Genetic mutations

In all living organisms, the hereditary information consists of two complementary strands of deoxyribonucleic acid, or DNA. DNA strands are constructed of subunits called nucleotides that consist of a nitrogenous base, a deoxyribose sugar, and a phosphate. Generally, DNA strands consist of millions of nucleotides attached to each other like the links of a chain. There are four different nucleotides found in DNA: adenine (A), thymine (T), guanine (G), and cytosine (C). Each nucleotide bonds only to one other type of nucleotide, known as its complementary base. The two DNA strands are held together by hydrogen bonds between complementary bases. Adenine and thymine form one complementary pair, and guanine and cytosine form the other. In other words, if there is an adenine molecule in one strand, it is hydrogen bonded to thymine in the complementary strand; if there is guanine in one strand, it is hydrogen bonded to cytosine in the other strand. Thus, the amount of A is equal to T, and the amount of G is equal to C. The order of nucleotides in a strand specifies the order of the amino acids that make up proteins.

Genetics is the study of how the information in DNA molecules is expressed and how DNA molecules account for the heredity of an organism. Changes in the sequence of nucleotides in DNA may alter an organism’s proteins, which in turn may change one or more of that organism’s traits. DNA changes are called mutations, and the organisms that harbor mutations are known as mutants. The original or naturally occurring version of such a trait or organism is referred to as the “wild type.” The characterization of mutations and mutants has been and still is one of the best ways of discovering the function of genes and determining how organisms maintain themselves, evolve, and develop. A study of mutations and mutants also has shed light on numerous genetic diseases.

Heat: The Cause of Most Spontaneous Mutations

Most mutations are caused by the instability of the nucleotide bases. Sometimes bases hit by rapidly moving water molecules briefly alter their chemistry. These chemical changes are known as tautomeric shifts. Tautomeric shifts alter the distribution of electrons and protons in the bases, causing them to form abnormal pairings with bases in the complementary strand. For example, an abnormal adenine (A*) pairs with C, rather than T, and an abnormal guanine (G*) pairs with T rather than C.

When a DNA molecule is being replicated, spontaneous tautomer shifts can result in permanent mutations. Spontaneous mutations occur, for example, when an A in the template strand undergoes a tautomer shift (A→A*) just as the DNA polymerase reaches it. A cytosine pairs with the A* and becomes part of the new strand being synthesized by the DNA polymerase. When this new strand, with a C in it instead of a T, functions as a template, the complementary strand will have a G in it rather than an A. This type of tautomeric shift during DNA replication converts what normally would have been an A·T base pair in “granddaughter” DNA to a G·C base pair.

Chemicals That Cause Mutations

Mutations are induced by many chemical and physical agents called mutagens. Many chemicals act as mutagens. Nitrous acid, for example, diffuses into cells and removes amino groups from DNA bases. These chemically altered bases no longer pair normally. When DNA is replicated or repaired, incorrect nucleotides are inserted opposite the chemically altered bases. Nitrous acid changes A to hypoxanthine, which pairs with C, and changes G to xanthine, which pairs with T.

Base analogues are molecules that closely resemble normal nucleotides and consequently are incorporated into DNA that is being repaired or replicated. A base analogue to thymine, such as 5-bromouracil (5BU), is efficiently incorporated into DNA. 5BU spontaneously undergoes tautomeric shifts at a high rate. The abnormal form of 5BU pairs with G rather than A. Thus, 5BU introduces many base-pair transitions in newly synthesized DNA molecules.

The most potent mutagens are alkylating agents, such as nitrosamines, methyl bromide, and ethylene oxide. These mutagens attach methyl or ethyl groups (alkyl groups) to A and G. This causes A and G to undergo tautomeric shifts at a higher-than-normal rate.

High-Energy Electromagnetic Radiation and Particles

Ultraviolet (UV) light is a powerful mutagen. It generally penetrates cells but is readily absorbed by thymine and cytosine bases in DNA. When two thymines or two cytosines next to each other in a strand absorb UV light, they often react chemically with each other to form thymine or cytosine dimers that distort the DNA. These distorted regions stimulate a repair system that cuts out the dimers, as well as some DNA on either side, and replaces them with normal nucleotides. Excessive repair leads to an increased occurrence of spontaneous mutations. Sometimes a distortion in the template allows the DNA polymerase to add or to leave out nucleotides as it moves along the template during strand synthesis. This may explain how some additions and some deletions occur.

Very energetic electromagnetic radiation, such as X-rays and gamma rays, as well as high-energy particles released from radioactive atoms, also induce mutations. These energetic mutagens easily penetrate cells and chemically alter many molecules in their path by stripping away electrons. Ions and radicals formed by these mutagens react with the DNA, causing bases to be released and DNA to break. DNA deletions, transpositions, and inversions may be promoted by DNA breakage.

When a gene is mutated, the protein the gene codes for generally becomes nonfunctional. In bacteria that have only one copy of each gene, traits are immediately altered by a mutation. However, in organisms that have more than one copy of a gene, a mutation in only one gene may not produce a new trait because the wild-type (normal) gene often provides enough of the essential protein. When such organisms are missing both genes, however, they may fail to develop, or they may develop in a different way.

