The Nature of the Gene

I. How genes work or “What does a piece of deoxyribonucleic acid have to do with
the color of my cat?”

II. Preliminary thoughts on relationship between genes and phenotypes

A. 1902: William Bateson and Archibald Garrod studied alkaptonuria, a human
disease characterized by urine that turns black upon exposure to air and a tendency to
develop arthritis later in life.
They made two observations (1) disease seemed to be inherited as a recessive trait
and (2) people with disease secreted homogentisic acid (HA) in their urine (normal
people do not secrete HA)
They hypothesized that normal people can metabolize HA while people with
alkaptonuria can not metabolize HA. Furthermore, they concluded that alkaptonuria is a
genetic disease that is caused by the absence of an enzyme needed to metabolize HA
(inborn error of metabolism).

B. Table 12-4: Over 40 human diseases result from inborn errors in metabolism.

C. Another important implication of this work was that the position of a block in a
metabolic pathway can be determined by the accumulation of a product that proceeds
the block.

If a mutant is blocked in a metabolic pathway at some point, it can not make any of the
intermidiates in the pathway that are after the block.
 If you supply the mutant with an intermediate compound that is made before
the block, there will be no effect (no final product).
 If you supply the mutant with an intermediate compound that is made after the
block, the mutant can now make the end product
 Compound made late in the pathway will support the growth of more mutants.
 Mutants late in the pathway can not be restored with as many compounds as
mutant that are early in the pathway.
III. Genes control the production of enzymes: The one gene – one enzyme hypothesis

1940s First convincing evidence that genes are responsible for the synthesis of enzymes.

Irradiated Neurospora (haploid fungus) to induce mutagenesis. They then screened for
arginine auxotrophs and found three that contained mutations that mapped to different
locations on the chromosome (arg-1 arg-2 arg-3).

Each of the mutants would grow when media was supplemented with arginine. Other
compounds similar to arginine could also support growth:

strain supplement
orthinine Citrulline arginine
wt + + +
arg-1 + + +
arg-2 - + +
arg-3 - - +

Based on this data Beadle and Tatum proposed the following enzymatic pathway for the
production of arginine:

Note that this pathway was inferred entirely through genetic analysis; later biochemical
work confirmed it.

Thus, examination of the one gene – one enzyme hypothesis showed that genes somehow
were responsible for the function of enzymes and that each gene controlled one specific
enzyme.
IV. How do genes control the functioning of proteins?
A. Review of protein structure: Figures shown are using hemoglobin as an example
- (From: AN INTRODUCTION TO GENETIC ANALYSIS 6/E BY Griffiths,
Miller, Suzuki, Leontin, Gelbart  1996 by W. H. Freeman and Company. Used
with permission.)
1. Proteins are macromolecules composed of a chain of amino acids linked end
to end in a linear fashion (primary structure). Each protein has a distinct linear
sequence of amino acids. This was first shown by Frederick Sanger et al. with the
sequencing of the protein insulin.

2. Polypeptides can bend into regularly repeating structures generated by

hydrogen bonding between amino acids that are close together in the linear
sequence (secondary structure). The most common secondary structures are alpha
helices (Figure 12-5) and beta sheets (Figure 12-6).

3. Proteins have a 3 dimensional shape that is a result of interactions between

different amino acids in the protein ( tertiary structure). Interactions can be
between amino acids that are close together or far apart in the primary
structure.
 4. Two or more folded proteins can bind together to form quartenary structure.

5. Proteins can be enzymatic or structural.

B. The relationship between gene mutation and altered proteins (sickle cell anemia).
1. 1910: J. Herrick first descibes sickle cell anemia. Red blood cells of affected
individuals sickle at low oxygen tension causing breakage of the cell and
clogging of the capillaries.
2. 1949: J. Neel and E. Beet showed that sickle cell anemia is inherited as a
recessive trait. Pedegree analysis showed that there were two alleles of the Hb
(hemoglobin) gene which controlled the sickle cell phenotype. HbA is the normal
allele, and HbS is the sickle cell allele. The HbA allele showed complete
dominance to HbS in terms of anemia, but incomplete dominance in terms of
RBC shape.
All of these studies together established that a single inherited gene provided the
information for a single protein and that a mutation in the gene was associated
with an amino acid change in the protein which was associated with a change in
the activity of the protein which is associated with the anemic phenotype.
Mutational Sites
Mutation, an alteration in the genetic material (the genome) of a cell of a living
organism or of a virus that is more or less permanent and that can be transmitted
to the cell’s or the virus’s descendants. (The genomes of organisms are all
composed of DNA, whereas viral genomes can be of DNA or RNA; see
heredity: The physical basis of heredity.) Mutation in the DNA of a body cell of
a multicellular organism (somatic mutation) may be transmitted to descendant
cells by DNA replication and hence result in a sector or patch of cells having
abnormal function, an example being cancer. Mutations in egg or sperm cells
(germinal mutations) may result in an individual offspring all of whose cells
carry the mutation, which often confers some serious malfunction, as in the case
of a human genetic disease such as cystic fibrosis.

