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Mutations and New Variation: Overview

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Mutations and New
Variation: Overview
Mark O Johnston, Dalhousie University, Halifax, Nova Scotia, Canada
A mutation is a heritable change in the genetic material that is not due to genetic
recombination. Mutation alters the structure or number of genes or entire chromosomes.
History of Meaning of the Word
The word ‘mutation’ was first used to indicate a hereditary
change by the Dutch botanist and evolutionary biologist
Hugo De Vries (1848–1935), perhaps as early as 1886. He
discussed his conception of mutation and its role in
evolution at length in The Mutation Theory (1901–1903)
and Plant Breeding (1907). De Vries felt that evolution by
natural selection, proposed by Charles Darwin (1809–
1882) and Alfred Russel Wallace (1823–1913) in 1858, was
incapable of producing new species, even over long time
spans. In his view natural selection did operate, but it could
not change the phenotype by an amount that seemed to be
required for a new species to arise. He instead proposed
that there are discrete heritable particles, or ‘pangenes’,
that could change to new forms and instantaneously create
new species. Pangenes might remain latent for many
generations only to express themselves suddenly. They
equally were thought capable of changing to a new form. In
either case, De Vries termed the changed particles
‘mutations’.
De Vries underestimated the power of natural selection.
Over time and without the aid of new variation from
mutations, selection can in fact shift the mean of a
phenotypic trait far beyond that of any individual in the
original population. This is because most phenotypic traits
are influenced by a large number of genes (loci), each of
which has a number of alleles. Recombination during
meiosis and mating brings alleles at different loci into new
combinations, which can then be favoured or disfavoured
by selection. Good examples of enormous phenotypic
shifts caused by humans are breeds of dog, all of which
descend from a wolf-like ancestor, and oil content of corn.
We also now know that De Vries vastly overestimated
both the frequency of mutations of large phenotypic effect
and the proportion of such mutations that are even
potentially beneficial. These misunderstandings resulted
from his somewhat unfortunate choice of experimental
organism, the large-flowered evening primrose, Oenothera
lamarckiana (Onagraceae), which, as a result of rare
recombination and a bizarre genetic system, sometimes
produced greatly altered but true-breeding progeny that he
thought were new species. Nevertheless, De Vries’s concept
of mutation as a heritable change has remained intact.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Introductory article
Article Contents
. History of Meaning of the Word
. Importance of Mutations in Evolution
. Variation in Mutation Rates
. New Variants: Mutation Versus Recombination
. Somatic Versus Germline Mutation
. Kinds of Mutation
. Advantageous, Disadvantageous and Neutral
Mutations (Relation to Neutral Theory)
Importance of Mutations in Evolution
Mutations are important in evolution in several ways. All
current genetic variation originally arose because of
mutation. Mutations are therefore the ultimate source of
differences among species. Mutations span the entire range
of fitness effects from lethal to mildly deleterious to neutral
to beneficial. The great majority of mutations are believed
to occupy the range from mildly deleterious to nearly
neutral (or possibly neutral). Very, very few are immedi-
ately beneficial. This is because any change to an organism
that has long been subject to selection will tend to be
detrimental; any beneficial changes are already part of the
genome. Mutations with large beneficial effects should
reach high frequency in a population, while those with
large deleterious effects will reach low frequency (they must
first avoid being lost when rare; see ‘Advantageous,
Disadvantageous and Neutral Mutations’ section, below).
Mutations of small effect, however, are by their very
definition subject to weak natural selection and may
remain in a population for long periods. This creates one of
the most interesting aspects of the evolutionary biology of
mutations: the importance of mildly deleterious mutations.
Most mutations are harmful and are thus reduced in
frequency by natural selection. One might therefore
assume that the low frequency of individual deleterious
mutations causes them to be relatively unimportant in
evolution. This is incorrect. Instead, there is a balance
between the continued input of mutations and their
removal by selection, so that a population has a standing
equilibrium frequency of mutations. Mutations with very
slightly harmful effects are removed less efficiently than
those with greater effects, so their equilibrium frequency is
higher. In addition, because mutations can occur at any of
thousands to millions of places in the genome, a typical
individual may possess a large number of slightly
deleterious mutations. The existence of mutations in a
population creates a ‘genetic mutational load’, which is
defined as the fraction by which the average fitness of
individuals in a population is reduced because of muta-
tions. Mutational load depends upon a number of factors,
1
 Mutations and New Variation: Overview
including the mutation rate and the effects on heterozygote
fitness.
It is probable that many of life’s most impressive features
have evolved, at least in part, as means to ameliorate the
effects of deleterious mutations. These features include (1)
sexual reproduction and genetic recombination (crossing
over and independent assortment); (2) diploidy; (3) mate
choice, typically of males by females; and (4) self-
fertilization versus outcrossing in plants (and in those
hermaphroditic animals capable of self-fertilization).
Several other processes, such as population extinction,
the phenomenon of ageing (senescence) and degeneration
of Y-chromosomes, may also be greatly affected by
deleterious mutations. These are some of the most active
areas of empirical and theoretical research in evolutionary
biology.
Variation in Mutation Rates
The rate of mutation is the result of a balance between the
production and correction of errors. Proofreading and
error correction are energetically very expensive. It is for
this reason that mutation rates in all organisms exceed
zero. It has also been proposed that a mutation rate of zero
would stop adaptive evolution. This explanation may be
more valid for organisms such as viruses and prokaryotes
(bacteria) that never or rarely undergo genetic recombina-
tion. For eukaryotes like plants and animals, however,
genetic recombination produces vastly more genetic
variation in any one generation than does mutation
(‘New Variants: Mutation Versus Recombination’ section,
below).
Mutations may occur at times other than during cell
division, but most arise when new genetic material is
produced from old. In eukaryotes, that is, the protists,
plants, fungi and animals, mutations thus arise during
mitosis and meiosis. The ‘rate of mutation’ is the number of
new mutations per target region per time unit. Target
regions typically are bases (most RNA (ribonucleic acid)
viruses and the unusual single-stranded DNA (deoxyribo-
nucleic acid) viruses like FX174), base pairs (other
organisms), genes, gametes or genomes. Time units
typically are replication or sexual generation. For example,
a mutation rate of 2.5
10 2 10 per base pair (bp) per
replication means that on average 2.5 mutations will arise
for every 1010 bp during each replication of DNA. Many
mutation rates are extrapolated to cover the whole
genome, under the assumption that the rate in the
remainder of the genome is equivalent to that in the
measured target region. From the example above, if a
diploid genome consists of 6
109 bp (e.g. humans), and
the mutation rate is equal at all base pairs, then the
2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
mutation rate expressed per base pair per diploid genome is
1.5, as shown in eqn [1].
G:H
IJIJ KLMNMOPQR Y
IJZ ST I:H KLMNMOPQR


