Gene Mutation

The term mutation was originally coined by Dutch botanist Hugo De Vries (1848–1935) to describe a new approach to explain evolution, although it is quite different than the current definition. De Vries discovered new forms of the Evening Primrose (Oenothera lamarcklana) that were growing in a meadow. He attributed these new varieties and the method for which new species arise to what he called mutations. As a result of his observations, Gregor Mendel's principles of heredity were rediscovered and helped to explain variability within and between species.

Today, technological advances in deoxyribonucleic acid (DNA) analysis have provided scientists with tools to rapidly sequence the human genome. One of the main benefits of this technology is to identify mutations or alterations in the DNA sequence that might be associated with disease. A growing field called bioinformatics is becoming a useful field in understanding and identifying gene mutations by addressing the computational challenges of analyzing the large amount of sequencing data. DNA chips or microarrays have also recently emerged with applications that involve whole-genome scanning mutation detection.

There are many different types of mutations in the human genome and are either considered major gene rearrangements or point mutations, both of which are discussed in more detail below. Major gene rearrangements involve DNA sequences that have deletions, duplications, or insertions. Point mutations are single substitutions of a specific letter of the DNA alphabet (i.e. adenine, guanine, cytosine, or thymine). Alterations in the DNA sequence can result in an alteration of the protein sequence, expression, and/or function.

Genes represent the basic hereditary unit that allows species to pass its information from one generation to the next. The human gene pool is the set of all genes carried within the human population. Genetic changes (including mutations) can be beneficial, neutral or deleterious. Beneficial mutations are less common and result in a selective survival advantage for a particular gene, cell, or whole organism. Beneficial mutations can become integrated into the human gene pool, particularly when it allows an organism to live longer or to reproduce. Neutral gene mutations usually involve point mutations that do not change the amino acid sequence or affect transcription/translation. Deleterious mutations are gene mutations leading to alterations in gene expression or protein function that results in human disease or is fatal. Recombination, or the crossing over and exchange of information between chromosomes during meiosis, can lead to gene rearrangements if the chromosomes are paired inappropriately.

Point mutations within a gene can be nonsense mutations (early termination of protein synthesis), missense mutations (a mutation that results an a substitution of one amino acid for another in a protein), or silent mutations that cause no detectable change in the corresponding protein sequence. Accordingly, the effects of point mutations range from 100% lethality (usually early in fetal development) to no observable (phenotypic) change.

There are four main types of genetic rearrangements: deletions, duplications, inversions, and translocations that are often caused by chemical and radioactive agents. Deletions result in the loss of DNA or a gene. Deletions can involve either the loss of a single base or the loss of a larger portion of DNA. Duplications can result in multiple copies of genes, and are caused most commonly by unequal crossover or chromosome rearrangements. During crossing over in meiosis, misaligned chromosomes can result in one of the chromsomes having extra material (duplication), while the other loses the same material that is duplicated in the other chromosome (deletion). Inversions, or changes in the orientation of chromosomal regions, may cause deleterious effects if the inversion involves a gene or an important sequence involved in the regulation of gene expression. Translocations are a type of rearrangement that occurs when a portion of two different chromosomes (or a single chromosome in two different places) breaks and rejoins such that the DNA sequence or gene is lost, repeated, or interrupted. If this affects the sequence of a gene or genes, it can result in disease.

The frequency of a mutation in a given population may be strikingly different from another population. There are many reasons for this including gene flow, genetic drift, and natural selection. Gene flow occurs when individuals move from one place to another. These migrations allow the introduction of new variations of the same gene (alleles) when they mate and produce offspring with members of their new group. In effect, gene flow acts to increase the gene pool in the new group. Because genes are usually carried by many members of a large population that have undergone random mating for several generations, random migrations of individuals away from the population or group usually do not significantly change the gene pool of the group left behind.

Genetic drift is represented by fluctuations in gene frequencies and occurs by chance, usually in very small populations, or due to sampling errors. During reproduction, one allele (one form of a gene) is passed to the next generation while the other is not. The allele that is not passed on, by chance, can affect the gene frequency if the population is very small. Random genetic drift can occur as a result of sampling error. Genetic drift can be profoundly affected by geographical barriers, catastrophic events (i.e. natural disasters or wars that significantly affect the reproductive availability of selected members of a population), as well as other political-social factors.

Natural selection is based upon the differences in the viability and reproductive success of different genotypes with a population (differential reproductive success). If a gene mutation results in the ability of an organism to live longer by protecting it from environmental threats or allowing it to become more reproducible, than this mutation will have a survival advantage.

There are three basic types of natural selection. Directional selection occurs when an extreme phenotype is favored (high or low body fat). Stabilizing selection takes place when intermediate phenotype is fittest (e.g., neither too high nor too low a body fat content) and for this reason it is often referred to as normalizing selection. Disruptive selection occurs when two extreme phenotypes are better that an intermediate phenotype. In studying changes in the human genome, natural evolutionary mechanisms are complicated by geographic, ethnic, religious, and social groups and customs. Accordingly, the effects of various evolution mechanisms on human populations are not as easy to predict. Increasingly sophisticated statistical studies are carried out by population geneticists to characterize changes in the human genome.