Mutations result either from accidents during the normal chemical transactions
of DNA, often during replication, or from exposure to high-energy
electromagnetic radiation (e.g., ultraviolet light or X-rays) or particle radiation or
to highly reactive chemicals in the environment. Because mutations are random
changes, they are expected to be mostly deleterious, but some may be beneficial
in certain environments. In general, mutation is the main source of genetic
variation, which is the raw material for evolution by natural selection.

The genome is composed of one to several long molecules of DNA, and

mutation can occur potentially anywhere on these molecules at any time. The
most serious changes take place in the functional units of DNA, the genes. A
mutated form of a gene is called a mutantallele. A gene is typically composed of
a regulatory region, which is responsible for turning the gene’s transcription on
and off at the appropriate times during development, and a coding region, which
carries the genetic code for the structure of a functional molecule, generally a
protein. A protein is a chain of usually several hundred amino acids.

Cells make 20 common amino acids, and it is the unique number and sequence
of these that give a protein its specific function. Each amino acid is encoded by a
unique sequence, or codon, of three of the four possible base pairs in the DNA
(A–T, T–A, G–C, and C–G, the individual letters referring to the four
nitrogenous bases adenine, thymine, guanine, and cytosine). Hence, a mutation
that changes DNA sequence can change amino acid sequence and in this way
potentially reduce or inactivate a protein’s function. A change in the DNA
sequence of a gene’s regulatory region can adversely affect the timing and
availability of the gene’s protein and also lead to serious cellular malfunction.
On the other hand, many mutations are silent, showing no obvious effect at the
functional level. Some silent mutations are in the DNA between genes, or they
are of a type that results in no significant amino acid changes.
Mutations are of several types. Changes within genes are called point mutations.
The simplest kinds are changes to single base pairs, called base-pair
substitutions. Many of these substitute an incorrect amino acid in the
corresponding position in the encoded protein, and of these a large proportion
result in altered protein function. Some base-pair substitutions produce a stop
codon. Normally, when a stop codon occurs at the end of a gene, it stops protein
synthesis, but, when it occurs in an abnormal position, it can result in a truncated
and nonfunctional protein. Another type of simple change, the deletion or
insertion of single base pairs, generally has a profound effect on the protein
because the protein’s synthesis, which is carried out by the reading of triplet
codons in a linear fashion from one end of the gene to the other, is thrown off.
This change leads to a frameshift in reading the gene such that all amino acids
are incorrect from the mutation onward. More-complex combinations of base
substitutions, insertions, and deletions can also be observed in some mutant
genes.
Mutations that span more than one gene are called chromosomal mutations
because they affect the structure, function, and inheritance of whole DNA
molecules (microscopically visible in a coiled state as chromosomes). Often
these chromosome mutations result from one or more coincident breaks in the
DNA molecules of the genome (possibly from exposure to energetic radiation),
followed in some cases by faulty rejoining. Some outcomes are large-scale
deletions, duplications, inversions, and translocations. In a diploid species (a
species, such as human beings, that has a double set of chromosomes in the
nucleus of each cell), deletions and duplications alter gene balance and often
result in abnormality. Inversions and translocations involve no loss or gain and
are functionally normal unless a break occurs within a gene. However, at meiosis
(the specialized nuclear divisions that take place during the production of
gametes—i.e., eggs and sperm), faulty pairing of an inverted or translocated
chromosome set with a normal set can result in gametes and hence progeny with
duplications and deletions.
Loss or gain of whole chromosomes results in a condition called aneuploidy.
One familiar result of aneuploidy is Down syndrome, a chromosomal disorder in
which humans are born with an extra chromosome 21 (and hence bear three
copies of that chromosome instead of the usual two). Another type of
chromosome mutation is the gain or loss of whole chromosome sets. Gain of sets
results in polyploidy—that is, the presence of three, four, or more chromosome
sets instead of the usual two. Polyploidy has been a significant force in the
evolution of new species of plants and animals.