ST  UVTWOXNMOPQ [VQPKV [VQPKV  UVTWOXNMOPQ
I
Extrapolation must in general be used cautiously, as rates
are known to vary from locus to locus and with individual
age. Mutation rates have been measured in a variety of
organisms. (For descriptions of the various sorts of
mutation, see ‘Kinds of Mutation’ section, below.)
RNA viruses
For RNA-based viruses that cause host-cell lysis, the
average mutation rate is about one per genome per
replication, with much variation and uncertainty in this
value (Table 1). The estimates are extrapolations from
mutation frequencies at specific target stretches of the
RNA molecule. Because a virus replicates multiple times
following infection, the host cell typically contains many
different mutant viral genotypes. This variety probably
increases the probability of successful infection of a new
host cell.
DNA-based microbes
DNA-based microbes probably provide the most reliable
estimates of per-genome mutation rates. This hotchpotch
group includes a variety of taxonomically well-differen-
tiated organisms – viruses, prokaryotes and eukaryotes –
that vary greatly in genome size. Bacteriophages (viruses)
possess from 103 to 105 bp, the bacterium Escherichia coli
about 106 bp and the fungi Saccharomyces cerevisiae
(yeast) and Neurospora crassa (pink bread mould) each
about 107 bp. One of the most striking results in studies of
mutation rates in these organisms is that the mutation rate
per base pair per replication decreases in species with larger
genomes. The result is a nearly constant mutation rate per
genome per replication of about 0.003 (Table 1).
Retroelements
Retroelements, such as retroviruses and retrotransposons,
are mobile genetic elements that spend part of the life cycle
as single-stranded RNA and part incorporated into a host
genome as double-stranded DNA. A retrovirus is capable
of producing new, complete virus particles that can then
infect new host cells. An example is human immunodefi-
ciency virus (HIV), the cause of acquired immune
deficiency syndrome (AIDS). A retrotransposon, in
contrast, cannot leave the host cell and so increases its
numbers by inserting copies of itself into different parts of
the same cell’s DNA. Examples are Ty1 in yeast, Ta1 of the
annual herb Arabidopsis thaliana and copia in Drosophila
 Mutations and New Variation: Overview

