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Genetic Mutation
By: Dr. Laurence Loewe (School of Biological Sciences, University of Edinburgh, Scotland,
UK.) © 2008 Nature Education
Citation: Loewe, L. (2008) Genetic mutation. Nature Education 1(1)
Is it possible to have “too many” mutations? What about “too few”? While
mutations are necessary for evolution, they can damage existing adaptations
as well.
What is a mutation?
The diversity of beetle species.
Genetic mutation is the basis of species diversity among beetles, or any other organism.
John C. Abbott / www.abbottnaturephotography.com
Mutations are changes in the genetic sequence, and they are a main cause of diversity among
organisms. These changes occur at many different levels, and they can have widely differing
consequences. In biological systems that are capable of reproduction, we must first focus on
whether they are heritable; specifically, some mutations affect only the individual that carries them,
while others affect all of the carrier organism's offspring, and further descendants. For mutations to
affect an organism's descendants, they must: 1) occur in cells that produce the next generation, and
2) affect the hereditary material. Ultimately, the interplay between inherited mutations and
environmental pressures generates diversity among species
Although various types of molecular changes exist, the word "mutation" typically refers to a change
that affects the nucleic acids. In cellular organisms, these nucleic acids are the building blocks of
DNA, and in viruses they are the building blocks of either DNA or RNA. One way to think of DNA and
RNA is that they are substances that carry the long-term memory of the information required for an
organism's reproduction. This article focuses on mutations in DNA, although we should keep in
mind that RNA is subject to essentially the same mutation forces.
If mutations occur in non-germline cells, then these changes can be categorized as somatic
mutations. The word somatic comes from the Greek word soma which means "body", and somatic
mutations only affect the present organism's body. From an evolutionary perspective, somatic
mutations are uninteresting, unless they occur systematically and change some fundamental
property of an individual--such as the capacity for survival. For example, cancer is a potent somatic
mutation that will affect a single organism's survival. As a different focus, evolutionary theory is
mostly interested in DNA changes in the cells that produce the next generation.
Are Mutations Random?
The statement that mutations are random is both profoundly true and profoundly untrue at the
same time. The true aspect of this statement stems from the fact that, to the best of our knowledge,
the consequences of a mutation have no influence whatsoever on the probability that this mutation
will or will not occur. In other words, mutations occur randomly with respect to whether their effects
are useful. Thus, beneficial DNA changes do not happen more often simply because an organism
could benefit from them. Moreover, even if an organism has acquired a beneficial mutation during
its lifetime, the corresponding information will not flow back into the DNA in the organism's
germline. This is a fundamental insight that Jean-Baptiste Lamarck got wrong and Charles Darwin
got right.
However, the idea that mutations are random can be regarded as untrue if one considers the fact
that not all types of mutations occur with equal probability. Rather, some occur more frequently
than others because they are favored by low-level biochemical reactions. These reactions are also
the main reason why mutations are an inescapable property of any system that is capable of
reproduction in the real world. Mutation rates are usually very low, and biological systems go to
extraordinary lengths to keep them as low as possible, mostly because many mutational effects are
harmful. Nonetheless, mutation rates never reach zero, even despite both low-level protective
mechanisms, like DNA repair or proofreading during DNA replication, and high-level mechanisms,
like melanin deposition in skin cells to reduce radiation damage. Beyond a certain point, avoiding
mutation simply becomes too costly to cells. Thus, mutation will always be present as a powerful
force in evolution.
Types of Mutations
So, how do mutations occur? The answer to this question is closely linked to the molecular details of
how both DNA and the entire genome are organized. The smallest mutations are point mutations, in
which only a single base pair is changed into another base pair. Yet another type of mutation is the
nonsynonymous mutation, in which an amino acid sequence is changed. Such mutations lead to
either the production of a different protein or the premature termination of a protein.
As opposed to nonsynonymous mutations, synonymous mutations do not change an amino acid
sequence, although they occur, by definition, only in sequences that code for amino acids.
Synonymous mutations exist because many amino acids are encoded by multiple codons. Base pairs
can also have diverse regulating properties if they are located in introns, intergenic regions, or even
within the coding sequence of genes. For some historic reasons, all of these groups are often
subsumed with synonymous mutations under the label "silent" mutations. Depending on their
function, such silent mutations can be anything from truly silent to extraordinarily important, the
latter implying that working sequences are kept constant by purifying selection. This is the most
likely explanation for the existence of ultraconserved noncoding elements that have survived for
more than 100 million years without substantial change, as found by comparing the genomes of
several vertebrates (Sandelin et al., 2004).
Mutations may also take the form of insertions or deletions, which are together known as indels.
