Genetic Mutation (2024)

Mutations are changes in the genetic sequence, and they area main cause of diversity among organisms. These changes occur at manydifferent levels, and they can have widely differing consequences. Inbiological systems that are capable of reproduction, we must first focus on whether they are heritable; specifically, somemutations affect only the individual that carries them, while others affect allof the carrier organism's offspring, and further descendants. For mutations to affect an organism's descendants, theymust: 1) occur in cells that produce the next generation, and 2) affectthe 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 DNAor RNA. One way to think of DNA and RNA is that they are substances that carry the long-term memoryof the information required for an organism's reproduction. This articlefocuses 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 changescan 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, somaticmutations are uninteresting, unless they occur systematically and change somefundamental 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 ismostly interested in DNA changes in the cells that produce the next generation.

The statement that mutations are random is both profoundlytrue and profoundly untrue at the same time. The true aspect of this statement stemsfrom the fact that, to the best of our knowledge, the consequences of amutation have no influence whatsoever on the probability that this mutation willor will not occur. In other words, mutations occur randomly with respect towhether their effects are useful. Thus, beneficial DNA changes do not happenmore often simply because an organism could benefit from them. Moreover, evenif an organism has acquired a beneficial mutation during its lifetime, thecorresponding information will not flow back into the DNA in the organism'sgermline. This is a fundamental insight that Jean-Baptiste Lamarck got wrongand Charles Darwin got right.

However, the idea that mutations are random can be regardedas untrue if one considers the fact that not all types of mutations occur withequal probability. Rather, some occur more frequently than others because they arefavored by low-level biochemical reactions. These reactions are also the mainreason why mutations are an inescapable property of any system that is capableof reproduction in the real world. Mutation rates are usually very low, andbiological systems go to extraordinary lengths to keep them as low as possible,mostly because many mutational effects are harmful. Nonetheless, mutation ratesnever reach zero, even despite both low-level protective mechanisms, like DNArepair or proofreading during DNA replication, and high-level mechanisms, likemelanin deposition in skin cells to reduce radiation damage. Beyond a certainpoint, avoiding mutation simply becomes too costly to cells. Thus, mutationwill always be present as a powerful force in evolution.

So, how do mutations occur? The answer to this question isclosely linked to the molecular details of how both DNA and the entire genome areorganized. The smallest mutations are point mutations, in which only a singlebase pair is changed into another base pair. Yet another type of mutation isthe nonsynonymous mutation, in which an amino acid sequence is changed. Suchmutations lead to either the production of a different protein or the prematuretermination of a protein.

As opposed to nonsynonymous mutations, synonymous mutationsdo not change an amino acid sequence, although they occur, by definition, onlyin sequences that code for amino acids. Synonymous mutations exist because manyamino acids are encoded by multiple codons. Base pairs can also have diverseregulating properties if they are located in introns,intergenic regions, or even within the coding sequence of genes. For somehistoric reasons, all of these groups are often subsumed with synonymousmutations under the label "silent" mutations. Depending on their function, suchsilent mutations can be anything from truly silent to extraordinarily important,the latter implying that working sequences are kept constant by purifyingselection. This is the most likely explanation for the existence of ultraconservednoncoding elements that have survived for more than 100 million years withoutsubstantial 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 codingsequences 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 proteinapproximately intact). At the intermediate level, indels can affect parts of agene or whole groups of genes. At the largest level, whole chromosomes or even wholecopies of the genome can be affected by insertions or deletions, although suchmutations are usually no longer subsumed under the label indel. At this highlevel, it is also possible to invert or translocate entire sections of achromosome, and chromosomes can even fuse or break apart. If a large number ofgenes are lost as a result of one of these processes, then the consequences areusually very harmful. Of course, different genetic systems react differently tosuch events.

Finally, still other sources of mutations are the manydifferent types of transposable elements, which are small entities of DNA that possessa mechanism that permits them to move around within the genome. Some of these elementscopy 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 middleof another gene), activate dormant gene functions (by perfect excision from agene that was switched off by an earlier insertion), or occasionally lead tothe production of new genes (by pasting material from different genes together).

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.

Many direct and indirect methods have been developed to helpestimate rates of different types of mutations in various organisms. The maindifficulty in estimating rates of mutation involves the fact that DNA changesare extremely rare events and can only be detected on a background of identicalDNA. Because biological systems are usually influenced by many factors, directestimates of mutation rates are desirable. Direct estimates typically involve useof 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 manybase pairs within this region of DNA from many individuals in the pedigree,counting all the observed mutations. These observations are then combined withthe number of generations that connect these individuals to compute the overallmutation rate (Haag-Liautard et al.,2007). Such direct estimates should not be confused with substitution ratesestimated over phylogenetic time spans.

Mutation rates can vary within a genome and between genomes.Much more work is required before researchers can obtain more precise estimatesof the frequencies of different mutations. The rise of high-throughput genomicsequencing methods nurtures the hope that we will be able to cultivate a moredetailed and precise understanding of mutation rates. Because mutation is oneof the fundamental forces of evolution, such work will continue to be ofparamount importance.