Table 1 Mutation rates for various organisms, genes and chromosomes

Organism and/or mutational target Rate Expressed per
Lethal alleles, wholly or largely recessive
Drosophila melanogaster (fly) 1 × 10–2 haploid genome per generation
Caenorhabditis elegans (nematode) 7 × 10–3 haploid genome per generation
Ferns, chlorophyll deficiency only (1 to 1.5) × 10–2 haploid genome per generation
Annual plants, 11 species, chlorophyll deficiency only (1.6 to 4.5) × 10–4 haploid genome per generation
Mangroves, 2 species, chlorophyll deficiency only (1 to 5) × 10–3 haploid genome per generation
Pinus sylvestris (pine), chlorophyll deficiency only 4.2 × 10–3 haploid genome per generation
Mildly deleterious alleles affecting fitness or fitness components
Herbaceous, annual flowering plants (several species, lifetime 0.1 to > 1 diploid genome per generation
fitness)
Caenorhabditis elegans (nematode, lifetime fitness) (1.2 to 6) × 10–3 diploid genome per generation
Drosophila melangogaster (fly, egg-to-adult survival) 0.3 to 1.5 or greater diploid genome per generation
Daphnia (aquatic crustacean, several fitness-related traits) 0.4 to 1.2 diploid genome per generation
Escherichia coli (bacterium) 2 × 10–4 haploid genome per replication
Lytic single-stranded RNA viruses (8 to 65) × 10–1 genome per replication
Retroviruses (extrapolated from rates at specific loci) (4 to 43) × 10–2 genome per replication
DNA-based microbes
Bacteriophages (viruses) (2 to 70) × 10–8 base pair per replication
∼4 × 10–3 genome per replication
Escherichia coli (bacterium) 5 × 10–10 base pair per replication
2.5 × 10–3 genome per replication
Saccharomyces cerevisiae (brewer’s/baker’s yeast, a fungus) 2 × 10–10 base pair per replication
2.7 × 10–3 genome per replication
Neurospora crassa (pink bread mould, a fungus) 7 × 10–11 base pair per replication
3 × 10–3 genome per replication
Higher eukaryotes (animals only): estimates per base pair from specific loci and extrapolations therefrom to rates for whole
genome
Caenorhabditis elegans (nematode) 2 × 10–1 base pair per replication
2 × 10 –2 genome per replication
3.6 × 10–2 effective genome per sexual generation
Drosophila melanogaster (fly) 3 × 10–10 base pair per replication
6 × 10 –2 genome per replication
1.4 × 10–1 effective genome per sexual generation
Mus musculus (mouse) 2 × 10–10 base pair per replication
5 × 10 –1 genome per replication
9 × 10–1 effective genome per sexual generation
Homo sapiens (human) 5 × 10–11 base pair per replication
2 × 10 –1 genome per replication
1.6 effective genome per sexual generation
Large phenotypic effects, often individual genes
Escherichia coli streptomycin resistance 10–9 cell per generation
Drosophila melanogaster
males, brown eyes 3 × 10–5 gamete per generation
continued

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3

 Mutations and New Variation: Overview

Table 1 – continued
Organism and/or mutational target Rate Expressed per
eyeless 6 × 10–5 gamete per generation
yellow body 1.2 × 10–4 gamete per generation
coat colour ‘a’ 7.1 × 10–5 gamete per generation
coat colour ‘c’ 9.7 × 10–6 gamete per generation
coat colour ‘d’ 1.9 × 10–5 gamete per generation
coat colour ‘ln’ 1.5 × 10–5 gamete per generation
Homo sapiens
Achondroplasia (dwarfism) ∼1 × 10–5 gamete per generation
Huntington disease (Huntington chorea) (0.3–5) × 10–6 gamete per generation
Retinoblastoma ∼1 × 10–5 gamete per generation
Dystrophia myotonica ∼1 × 10–5 gamete per generation
Neurofibromatosis (5–10) × 10–5 gamete per generation
Von Hippel–Lindau syndrome (2.3–4.4) × 10–6 gamete per generation
Chromosome structural mutations
Reciprocal translocations, two Drosophila species 10–4 to 10–3 gamete per generation
Fusion producing trisomy 21 (Down syndrome, humans) 3 × 10–5 gamete per generation
Various rearrangements, Rumex acetosa, a dioecious plant 2 × 10–2 gamete per generation

Sources: Drake JW et al. (1998) Rates of spontaneous mutation. Genetics 148: 1667–1686; Klekowski EJ (1998) Mutation rates in mangroves and
other plants. Genetica 102/103: 325–331; Russell PJ (1992) Genetics, 3rd edn. New York: Harper Collins; King M (1993) Species Evolution:
The Role of Chromosome Change. Cambridge: Cambridge University Press.

melanogaster. In the life cycle of a retroelement, mutation
can thus occur during any of the following three stages: (1)
during transcription of DNA in the production of the new
RNA genome; (2) during production of DNA from RNA
through the use of reverse transcriptase; and (3) while the
particle is part of the host chromosome. Most mutation
occurs in the first two stages. The total mutation rate in
retroelements appears to be about 0.1 per genome per
replication, or approximately ten times lower than the rate
in lytic RNA viruses (Table 1).
Higher eukaryotes (plants and animals)
Phenotypically obvious mutations
Plants and animals are larger, more phenotypically
complex and more readily observable than microbes. As
a result, many studies have been conducted on the rate of
appearance of major mutations affecting phenotypic traits
like kernel colour in maize (corn), eye colour and wing
shape in Drosophila, coat colour in the mouse and various
disorders in humans (Table 1). It is in general not very
informative to extrapolate from these major mutations at
specific loci to rates per genome, for two reasons. First,
phenotypically obvious mutations constitute a small
fraction of all mutations. Extrapolation would therefore
underestimate the true rate of per-genome mutation.
Second, phenotypically obvious mutations can only occur
in coding regions, but much of the eukaryotic genome
consists of nonfunctional or ‘junk’ DNA. The ‘effective
genome’ size represents the quantity of functional DNA in
a genome; some rate estimates based on effective size are
presented in Table 1. (Plants, protists and animals therefore
possess much larger genomes than do prokaryotes.
Prokaryotic sizes in millions of base pairs (megabases,
Mb) are 0.6 to 13 Mb in eubacteria and 1.6 to 4.1 Mb in
archaebacteria. Genome sizes in eukaryotes range from 23
to 690 000 Mb in protists, 8.8 to 1470 Mb in fungi, 49 to
139 000 Mb in animals and 50 to 307 000 Mb in plants.)
Effects of age and gender
Age and gender may also influence the mutation rate. In
female humans, for example, the rate of chromosome
mutation, such as trisomy, increases with age. This age
effect is not caused by mutations accumulating during cell
division, because human ovarian cells do not repeatedly
divide to produce new eggs. Instead, females are born with
eggs that complete meiosis only in preparation for
potential fertilization. As a result, there are few cell
divisions separating eggs of consecutive generations. In
males, sperm are continually produced over many years

