An individual's genotype is the composition, in the individual's genome, of a specific region of DNA that varies within a population. (The genome of the individual is the total collection of the DNA in a cell's chromosomes. It includes all of the individual's genes, as well as the DNA sequences that lie between them.)
A genotype could represent a single DNA nucleotide, at a specific location on a chromosome. It could also be a sequence repeated multiple times, a large duplication, or a deletion. Most variation in genotypes does not cause any difference in the proteins being produced by the cell, because genes, which code for proteins, occupy only about 2 percent of the total genome. However, when a specific genotype does affect the composition or expression of a protein, disease or changes in physical appearance can result. The physical effect of a particular genotype is known as its phenotype, or trait.
Alleles, Polymorphisms, and Mutations
An individual genotype is composed of two distinct parts, the inherited sequences from the maternal and paternal genomes. Therefore, for every genotype, there are two copies of the sequence. For genes, we refer to these individual sequence copies on each chromosome that make up a genotype as the two alleles. Alleles may be identical or different, and various combinations of alleles can create a range of phenotypes.
A DNA change within a gene may or may not alter the protein that is encoded by the gene. If the change contributes to normal genetic variability and is found in more than 1 percent of the population being studied, the variation is called a polymorphism. Variations in a gene that modify, seriously disrupt, or prevent the functioning the encoded protein are called mutations. The effect of a mutation can range from harmless to harmful depending on the type of mutation.
One type of sequence variation is the substitution of one nucleotide for another, which can thus affect the three base-pair unit (codon) that codes for a specific amino acid. In some cases, where the substitution does not change the amino acid, the result is a neutral or silent mutation. A substitution that alters the coding sequence, and thus substitutes a different amino acid, is called a missense mutation. This type of mutation can have a beneficial effect whereby there is a positive gain of function for the protein, it can also have a drastically negative effect and result in loss of function or the gain of a new function that is deleterious to the organism. By far the most severe change is a nucleotide substitution that creates a stop codon where one should not be. This phenomenon, called a nonsense mutation, will prevent the full formation of the protein. A nonsense mutation can completely abolish the function of the protein, which can be lethal to the organism if the protein is essential for sustaining a key biological process.
Dominant, Codominant, and Recessive Genes
Differences in phenotype can result from differences in genotype. Two individuals may have different bases at a particular location in the coding region of a gene. While this will result in different codons in that part of the sequence, the two different codons may code for the same amino acid, which will in turn result in the same protein. Thus it can be said that the two individuals have different genotypes in their DNA, but that their phenotypes are identical. This example illustrates the first factor one must look for in predicting phenotypes: how the genotype affects the translation of DNA.
The second factor is the inheritance pattern of the genotype. If each parent transmits an identical gene sequence, A, to a child, then the genotype of the offspring will be AA. This is called a homozygous genotype. However, if the child inherits a different allele, a, from one of the parents, then its resulting genotype, Aa, contains two different sequences. Such genotypes are called heterozygous.
An Aa genotype can result in the same phenotype as either an AA or aa genotype, if one of the alleles acts in a dominant fashion. If the A allele is dominant over the a allele, then the phenotype of a heterozygous (Aa) individual will be the same as the phenotype of a homozygous dominant (AA) individual.
Huntington's disease, a nervous system disorder, follows a dominant inheritance pattern. The presence of one mutated Huntington gene will result in the conditions of the disease. Even if a patient has one normal Huntington gene on another chromosome, one mutated copy is enough to produce Huntington's disease. Thus, the Huntington allele is said to be dominant over the normal allele.
Another type of inheritance pattern is called recessive. Here, two copies of the mutant allele, a, must be inherited (resulting in genotype aa) to cause a change in phenotype. This is exemplified by cystic fibrosis, a recessive disorder marked by digestive and respiratory problems. In this case a heterozygous individual (genotype Aa) who carries one copy of the faulty gene will not display clinical symptoms, because the normal gene is dominant over the CFTR gene. The normal gene is able to express the protein that epithelial cells need for transporting chloride. If two parents are heterozygous for the mutated cystic fibrosis gene, there is a 25 percent chance that their child will inherit a mutated copy from each parent and will have the disease. Heterozygous carriers, who live normal lives, pass on the mutant gene to half of their children, enabling it to stay within the population for generations and to persist at relatively high frequencies.
Although it is convenient to illustrate inheritance concepts by talking about diseases, if we consider the diversity of phenotypes expressed by all organisms in the living world it is obvious that not all variation is bad and most genetic changes do not lead to disease.
Multiple Alleles and Pleiotropy
Some genetic loci are multiallelic, having more than one allele that will manifest in a variety of phenotypes. In most mammal species, for example, the immune response genes of the major histocompatibility complex are extremely polymorphic—meaning that there are many different alleles at each gene locus. The combination of alleles in each individual may result in either susceptibility or resistance to specific disease-causing agents.
The human blood group system is another example of multiple alleles resulting in many different phenotypes. The genes that determine ABO blood type encode enzymes that add particular sugar groups to proteins in blood cells. A person's specific blood type is due to the presence or absence of A and B sugar-protein complexes on the surface of red blood cells.
There are three alleles involved, A, B, and O, and six possible genotypes: AA, BB, OO, AB, AO, and BO. The various genotypes result in four different phenotypes or blood types: A, B, O, and AB. Individuals have blood type A if their genotypes are AA or AO. Individuals have blood type B if their genotypes are BB or BO. Individuals have blood type O if their genotype is OO, and they have blood type AB if their genotype is AB.
Many of these examples describe the concept of genotype and phenotype in terms of proteins or diseases that have been thoroughly analyzed by scientists. However, genotypic differences are abundant in nature and are evident in the most extraordinary ways.
A small mutation in a viral gene may make an otherwise harmless strain of the influenza virus capable of causing disease or even death. Other genetic variations in mammals, including humans, may influence aggression or other social interactions.
Some genes affect more than one unrelated characteristic. These genes are said to be pleiotropic. One gene, for example, produces melanin, which is responsible for skin pigmentation and is also involved in nerve pathways. If there is a certain mutation in the melanin gene, no melanin will be produced. In humans, this condition, called albinism, causes white skin and, usually, vision problems. In domestic cats, it causes a white-hair, blue-eye phenotype along with hearing loss.
In the past, scientists thought that pleiotropic genes were unusual. However, the Human Genome Project has shown that humans have only about one-third of the number of genes that was predicted. It is now believed that most genes are pleiotropic, serving many functions.
—Joelle van der Walt and Jeffery M. Vance