A few mutations are beneficial to the organism that acquires them and may make the organism better adapted to its environment. These beneficial mutations may make a protein work a little better or in a different way. Some mutations are also beneficial because they create diversity in a population. Diversity promotes the survival of a population by ensuring that some organisms will survive if the environment drastically changes. A population that is too well adapted to a particular environment will not survive if there are significant changes in the environment. There have been at least five major mass extinctions during the history of life on Earth, in some cases eliminating more than 85 percent of all species. The organisms that survived these mass extinctions were much less specialized than the organisms that did not.

Usefulness of Mutations

Mutations have been extremely useful in the study of organisms. Mutations allow scientists to understand what a particular gene and its product do. If the mutation eliminates the gene (and product), scientists can guess what the gene does by looking at the affected organism. For example, if a mutation changes eye color, such as from red to white, the affected gene most likely has something to do with pigment synthesis or deposition of the pigment in the eye.

The study of mutations and mutant organisms has helped scientists unravel anabolic (synthetic) and catabolic (degrading) pathways, determine how parental genes combine to produce new characteristics in progeny, clarify what genes are and what they do, establish how genes are regulated, and even decipher how multicellular organisms develop and evolve.

Mutations in Development and Evolution

The study of mutations and mutant organisms at the end of the twentieth century led to an understanding of how multicellular organisms develop and evolve. One of the most useful organisms in unraveling the development problem has been the small fruit fly Drosophila melanogaster. Thousands of mutations that affect the development of this organism have been characterized. Scientists found that a hierarchy of genes are involved in development. First, maternal genes are expressed. These genes activate gap genes, which in turn activate pair-rule genes. All these gene categories are known to be involved in regulating the expression of homeotic genes. Maternal, gap, pair-rule, and homeotic gene products all function as transcriptional activators and repressors. For example, the maternal gene product called bicoid stimulates its own synthesis, and it also inhibits the synthesis of another maternal-effect gene product called nanos.

Maternal Genes→Gap Genes→Pair Rule Genes→Homeotic Genes

This gene hierarchy is responsible for the anterior-posterior segmentation seen in Drosophila. Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus shared the 1995 Nobel Prize in Physiology or Medicine for their studies of the genes that control Drosophila development.

Homeotic genes are found in all multicellular organisms. Homeotic genes similar to those found in Drosophila control the development of segments, most visibly exemplified by the vertebrae and the bones in animals’ appendages. Mutations in homeotic genes or their controlling sites affect the development of segments. Segments can be eliminated or modified by homeotic-gene-controlling site mutations.

One well-studied homeotic gene in Drosophila is the gene Antennapedia (Antp). Certain mutations in the controlling sites for this gene result in legs developing rather than head antennae. Another homeotic gene is Ultrabithorax (Ubx). Some mutations in the controlling sites for Ubx result in a second pair of wings developing where the fly would normally develop halteres, or tiny, winglike appendages that promote stable flight. Other mutations in the controlling sites for Ubx produce a second pair of winglike structures that are half haltere (anterior portion), half wing (posterior portion). By studying mutations and the altered traits, scientists have discovered that controlling-site mutations change when and where proteins are synthesized. For example, if a protein is to be produced in seven segments along the anterior-posterior axis of an animal, there must be at least seven different controlling sites that can respond to the different activators and repressors produced in each segment.

Numerous studies suggest that Antp and Ubx are transcriptional repressor-activators that not only repress the development of legs and wings but also stimulate the development of antennae and halteres, respectively. The study of Drosophila mutants is beginning to clarify how antennae and mouthparts evolved from leglike appendages and how halteres evolved from wings. The study of genes and controlling sites has led to the understanding of their role in the maintenance, development, and evolution of every organism.

In the twenty-first century, researchers identified genetic mutations that contribute to brain disorders like epilepsy and Alzheimer's disease. Another study found that animals, regardless of life span, size, and species, have similar genetic mutations at the end of their lives. For example, each year, giraffes are estimated to have ninety-nine genetic mutations, while lions have 160 and mice have slightly under 800 on average. Humans have less than fifty. However, because of the life expectancy and aging process differences between species, the total mutations in each animal are about equal for most species by the time they die. This finding supports the theory that somatic mutations are significant in animal and human aging and that our genetic code mutations are linked to lifespan. However, this does not consider the germline mutation rate between species, which researchers have found to be lower in mammals than in birds and reptiles.

Principal Terms

Allele: One of many possible sequences of a gene

Controlling site: A sequence of nucleotides generally fifteen to sixty nucleotides long, to which a transcriptional activator or repressor binds

Gene: A sequence of one thousand to ten thousand nucleotides, which usually specifies a protein

Mutation: A change in the nucleotide sequence of a gene or of a controlling site; changes in genes alter the protein, whereas changes in controlling sites determine where and how much of a protein is produced

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