4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


from a set of continually dividing cells, so that the number
of replications preceding sperm production increases with
age. Human males have a much higher rate of gene
mutation than females, and this rate increases with age.
(The increase is nonlinear, indicating that a factor other
than simply number of cell divisions is operating.) Such
gender and age-of-male differences in mutation rate are
known in several human disorders such as Apert syndrome
(achrocephalosyndactyly), haemophilia, Lesch–Nyhan
syndrome and multiple endocrine neoplasia type A and
type B. The existence of higher mutation rates in males
than in females, and in older than in younger males,
appears to apply only to substitution mutations, and not to
deletions or chromosome mutations. It therefore appears
that the number of DNA replications (or cell divisions)
influences the mutation rate of base pair substitutions but
not of deletions or chromosome mutations.
Total genomic deleterious mutation rate
From the point of view of many areas of evolutionary
biology, the most important mutations are those that
decrease fitness (‘Importance of Mutations in Evolution’
section, above). This is a large class ranging from nearly
neutral to highly deleterious. Most of these will be mildly
deleterious and phenotypically undetectable in indivi-
duals. Despite being of the greatest interest, the total
deleterious mutation rate per genome per generation has
been measured only a few times, and the results are mixed
(Table 1). One method consists of experimentally prevent-
ing the action of natural selection over several to many
generations, thus allowing deleterious mutations to
accumulate, and then comparing the resultant individuals
to ones in which mutations were not allowed to accumulate
(or to the original individuals). Under the heading ‘Mildly
deleterious alleles affecting fitness or fitness components’ in
Table 1, this mutation-accumulation method was used in
the estimates presented for Caenorhabditis elegans, some
values of D. melanogaster, E. coli and the lowest value for
the annual plants. A different, indirect method assumes
that a population consists of individuals in mutation-
selection balance and uses various statistical techniques,
such as comparisons between inbred and outbred progeny,
to estimate the total genomic mutation rate. In Table 1
indirect methods were used for annual plants, Daphnia and
some values of D. melanogaster. The genomic rate of
mutation to deleterious alleles remains a major unsolved
problem in evolutionary biology.
New Variants: Mutation Versus
Recombination
All alleles at all loci currently present in any population
ultimately arose as mutations. At any particular time, it is
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Mutations and New Variation: Overview
genetic recombination and sex, rather than mutation, that
creates most new genetic variants. Sex is the union of
gametes, whether from an unrelated individual (outcross-
ing) or the same individual (self-fertilization). Recombina-
tion in eukaryotes has two aspects, crossing over and
independent segregation (independent assortment). Cross-
ing over is the reciprocal exchange of genetic material
between a pair of homologous chromosomes. Independent
assortment (Mendel’s second law) means that the indivi-
dual homologues of each chromosome pair behave
independently, so that all possible combinations are
equally likely to be found in the gametes. Consider for
simplicity a diploid eukaryote with three chromosomes
and 11 loci on each chromosome, each with two possible
allelic states. If the population consists of 105 individuals,
and the mutation rate is 10 2 6 per locus per generation,
then in each generation there will be about 3.3 new alleles
(3
11
105
10 2 6). Compare this number to the num-
ber, n, of possible genotypes created by recombination:
there are 233 5 more than 8
109 potential gamete types;
many of these will never have existed in the population
before. The general formula is, n 5 Pc Pgacg, where acg is
the number of alleles present in the population at locus g on
chromosome c, and Psubscript indicates taking the product
over all values of the subscript. Because gametes unite in
pairs, there are n (n 1 1)/2 possible diploid genotypes,
which in our example exceeds 3
1019. In the more realistic
case of a species possessing more than one allele at 50 000
loci, the numbers become astronomical. With only two
possible alleles per locus, n 5 250 000  1015 051, and the
number of possible diploid genotypes exceeds 1030 000.
Such genotypic variety will not be found in real popula-
tions because the number of genotypes exceeds the size of
any population and because this variety requires crossing
over between all possible loci. Nevertheless, it is clear that
the amount of variation generated by recombination and
sexual union is vastly greater than that generated by
mutation alone in a particular generation.
Somatic Versus Germline Mutation
Mutations may appear in any type of cell. In order for them
to contribute to genetic variation in future generations,
however, they must be present in germ (gamete or gamete-
producing) cells. Thus, although mutations may occur in
somatic cells of, say, an animal, they are evolutionarily
irrelevant, except insofar as they decrease the fitness of the
individual in which they occur and so select for decreased
somatic mutation rates. In many organisms, such as plants
and fungi, reproductive structures are continually pro-
duced from somatic cells. That is, there is no separation of
germline and somatic line. In such organisms, a somatic
mutation may become incorporated into reproductive
