhibition

of the

operator

Enzyme A

Enzyme B

Enzyme C

Substrates

Synthesized

product

(Negative feedback)

■ FIGURE 3-5 ■ Function of the operon to control biosynthesis.

The synthesized product exerts negative feedback to inhibit func-

tion of the operon, in this way automatically controlling the con-

centration of the product itself. (Guyton A., Hall J.E. [2000].

Textbook of medical physiology [10th ed., p. 31]. Philadelphia: W.B.

Saunders with permission from Elsevier Science)

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