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CHAPTER

Introduction

to Molecular

Genetics and

Genomics

CHAPTER OUTLINE

1.1

PRINCIPLES

DNA: The Genetic Material

Experimental Proof of the Genetic

Function of DNA

Genetic Role of DNA in

Bacteriophage

• Inherited traits are affected by genes.

• Genes are composed of the chemical deoxyribonucleic acid

(DNA).

• DNA replicates to form copies of itself that are identical

(except for rare mutations).

• DNA contains a genetic code specifying what types of

enzymes and other proteins are made in cells.

• DNA occasionally mutates, and the mutant forms specify

altered proteins that have reduced activity or stability.

• A mutant enzyme is an “inborn error of metabolism” that

blocks one step in a biochemical pathway for the metabolism

of small molecules.

• Traits are affected by environment as well as by genes.

• Organisms change genetically through generations in the

process of biological evolution.

1.2

DNA Structure: The Double Helix

1.3

An Overview of DNA Replication

1.4

Genes and Proteins

Inborn Errors of Metabolism as a

Cause of Hereditary Disease

Mutant Genes and Defective Proteins

1.5

Gene Expression: The Central Dogma

Transcription

Translation

The Genetic Code

1.6

Mutation

Protein Folding and Stability

1.7

Genes and Environment

1.8

Evolution: From Genes to Genomes, from

Proteins to Proteomes

The Molecular Unity of Life

Natural Selection and Diversity

CONNECTIONS

Shear Madness

Alfred D. Hershey and Martha Chase 1952

Independent Functions of Viral Protein and Nucleic Acid in Growth

of Bacteriophage

The Black Urine Disease

Archibald E. Garrod 1908

Inborn Errors of Metabolism

unique set of inherited characteristics

that makes it different from other

species. Each species has its own develop-

mental plan—often described as a sort of

“blueprint” for building the organism—

which is encoded in the DNA molecules pre-

sent in its cells. This developmental plan

determines the characteristics that are in-

herited. Because organisms in the same

species share the same developmental plan,

organisms that are members of the same

species usually resemble one another, al-

though some notable exceptions usually are

differences between males and females. For

example, it is easy to distinguish a human

being from a chimpanzee or a gorilla. A hu-

man being habitually stands upright and has

long legs, relatively little body hair, a large

brain, and a ﬂat face with a prominent nose,

jutting chin, distinct lips, and small teeth.

All of these traits are inherited—part of our

developmental plan—and help set us apart

as Homo sapiens.

But human beings are by no means

identical. Many traits, or observable charac-

teristics, differ from one person to another.

There is a great deal of variation in hair

color, eye color, skin color, height, weight,

personality traits, and other characteristics.

Some human traits are transmitted biologi-

cally, others culturally. The color of our

eyes results from biological inheritance, but

the native language we learned as a child

results from cultural inheritance. Many

traits are inﬂuenced jointly by biological in-

heritance and environmental factors. For

example, weight is determined in part by

inheritance but also in part by environ-

ment: how much food we eat, its nutri-

tional content, our exercise regimen, and so

forth. Genetics is the study of biologically

inherited traits, including traits that are in-

ﬂuenced in part by the environment.

The fundamental concept of genetics is

that:

terms of the abstract rules by which heredi-

tary elements (he called them “factors”) are

transmitted from parents to offspring. His

objects of study were garden peas, with

variable traits like pea color and plant

height. At one time genetics could be stud-

ied only through the progeny produced

from matings. Genetic differences between

species were impossible to deﬁne, because

organisms of different species usually do not

mate, or they produce hybrid progeny that

die or are sterile. This approach to the study

of genetics is often referred to as classical ge-

netics, or organismic or morphological ge-

netics. Given the advances of molecular, or

modern, genetics, it is possible to study dif-

ferences between species through the com-

parison and analysis of the DNA itself. There

is no fundamental distinction between clas-

sical and molecular genetics. They are dif-

ferent and complementary ways of studying

the same thing: the function of the genetic

material. In this book we include many ex-

amples showing how molecular and classi-

cal genetics can be used in combination to

enhance the power of genetic analysis.

The foundation of genetics as a molecu-

lar science dates back to 1869, just three

years after Mendel reported his exper-

iments. It was in 1869 that Friedrich

Miescher discovered a new type of weak

acid, abundant in the nuclei of white blood

cells. Miescher’s weak acid turned out to be

the chemical substance we now call DNA

(deoxyribonucleic acid). For many years

the biological function of DNA was un-

known, and no role in heredity was as-

cribed to it. This ﬁrst section shows how

DNA was eventually isolated and identiﬁed

as the material that genes are made of.

1.1 DNA: The Genetic Material

That the cell nucleus plays a key role in in-

heritance was recognized in the 1870s by

the observation that the nuclei of male and

female reproductive cells undergo fusion in

the process of fertilization. Soon thereafter,

chromosomes were ﬁrst observed inside

the nucleus as thread-like objects that

become visible in the light microscope

when the cell is stained with certain dyes.

Chromosomes were found to exhibit a

characteristic “splitting” behavior in which

each daughter cell formed by cell division

Inherited traits are determined by the ele-

ments of heredity that are transmitted from

parents to offspring in reproduction; these

elements of heredity are called genes.

The existence of genes and the rules

governing their transmission from gen-

eration to generation were ﬁrst articulated

by Gregor Mendel in 1866 (Chapter 3).

Mendel’s formulation of inheritance was in

Chapter 1 Introduction to Molecular Genetics and Genomics

E ach species of living organism has a

receives an identical complement of chro-

mosomes (Chapter 4). Further evidence for

the importance of chromosomes was pro-

vided by the observation that, whereas the

number of chromosomes in each cell may

differ among biological species, the number

of chromosomes is nearly always constant

within the cells of any particular species.