structures, such as during flower development, and thus
5
 Mutations and New Variation: Overview
become transmitted to the gametes. Plants, which may
live hundreds or thousands of years and undergo an
enormous number of cell divisions, appear to have several
features that reduce the probability that somatic mutations
accumulate and are transferred to gametes. For example, a
reserve of rarely dividing cells (the ‘quiescent centre’)
sits behind a growing root or shoot tip. A small fraction
of these cells divide to produce developmental initials,
which are the cells that subsequently undergo numerous
divisions.
Kinds of Mutation
Gene mutations
Spontaneous gene mutations result from errors during
replication of DNA, errors during recombination, sponta-
neous lesions and transposable elements. Induced muta-
tions are caused by specific mutagenic agents, such as
ultaviolet radiation or aflatoxin B1. Many mutagens are
carcinogenic. As a group, induced mutations are more
common than spontaneous mutations.
At the DNA level
There are four classes of gene mutation at the level of
DNA: substitutions, deletions, insertions and inversions
(Figure 1). A substitutional mutation, also called a point
mutation, changes a single nucleotide base pair in the DNA
molecule. There are two purine bases, adenine (A) and
guanine (G), and two pyrimidine bases, cytosine (C) and
thymine (T). In the normal double-stranded DNA
molecule, A on one strand is paired with T on the
complementary strand, and C with G. Substitutional
mutations therefore generally replace base pairs rather
than the base on only one strand. In fact, the whole
nucleotide, consisting of phosphate group, sugar and the
base, is typically substituted, rather than simply the base.
Substitutional mutations are either transitions or transver-
sions. Transitions replace a purine with a purine or a
pyrimidine with a pyrimidine. The four kinds of transition
mutation are AT$GC and CG$TA. Transversions are
substitutions of a purine for a pyrimidine, or vice versa.
The eight kinds are AT$CG, AT$TA, GC$CG and
GC$TA. Deletion mutations simply remove one or more
base pairs, while insertion mutations add one or more base
pairs. Inversions reverse the order of a section (of at least
two base pairs) of DNA.
Above the DNA level: protein-coding genes
Mutations are also classified by their effects. They can
affect the fitness (success at surviving and reproducing) of
an individual organism by being lethal, mildly deleterious,
neutral or beneficial. These fitness consequences influence
the evolutionary fate of mutations, as explained in other
6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
parts of this article. Any such effects on fitness, however,
result from direct consequences at the level of any of the
three types of gene: protein coding, RNA (ribonucleic acid)
specifying and regulatory. Protein-coding genes are
transcribed and translated, RNA-specifying genes are only
transcribed and regulatory genes are neither transcribed
nor translated but perform functions such as specifying
sites of DNA replication and recombination.
Mutations in protein-coding genes are currently much
better understood than mutations in RNA-specifying or
regulatory genes. Recall that a protein is constructed
through the processes of transcription and translation.
During transcription, one strand of double-stranded DNA
is used as a template for constructing a complementary
messenger RNA (mRNA) molecule, which is single
stranded. (Transcription more generally refers to reading
DNA to construct any of the four kinds of RNA: mRNA,
transfer RNA (tRNA), ribosomal RNA (rRNA) and small
nuclear RNA (snRNA)). mRNA contains groups of three-
base sequences, called codons, that each specify a
particular amino acid. At the ribosome, the three-base
anticodon of a tRNA, bearing a specific amino acid, binds
to the complementary codon of the mRNA, adding a new
amino acid to the protein under construction. The one-to-
one matching of anticodon with codon determines the
amino acid sequence, and thus the functional properties, of
the final protein.
The four kinds of mutation at the level of DNA can have
a variety of effects at the mRNA or protein level. ‘Missense’
mutations cause a gene to transcribe a different mRNA
codon so that a different amino acid is specified. For
example, a mutation in a DNA sequence from 3’–TTG–5’
to 3’–TCG–5’ (a transition) changes the mRNA codon
from 5’–AAC–3’ to 5’–AGC–3’. The resulting protein will
have serine in place of asparagine. ‘Nonsense’ mutations
change an amino-acid-specifying codon to one of the three
chain-terminating or ‘stop’ codons, UAA, UAG and UGA
(the base U (uracil) replaces thymine in RNA molecules).
The resulting protein is prematurely terminated. ‘Frame-
shift’ mutations are insertions or deletions of a base pair or
any number of base pairs that is not an integer multiple of
three. The reading frame along the mRNA is shifted,
resulting in altered amino acids, premature termination or
lack of appropriate termination.
In molecular genetics, mutations are considered ‘neu-
tral’ or ‘nonneutral’ according to their effects on protein
function. Missense, nonsense and frameshift mutations
alter the gene product and are therefore all nonneutral.
Substitutional mutations, however, may in some cases
have no discernible effect on the protein product. Because
there are 61 amino-acid-specifying codons and only 20
amino acids, most amino acids are specified by more than
one codon. Therefore, many mutations are ‘synonymous’
(‘silent’), because they do not alter the specifed amino acid.
All other mutations in protein-coding genes are nonsynon-
ymous. Each base of a three-base codon can mutate to any
 Mutations and New Variation: Overview

