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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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If all members of a species have the same set of genes, how can there be genetic variation? Asindicated earlier, the answer is that genes come in different forms called alleles. In apopulation, for any given gene there can be from one to many different alleles; however, becausemost organisms carry only one or two chromosome sets per cell, any individual organism can carryonly one or two alleles per gene. The alleles of one gene will always be found in onechromosomal position. Allelic variation is the basis for hereditary variation.

Types of variation

Because a great deal of genetics concerns the analysis of variants, it is important tounderstand the types of variation found in populations. A useful classification is intodiscontinuous and continuous variation (Figure 1-12).Allelic variation contributes to both.


Figure 1-12

Discontinuous and continuous variation in natural populations. In populations showingdiscontinuous variation for a particular character, each member possesses one of severaldiscrete alternatives. For example, in the left-hand panel, a population of (more...)

Most of the research in genetics in the past century has been on discontinuous variationbecause it is a simpler type of variation, and it is easier to analyze. In discontinuous variation, a character is found in apopulation in two or more distinct and separate forms called phenotypes. Suchalternative phenotypes are often found to be encoded by the alleles of one gene. A good exampleis albinism in humans, which concerns phenotypes of the character of skin pigmentation. In mostpeople, the cells of the skin can make a dark brown or black pigment called melanin, thesubstance that gives our skin its color ranging from tan color in people of European ancestryto brown or black in those of tropical and subtropical ancestry. Although always rare, albinosare found in all races; they have a totally pigmentless skin and hair (Figure 1-13). The difference between pigmented and unpigmented is caused bytwo alleles of a gene taking part in melanin synthesis. The alleles of a gene areconventionally designated by letters. The allele that codes for the ability to make melanin iscalled A and the allele that codes for the inability to make melanin(resulting in albinism) is designated a to show that they are related. Theallelic constitution of an organism is its genotype, which is the hereditary underpinning of the phenotype. Because humans havetwo sets of chromosomes in each cell, genotypes can be eitherA/A, A/a, ora/a (the slash shows that they are a pair). The phenotype ofA/A is pigmented, a/a isalbino, and A/a is pigmented. The ability tomake pigment is expressed over inability (A is said to bedominant, as we shall see in (Chapter 2).


Figure 1-13

An albino. The phenotype is caused by two doses of a recessive allele – a/ a. The dominant allele A determines one step in thechemical synthesis of the dark pigment melanin in the cells of skin, hair, and eye retinas.In a / a individuals, this (more...)

Although allelic differences cause phenotypic differences such as pigmented and albino, thisdoes not mean that only one gene affects skin color. It is known that there are several.However, the difference between pigmented, of whatever shade, and albino iscaused by the difference at one gene; the state of all the other pigment genesis irrelevant.

In discontinuous variation, there is a predictable one-to-one relation between genotype andphenotype under most conditions. In other words, the two phenotypes (and their underlyinggenotypes) can almost always be distinguished. In the albinism example, the Aallele always allows some pigment formation, whereas the white allele always results inalbinism when homozygous. For this reason, discontinuous variation has been successfully usedby geneticists to identify the underlying alleles and their role in cellular functions.

Geneticists distinguish two categories of discontinuous variation on the basis of simpleallelic differences. In a natural population, the existence of two or morecommon discontinuous variants is called polymorphism (Greek; many forms), and an example is shown in Figure 1-14a. The various forms are called morphs. It is oftenfound that morphs are determined by the alleles of a single gene. Why do populations showgenetic polymorphism? Special types of natural selection can explain a few cases, but, in othercases, the morphs seem to be selectively neutral.


Figure 1-14

A dimorphism. (a) The fruits of two different forms of Plectritiscongesta, the sea blush. Any one plant has either all wingless or all wingedfruits. In every other way, the plants are identical. (b) A Drosophilamutant with abnormal wings and a normal (more...)

Rare, exceptional discontinuous variants are called mutants, whereas the morecommon “normal” companion phenotype is called the wildtype. Figure 1-14b shows an example of a mutantphenotype. Again, in many cases, the wild-type and mutant phenotypes are determined by thealleles of one gene. Mutants can occur spontaneously in nature (for example, albinos) or theycan be obtained after treatment with mutagenic chemicals or radiations. Geneticists regularlyinduce mutations artificially to carry out genetic analysis because mutations that affect somespecific biological function under study identify the various genes that interact in thatfunction. Note that polymorphisms originally arise as mutations, but somehow the mutant allelebecomes common.


In many cases, an allelic difference at a single gene may result in discrete phenotypicforms that make it easy to study the gene and its associated biological function.

