"Changes in DNA" - Color Atlas of Genetics, Eberhard Passarge

When it was recognized that changes (mutations)

in genes occur spontaneously (T. H. Morgan,

1910) and can be induced by X-rays (H. J.

Muller, 1927), the mutation theory of heredity

became a cornerstone of early genetics. Genes

were defined asmutable units, but the question

what genes and mutations are remained. Today

we know that mutations are changes in the

structure of DNA and their functional consequences.

The study of mutations is important

for several reasons. Mutations cause diseases,

including all forms of cancer. They can be induced

by chemicals and by irradiation. Thus,

they represent a link between heredity and environment.

And without mutations, well-organized

forms of life would not have evolved.

The following two plates summarize the chemical

nature of mutations.

A. Error in replication

The synthesis of a new strand of DNA occurs by

semiconservative replication based on complementary

base pairing (see DNA replication).

Errors in replication occur at a rate of about 1 in

105. This rate is reduced to about 1 in 107 to 109

by proofreading mechanisms. When an error in

replication occurs before the next cell division

(here referred to as the first division after the

mutation), e.g., a cytosine (C) might be incorporated

instead of an adenine (A) at the fifth

base pair as shown here, the resulting mismatch

will be recognized and eliminated by

mismatch repair (see DNA repair) in most cases.

However, if the error is undetected and allowed

to stand, the next (second) divisionwill result in

a mutant molecule containing a CG instead of

an AT pair at this position. This mutationwill be

perpetuated in all daughter cells. Depending on

its location within or outside of the coding region

of a gene, functional consequences due to a

change in a codon could result.

B. Mutagenic alteration of a nucleotide

A mutation may result when a structural

change of a nucleotide affects its base-pairing

capability. The altered nucleotide is usually

present in one strand of the parent molecule. If

this leads to incorporation of awrong base, such

as a C instead of a T in the fifth base pair as

shown here, the next (second) round of replication

will result in two mutant molecules.

C. Replication slippage

A different class of mutations does not involve

an alteration of individual nucleotides, but results

from incorrect alignment between allelic

or nonallelic DNA sequences during replication.

When the template strand contains short tandem

repeats, e.g., CA repeats as in microsatellites

(see DNA polymorphism and Part II,

Genomics), the newly replicated strand and the

template strand may shift their positions relative

to each other. With replication or polymerase

slippage, leading to incorrect pairing of

repeats, some repeats are copied twice or not at

all, depending on the direction of the shift. One

can distinguish forward slippage (shown here)

and backward slippage with respect to the

newly replicated strand. If the newly synthesized

DNA strand slips forward, a region of nonpairing

remains in the parental strand. Forward

slippage results in an insertion. Backward slippage

of the new strand results in deletion.

Microsatellite instability is a characteristic feature

of hereditary nonpolyposis cancer of the

colon (HNPCC). HNPCC genes are localized on

human chromosomes at 2p15–22 and 3p21.3.

About 15% of all colorectal, gastric, and endometrial

carcinomas show microsatellite instability.

Replication slippage must be distinguished

from unequal crossing-over during

meiosis. This is the result of recombination between

adjacent, but not allelic, sequences on

nonsister chromatids of homologous chromosomes

(Figures redrawn from Brown, 1999).

References

Brown, T.A.: Genomes. Bios Scientific Publ., Oxford,

1999.

Dover, G.A.: Slippery DNA runs on and on and

on ... Nature Genet. 10:254–256, 1995.

Lewin, B.: Genes VII. Oxford University Press,

Oxford, 2000.

Rubinstein, D.C., et al.: Microsatellite evolution

and evidence for directionality and variation

in rate between species. Nature Genet.

10:337–343, 1995.

Strachan, T.A., Read, A.P.: Human Molecular

Genetics. 2nd ed. Bios Scientific Publ., Oxford,

1999.

Vogel, F., Rathenberg, R.: Spontaneous mutation

in man. Adv. Hum. Genet. 5:223–318, 1975.