Rare enol tautomeric

form of guanine A
–C–G
– –T C
– Wild-type
TGCAG
A
–C–G
– –T C
–
TGTAG
T C– A
DNA G–* –A G –C–A
– T– C– Mutant
T TGTAG
A replication
–C–G
– –T C
– A
–C– DNA
TGCAC TG replication
–G A
–C–G
– –T C
Parental DNA C –T –C – Wild-type
AG TGCAG
A
–C–G
– –T C
–
(a) TGCAG
A
–C–G
– –T C
– Wild-type
First-generation TGCAG
progeny
Second-generation
progeny

Addition Deletion
DNA synthesis DNA synthesis

5’ C G TT T T 5’ C TGAGAGA

3’ G CA A A A A CG T A C 3’ GAC TC T C T C T G C A
T
5’ CG T T T 5’ C T GAGAGA

3’ G C A A A A A CG TA C 3’ G A C T C T C T C T GC A
CT
T
5’ C G T T T T TGCA TG 5’ C T G A G A G A G A CG T

(b) 3’ G C A A A A A CG TA C 3’ G A C T C T C T C T GC A
CT

Figure 1 Gene mutations. (a) A GC!AT mutation caused by guanine shifting from its common (keto) form to a rare enol form at the time of DNA
replication. This enol form pairs with thymine instead of cytosine. During the subsequent replication, the newly incorporated thymine pairs normally with
adenine. It is also possible for guanine to convert to its rare enol form during its incorporation opposite a template strand, rather than at the time of
replication (not shown). In this case, guanine will be located opposite a thymine and replication will result in an AT!GC mutation. (b) Addition and
deletion mutations caused by strand slippage. On the left, addition mutations are caused by slippage of the newly synthesized strand. On the right, deletion
mutations are caused by slippage of the template strand. Repetitive bases (A on the left, CT on the right) stabilize the looped out portion of the DNA.
(Adapted from Gardner and Snustad (1984) Principles of Genetics, New York: Wiley; Griffiths et al. (1996) An Introduction to Genetic Analysis, New York: WH
Freeman.)

of three other bases, for a total of nine. There are therefore
61
9 5 549 possible codon changes from mutation. Of
these, 23 (4%) are nonsense, 392 (71%) are missense and
134 (25%) are synonymous. Overall, a random substitu-
tion thus has a 25% probability of being synonymous, but
the probability depends strongly on position in the codon:
4%, 0% and 69% for the first, second and third codon
position, respectively (5’ to 3’). While all synonymous
mutations are considered neutral, ‘nonsilent’ mutations
can in some cases also be neutral, because they substitute
an amino acid that is sufficiently similar to the nonmutant
amino acid that protein function is unaltered. In fact, many
geneticists reserve the term ‘neutral’ for nonsynonymous
but functionally equivalent substitutions.
Transposable genetic elements as mutations
Transposable genetic elements (TGEs) are stretches of
DNA that can move from one position to another in the
‘host’ genome. All TGEs code for an enzyme, transposase,
that effects transposition; some TGEs also code for
functional gene products. When transposition occurs, the
TGE may simply move to a new spot (conservative
transposition). More commonly, however, it leaves a copy
of itself behind (replicative transposition), thus becoming
more numerous in the genome, a kind of ‘selfish DNA’.
There are several broad classes of TGEs, including
insertion sequences, transposons and retroelements (the
last is described in ‘Retroelements’ section, above). Some
TGEs in bacteria confer resistance to antibiotics and heavy