Indels can have a wide variety of lengths. At the short end of the spectrum, indels of one or two
base pairs within coding sequences have the greatest effect, because they will inevitably cause a
frameshift (only the addition of one or more three-base-pair codons will keep a protein
approximately intact). At the intermediate level, indels can affect parts of a gene or whole groups of
genes. At the largest level, whole chromosomes or even whole copies of the genome can be affected
by insertions or deletions, although such mutations are usually no longer subsumed under the label
indel. At this high level, it is also possible to invert or translocate entire sections of a chromosome,
and chromosomes can even fuse or break apart. If a large number of genes are lost as a result of
one of these processes, then the consequences are usually very harmful. Of course, different genetic
systems react differently to such events.
Finally, still other sources of mutations are the many different types of transposable elements, which
are small entities of DNA that possess a mechanism that permits them to move around within the
genome. Some of these elements copy and paste themselves into new locations, while others use a
cut-and-paste method. Such movements can disrupt existing gene functions (by insertion in the
middle of another gene), activate dormant gene functions (by perfect excision from a gene that was
switched off by an earlier insertion), or occasionally lead to the production of new genes (by pasting
material from different genes together).
Effects of Mutations
Figure 1
A single mutation can have a large effect, but in many cases, evolutionary change is based on the
accumulation of many mutations with small effects. Mutational effects can be beneficial, harmful, or
neutral, depending on their context or location. Most non-neutral mutations are deleterious. In
general, the more base pairs that are affected by a mutation, the larger the effect of the mutation,
and the larger the mutation's probability of being deleterious.
To better understand the impact of mutations, researchers have started to estimate distributions of
mutational effects (DMEs) that quantify how many mutations occur with what effect on a given
property of a biological system. In evolutionary studies, the property of interest is fitness, but in
molecular systems biology, other emerging properties might also be of interest. It is extraordinarily
difficult to obtain reliable information about DMEs, because the corresponding effects span many
orders of magnitude, from lethal to neutral to advantageous; in addition, many confounding factors
usually complicate these analyses. To make things even more difficult, many mutations also interact
with each other to alter their effects; this phenomenon is referred to as epistasis. However, despite
all these uncertainties, recent work has repeatedly indicated that the overwhelming majority of
mutations have very small effects (Figure 1; Eyre-Walker & Keightley, 2007). Of course, much more
work is needed in order to obtain more detailed information about DMEs, which are a fundamental
property that governs the evolution of every biological system.
Estimating Rates of Mutation
Many direct and indirect methods have been developed to help estimate rates of different types of
mutations in various organisms. The main difficulty in estimating rates of mutation involves the fact
that DNA changes are extremely rare events and can only be detected on a background of identical
DNA. Because biological systems are usually influenced by many factors, direct estimates of
mutation rates are desirable. Direct estimates typically involve use of a known pedigree in which all
descendants inherited a well-defined DNA sequence. To measure mutation rates using this method,
one first needs to sequence many base pairs within this region of DNA from many individuals in the
pedigree, counting all the observed mutations. These observations are then combined with the
number of generations that connect these individuals to compute the overall mutation rate (HaagLiautard et al., 2007). Such direct estimates should not be confused with substitution rates
estimated over phylogenetic time spans.
Summary
Mutation rates can vary within a genome and between genomes. Much more work is required before
researchers can obtain more precise estimates of the frequencies of different mutations. The rise of
high-throughput genomic sequencing methods nurtures the hope that we will be able to cultivate a
more detailed and precise understanding of mutation rates. Because mutation is one of the
fundamental forces of evolution, such work will continue to be of paramount importance.
References and Recommended Reading
Drake, J. W., et al. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998)
Eyre-Walker, A., & Keightley, P. D. The distribution of fitness effects of new mutations. Nature
Reviews Genetics 8, 610–618 (2007) doi:10.1038/nrg2146 (link to article)
Haag-Liautard, C., et al. Direct estimation of per nucleotide and genomic deleterious mutation rates
in Drosophila. Nature 445, 82–85 (2007) doi:10.1038/nature05388 (link to article)
Loewe, L., & Charlesworth, B. Inferring the distribution of mutational effects on fitness in Drosophila.
Biology Letters 2, 426–430 (2006)
Lynch, M., et al. Perspective: Spontaneous deleterious mutation. Evolution 53, 645–663 (1999)
Orr, H. A. The genetic theory of adaptation: A brief history. Nature Review Genetics 6, 119–127
(2005) doi:10.1038/nrg1523 (link to article)
Sandelin, A., et al. Arrays of ultraconserved non-coding regions span the loci of key developmental
genes in vertebrate genomes. BMC Genomics 5, 99 (2004)