These features of chromosomes were well

understood by about 1900, and they made

it seem likely that chromosomes were the

carriers of the genes.

By the 1920s, several lines of indirect

evidence began to suggest a close relation-

ship between chromosomes and DNA.

Microscopic studies with special stains

showed that DNA is present in chromo-

somes. Chromosomes also contain various

types of proteins, but the amount and kinds

of chromosomal proteins differ greatly from

one cell type to another, whereas the

amount of DNA per cell is constant.

Furthermore, nearly all of the DNA present

in cells of higher organisms is present in the

chromosomes. These arguments for DNA as

the genetic material were unconvincing,

however, because crude chemical analyses

had suggested (erroneously, as it turned

out) that DNA lacks the chemical diversity

needed in a genetic substance. The favored

candidate for the genetic material was pro-

tein, because proteins were known to be an

exceedingly diverse collection of molecules.

Proteins therefore became widely accepted

as the genetic material, and DNA was as-

sumed to function merely as the structural

framework of the chromosomes. The ex-

periments described below ﬁnally demon-

strated that DNA is the genetic material.

Experimental Proof of the Genetic

Function of DNA

An important ﬁrst step was taken by

Frederick Grifﬁth in 1928 when he demon-

strated that a physical trait can be passed

from one cell to another. He was working

with two strains of the bacterium

Streptococcus pneumoniae identiﬁed as S and

R. When a bacterial cell is grown on solid

medium, it undergoes repeated cell divi-

sions to form a visible clump of cells called a

colony. The S type of S. pneumoniae synthe-

sizes a gelatinous capsule composed of

complex carbohydrate (polysaccharide).

The enveloping capsule makes each colony

large and gives it a glistening or smooth (S)

appearance. This capsule also enables the

bacterium to cause pneumonia by protect-

ing it from the defense mechanisms of an

infected animal. The R strains of S. pneumo-

niae are unable to synthesize the capsular

polysaccharide; they form small colonies

that have a rough (R) surface ( Figure 1.1 ).

This strain of the bacterium does not cause

pneumonia, because without the capsule

the bacteria are inactivated by the immune

system of the host. Both types of bacteria

FPO

R strain

S strain

Figure 1.1 Colonies of rough (R, the small colonies) and smooth (S, the large colonies) strains of

Streptococcus pneumoniae. The S colonies are larger because of the gelatinous capsule on the S cells.

[Photograph from O. T. Avery, C. M. MacLeod, and M. McCarty. Reproduced from the Journal of

Experimental Medicine, 1944, vol. 79, p. 137 by copyright permission of The Rockefeller University

Press.]

1.1 DNA: The Genetic Material

Living

S cells

Living

R cells

Heat-killed

S cells

Living R cells plus

heat-killed S cells

Mouse contracts

pneumonia

Mouse remains

healthy

Mouse remains

healthy

Mouse contracts

pneumonia

S colonies isolated

from tissue of dead mouse

R colonies isolated

from tissue

No colonies isolated

from tissue

R and S colonies isolated

from tissue of dead mouse

Figure 1.2 The Grifﬁth's experiment demonstrating bacterial transformation. A mouse remains

healthy if injected with either the nonvirulent R strain of S. pneumoniae or heat-killed cell fragments

of the usually virulent S strain. R cells in the presence of heat-killed S cells are transformed into the

virulent S strain, causing pneumonia in the mouse.

“breed true” in the sense that the progeny

formed by cell division have the capsular

type of the parent, either S or R.

Mice injected with living S cells get

pneumonia. Mice injected either with living

R cells or with heat-killed S cells remain

healthy. Here is Grifﬁth’s critical ﬁnding:

mice injected with a mixture of living R cells

and heat-killed S cells contract the disease—

they often die of pneumonia ( Figure 1.2 ).

Bacteria isolated from blood samples of

these dead mice produce S cultures with a

capsule typical of the injected S cells, even

though the injected S cells had been killed

by heat. Evidently, the injected material

from the dead S cells includes a substance

that can be transferred to living R cells and

confer the ability to resist the immunologi-

cal system of the mouse and cause pneumo-

nia. In other words, the R bacteria can be

changed—or undergo transformation —

into S bacteria. Furthermore, the new char-

acteristics are inherited by descendants of

the transformed bacteria.

Transformation in Streptococcus was orig-

inally discovered in 1928, but it was not

until 1944 that the chemical substance re-

sponsible for changing the R cells into S

cells was identiﬁed. In a milestone experi-

ment, Oswald Avery, Colin MacLeod, and

Maclyn McCarty showed that the sub-

stance causing the transformation of R cells

into S cells was DNA. In doing these exper-

iments, they ﬁrst had to develop chemical

procedures for isolating almost pure DNA

from cells, which had never been done be-

fore. When they added DNA isolated from

S cells to growing cultures of R cells, they

observed transformation: A few cells of

type S cells were produced. Although the

DNA preparations contained traces of pro-

tein and RNA (ribonucleic acid, an abun-

dant cellular macromolecule chemically

related to DNA), the transforming activity

was not altered by treatments that de-

stroyed either protein or RNA. However,

treatments that destroyed DNA eliminated

the transforming activity ( Figure 1.3 ). These

experiments implied that the substance re-

sponsible for genetic transformation was

the DNA of the cell—hence that DNA is the

genetic material.

Chapter 1 Introduction to Molecular Genetics and Genomics

Hearts - Introduction To Molecular Genetics And Geonomics.pdf

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