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 7

 Mutations and New Variation: Overview
metals. They usually, however, are harmful, because of
their multifarious effects. Specifically, transposable ele-
ments: (1) can change host gene expression by disrupting
regulatory genes; (2) increase host-DNA mutation rate
(the very act of disrupting host genes constitutes a
mutation); (3) can cause chromosomal changes such as
insertions and deletions (‘Structural mutations’ section,
below); (4) can transport host genes; (5) increase host
genome size by replicative transposition and because
transposition causes the short repeats of the host DNA
on both sides of the TGE. The continued autonomous
replication of TGEs is kept in check partly because
transposition rate declines as copy number increases in
the host genome and partly because of natural selection:
fitness declines as copy number increases.
Chromosome mutations
A chromosome mutation is a change in the number or
structure of chromosomes. Structural changes are con-
sidered chromosome rather than gene mutations if they
involve a sufficiently large block of DNA. Many closely
related species have chromosomal differences. For exam-
ple, humans and chimps are separated by nine inversions
and one translocation (definitions below). Whether chro-
mosome mutations are primary causes or incidental
byproducts of speciation is a matter of current dispute.
Structural mutations
Structural mutations include deletions, duplications,
inversions and translocations (Figure 2a). A chromosomal
deletion mutation is the loss of a segment of DNA. Loss of
genes can be fatal in a haploid organism and harmful or
fatal in a diploid which contains recessive deleterious
alleles on the homologous chromosome. Loss of the ends
of chromosomes causes them to become unstable. Loss of a
section containing the centromere disrupts proper move-
ment during meiosis, so that the entire chromosome may be
absent from some gametes. Duplication mutations occur
when a chromosome segment is copied to another, often
adjacent, position on the same chromosome. Excision
and backwards reinsertion of a segment results in an
inversion mutation. Inversions can disrupt the rate or
order of gene transcription. Inversion heterozygotes,
individuals with one member of a homologous pair
containing an inversion, tend to produce a large fraction
of inviable gametes because of problems during meiotic
crossing over. Translocation mutations are exchanges
of segments of DNA. They can occur within a chromosome
arm, between arms (both are examples of intrachromoso-
mal translocation) or between homologous chromosomes
(interchromosomal translocation). Interchromosomal
translocations can be reciprocal, in which each chromo-
some receives material from the other, or nonreciprocal, in
which one chromosome transfers a segment to a non-
8 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
homologue. Meiosis is normal in homozygotes for
reciprocal translocations but abnormal in such hetero-
zygotes. Here, problems with pairing result in a large
fraction of gametes that suffer reduced fitness as gametes or
after fertilization in the zygote.
Numerical mutations
Changes in chromosome number can involve whole
chromosome sets (polyploidy) or incomplete sets (aneu-
ploidy). The primary cause of aneuploidy is nondisjunc-
tion, in which the sister chromatids do not separate
properly in mitosis or the homologues do not separate
properly in meiosis (Figure 2b). In either case, some
daughter cells or gametes receive either an extra copy or
too few copies. Most aneuploid events are lethal in the
gamete or early embryo stage, and are not observed. An
exception in humans is trisomy (three haploid copies) at
chromosome 21, which causes Down syndrome.
Polyploidy is the increase or decrease in number of whole
chromosome sets. A triploid contains three haploid sets, a
tetraploid four, etc. Polyploidy is far commoner in plants
than in animals. The highest known somatic chromosome
number in flowering plants is 640 and in ferns is 1260. It is
estimated that 50–90% of plant species are the result of
polyploidizations at some time in their evolutionary past.
Most of these events united two related but dissimilar
genomes (allopolyploidy), possibly of different species,
rather than two nearly identical ones (autopolyploidy), for
example from the same individual or species. Whether
allopolyploidy or autopolyploidy, the numerical increase
may result from union of unreduced gametes or from
normal, reduced gametes. This zygote may either immedi-
ately multiply its chromosome number before developing
into a mature plant, or it may first develop and later form
some unreduced gametes that happen to unite in self-
fertilization. Newly arisen polyploid individuals are
usually unable to mate with the parental species. The
result is instantaneous sympatric speciation. Polyploidy in
plants typically causes increased cell and plant size, as well
as other biochemical changes, and thus may permit the
invasion of novel niches. Many of the most important
agricultural plants are polyploids, including banana,
canola (a type of rapeseed low in saturated fat), coffee,
cotton, oat, peanut, soybean, tobacco and wheat.
Advantageous, Disadvantageous and
Neutral Mutations (Relation to Neutral
Theory)
The evolutionary fate of a new mutation depends upon the
frequency with which it arises (m), its selective effect (s) and
the degree to which it affects individual fitness in the
heterozygous condition (the dominance level, h). If a
 Mutations and New Variation: Overview

Normal chromosome
A B C D E F G H

A B C D E F G H A B C D E F G H Nondisjunction Second division

at first division n+1

n+1
C D E F G H A B E F G H

Terminal deletion Interstitial deletion

n–1

A B C D E F G H A B C D B C D E F G H
n–1

Duplication (tandem)

A B C D E F G H A B C D D C B E F G H

Duplication (reverse) First division Nondisjunction

at second division
n+1

A B C D E F A B E D C F
n–1
Paracentric inversion

n
A B C D E F A D C B E F

Pericentric inversion n

(b)

Reciprocal translocation

Insertional translocation

(a)

Figure 2 Chromosome mutations. (a) Structural mutations. Wavy arrows in the diagrams for terminal and interstitual deletions indicate an agent
such as ionizing radiation. (b) Numerical mutations during meiosis. Aneuploid gametes are firmed by nondisjunction; that is, homologues (far left) do not
separate and move to opposite poles. Nondisjunction can occur during the first (upper diagrams) or second (lower diagrams) meiotic division. Circles
within chromosomes indicate centromeres. Nondisjunction may also occur during mitosis, in which case the sister chromatids do not properly move to
opposite poles. (Partly adapted from Griffiths et al. (1996) An Introduction to Genetic Analysis, New York: WH Freeman.)