Continuous variation of a character shows anunbroken range of phenotypes in the population (see Figure1-12). Measurable characters such as height, weight, and color intensity are goodexamples of such variation. Intermediate phenotypes are generally more common than extremephenotypes and, when phenotypic frequencies are plotted as a graph, a bell-shaped distributionis observed. In some such distributions, all the variation is environmental and has no geneticbasis at all. In other cases, there is a genetic component caused by allelic variation of oneor many genes. In most cases, there is both genetic and environmental variation. In continuousdistributions, there is no one-to-one correspondence of genotype and phenotype. For thisreason, little is known about the types of genes underlying continuous variation, and onlyrecently have techniques become available for identifying and characterizing them.

Continuous variation is encountered more commonly than discontinuous variation in everydaylife. We can all identify examples of continuous variation in plant or animal populations thatwe have observed – many examples exist in human populations. One area of genetics in whichcontinuous variation is important is in plant and animal breeding. Many of the characters thatare under selection in breeding programs, such as seed weight or milk production, have complexdetermination, and the phenotypes show continuous variation in populations. Animals or plantsfrom one extreme end of the range are chosen and selectively bred. Before such selection isundertaken, the sizes of the genetic and environmental components of the variation must beknown. We shall return to these specialized techniques in Chapter 20, but, for the greater part of the book, we shall be dealing with the genesunderlying discontinuous variation.

Molecular basis of allelic variation

Consider the difference between the pigmented and the albino phenotypes in humans. The darkpigment melanin has a complex structure that is the end product of a biochemical syntheticpathway. Each step in the pathway is a conversion of one molecule into another, with theprogressive formation of melanin in a step-by-step manner. Each step is catalyzed by a separateenzyme protein encoded by a specific gene. Most cases of albinism result from changes in one ofthese enzymes – tyrosinase. The enzyme tyrosinase catalyzes the last step of the pathway, theconversion of tyrosine into melanin.


To perform this task, tyrosinase binds to its substrate, a molecule of tyrosine, andfacilitates the molecular changes necessary to produce the pigment melanin. There is a specific“lock-and-key” fit between tyrosine and the active site of the enzyme. The active site is a pocket formed by several crucial aminoacids in the polypeptide. If the DNA of the tyrosinase-encoding gene changes in such a way thatone of these crucial amino acids is replaced by another amino acid or lost, then there areseveral possible consequences. First, the enzyme might still be able to perform its functionsbut in a less efficient manner. Such a change may have only a small effect at the phenotypiclevel, so small as to be difficult to observe, but it might lead to a reduction in the amountof melanin formed and, consequently, a lighter skin coloration. Note that the protein is stillpresent more or less intact, but its ability to convert tyrosine into melanin has beencompromised. Second, the enzyme might be incapable of any function, in which case themutational event in the DNA of the gene would have produced an albinism allele, referred toearlier as an a allele. Hence a person of genotypea/a is an albino. The genotypeA/a is interesting. It results in normal pigmentationbecause transcription of one copy of the wild-type allele (A) can provideenough tyrosinase for synthesis of normal amounts of melanin. Alleles are termedhaplosufficient if roughly normal function is obtained when there is only asingle copy of the normal gene. Alleles commonly appear to be haplosufficient, in part becausesmall reductions in function are not vital to the organism. Alleles that fail to code for afunctional protein are called null (“nothing”) alleles and aregenerally not expressed in combination with functional alleles (in individuals of genotypeA/a). The molecular basis of albinism is represented inFigure 1-15.

Figure 1-15

Molecular basis of albinism. Expression in cells containing 2, 1, and 0 copies of thenormal tyrosinase allele on chromosome 14. Melanocytes are specialized melanin-producingcells.

The mutational site in the DNA can be of a number of types. The simplest and most common typeis nucleotide-pair substitution, which can lead toamino acid substitution or to premature stop codons. Small deletions and duplication also are common. Even a single basedeletion or insertion produces widespread damage at the protein level; because mRNA is readfrom one end “in frame” in groups of three, a loss or gain of one nucleotide pair shifts thereading frame, and all the amino acids translationally downstream will be incorrect. Suchmutations are called frameshift mutations.

At the protein level, mutation changes the amino acid composition of the protein. The mostimportant outcomes are change in shape and size. Such change in shape or size can result in nobiological function (which would be the basis of a null allele), or reduced function. Morerarely, mutation can lead to new function of the protein product.


New alleles formed by mutation can result in no function, less function, or new function atthe protein level.

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