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 9

 Mutations and New Variation: Overview

mutation is beneficial (s 5 0), it should increase in
frequency to 100%, replacing the alternative allele(s) (but
see below). If it is deleterious, then the expected equili-
brium frequency (B) is as shown in eqn [2].
G
q^  q
hs
to be wholly dependent on statistical accidents of sampling
from one generation to the next. The competing theory
states that natural selection affects the rate of fixation of
mutations. The neutral theory makes several predictions
about rates of molecular evolution, most prominently that
the rate at which truly neutral mutations become fixed in a
G
I    sc  dh  hG s
I  G  species equals the mutation rate per generation. Rates of
In this scheme the fitnesses of the three possible genotypes
are standardized as 1 for the nonmutant homozygote, 1 2 s
for the mutant homozygote p and 1 2 hs for the hetero-
zygote. This simplifies to (m/s) for completely recessive
mutations (h 5 0) and to approximately m/hs for partially
recessive mutations (0 5 h 5 0.5). These formulae are
often used to estimate the mutation rate of alleles causing
human disorders, in which case B, h and s are estimated
from population surveys. They must be used with care
because equilibrium requires many generations, and
sociological, counselling and medical factors may have
altered the selection and dominance levels more recently
than a new equilibrium could be achieved.
Whether deleterious, neutral or beneficial, a new
mutation is rare and occurs in the heterozygous condition.
While rare, its fate is determined by chance events (random
genetic drift) rather than natural selection (except for lethal
dominants, which natural selection immediately eradi-
cates). Only upon drifting to appreciable frequency will
natural selection be sufficiently effective to increase the
frequency of a beneficial mutation or to decrease the
frequency of a deleterious one. The much higher mutation
rate to deleterious alleles than to beneficial alleles,
however, means that deleterious – and particularly very
slightly deleterious – alleles will reach appreciable fre-
quencies.
Most mutations with any phenotypic effect are probably
at least somewhat harmful. Of those with no phenotypic
effect, the proportion that are neutral is at the centre of one
of the grandest and most provocative theories in evolu-
tionary biology: the neutral theory of molecular evolution.
The neutral theory states that most nondeleterious
mutations have no effect on fitness and therefore most
evolution of DNA and proteins (i.e. molecular evolution)
results not from natural selection but rather from random
genetic drift. Whether an altered DNA sequence or protein
is ultimately lost or fixed (reaches 100%) is thus postulated
10 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
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molecular evolution can be inferred from molecular
differences among species with known times of evolu-
tionary divergence. The competing theories are difficult to
disprove, and there are data in support of each. It is clear,
however, that while selection has been of great importance
in adaptive phenotypic evolution, it has played a very weak
role in molecular evolution.
Further Reading
Crow JF (1986) Basic Concepts in Population, Quantitative, and
Evolutionary Genetics. New York: WH Freeman.
Crow JF (1997) The high spontaneous mutation rate: Is it a health risk?
Proceedings of the National Academy of Sciences of the USA 94: 8380–
8386.
Freeman S and Herron JC (1998) Evolutionary Analysis. Upper Saddle
River, NJ: Prentice Hall.
Futuyma DJ (1998) Evolutionary Biology, 3rd edn. Sunderland, MA:
Sinauer.
Genetics (1998) 148. [April; a special issue of this journal concerning
mutations]
Gillespie JH (1991) The Causes of Molecular Evolution. Oxford: Oxford
University Press.
Griffiths AJF, Miller JH, Suzuki DT, Lewontin RC and Gelbart WM
(1996) An Introduction to Genetic Analysis, 6th edn. New York: WH
Freeman.
Kimura M (1983) The Neutral Theory of Molecular Evolution. Cam-
bridge: Cambridge University Press.
King M (1993) Species Evolution: The Role of Chromosome Change.
Cambridge: Cambridge University Press.
Kondrashov AS (1997) Evolutionary genetics of life cycles. Annual
Review of Ecology and Systematics 28: 391–435.
Li W-H (1997) Molecular Evolution. Sunderland, MA: Sinauer
Associates.
Ridley M (1996) Evolution, 2nd edn. Cambridge, MA: Blackwell Science.
Russell PJ (1992) Genetics, 3rd edn. New York: Harper Collins.
Science (1998) 281 (5385) [25 September issue with several articles
concerning the evolution of sex, mate choice, etc.]
Woodruff RC and Thompson JN Jr (eds) (1998) Genetica 102/103. [A
special issue of this journal, Mutation and Evolution].