Biochemical mutations

SIGNIFICANCE: The study of the biochemistry behind a particular phenotype is often necessary to understand the modes of inheritance of mutant genes. Knowledge of the biochemistry of mutant individuals is especially useful in determining treatments for genetic diseases.

Proteins and Simple Dominant and Recessive Alleles

In order to understand how certain genotypes are expressed as phenotypes, knowledge of the biochemistry behind is essential. It is known that the various sequences of nucleotides in the DNA of genes code for the amino acid sequences of proteins. How the proteins act and interact in an organism determines that organism’s phenotype.

Simple dominant and recessive alleles are the easiest to understand. For example, in the genetic disease phenylketonuria (PKU), two alleles of the PKU locus exist: p⁺, which codes for phenylalanine hydroxylase, an enzyme that converts phenylalanine (a common amino acid in proteins) to tyrosine (another common amino acid); and p, which is unable to code for the functional form of the enzyme. Individuals with two normal alleles, p⁺p⁺, have the enzyme and are able to perform this conversion. However, individuals with two abnormal alleles, pp, do not have any of this enzyme and are unable to make this conversion. Since phenylalanine is not converted to tyrosine, the phenylalanine accumulates in the organism and eventually forms phenylketones, which are toxic to the nervous system and lead to intellectual disability. The heterozygote, p⁺p, has one normal and one abnormal allele. These individuals have phenylalanine and tyrosine levels within the normal range, since the enzyme can be used over and over again in the conversion. In other words, even when only one normal allele is present, enough enzyme is produced for the conversion to proceed at the maximum rate.

Many other inborn errors of metabolism follow this same pattern. In the case of albinism, for example, affected individuals are missing the enzyme necessary to produce the brown-black melanin pigments. Galactosemics are missing an essential enzyme for the breakdown of galactose.

Other Single-Gene Phenomena

Many other genetic phenomena can be explained by looking at the biochemistry behind them. For example, the “chinchilla coat” mutation in rabbits causes a gray appearance in the homozygous state, c^chc^ch. This occurs because the c^ch allele codes for a pigment enzyme that is partially defective. The partially defective enzyme works much more slowly than the normal enzyme, and a smaller amount of pigment is produced, leading to the gray phenotype. When this allele is with the fully defective c allele, c^chc, there is only half as much of an enzyme that works very slowly. As one might expect, there is less pigment produced, and the is an even lighter shade of gray called light chinchilla. The enzyme concentration does affect the rate of the reaction and, ultimately, the amount of product made. This phenomenon is known as incomplete, or partial, dominance. Genes for the red pigments in such flowers as four o’clocks (Mirabilis jalapa) and snapdragons show incomplete dominance, as do the hair, skin, and eye pigment genes of humans and the purple pigment genes of corn kernels.

Sometimes a mutation occurs that, instead of creating a defective enzyme, creates an enzyme with a different function. The B allele in the ABO blood-group gene codes for an enzyme that adds galactose to a short sugar chain that exists on the blood cell’s surface, forming the B antigen. The A allele codes for an enzyme that adds N-acetylgalactosamine to the same previously existing sugar chain, forming the A antigen. Anyone with two B alleles, I^BI^B, makes only the B antigen and thus has type-B blood. Those with two A alleles, I^AI^A, make only the A antigen and thus are type A. Heterozygotes, I^AI^B, have the enzymes to make both antigens, and they do. Since they have both antigens on their blood cells, they are classified as type AB. This phenomenon is known as codominance and is also seen in other blood-type genes.

Biochemistry can also explain other single-gene phenomena, such as the pigmentation pattern seen in Siamese cats and Himalayan rabbits. The Siamese-Himalayan allele codes for an enzyme that is so unstable that it falls apart and is completely nonfunctional at the normal body temperature of most mammals. Only at cooler temperatures can the enzyme retain its stability and function. Since mammals have lower temperatures at their extremities, it is there that the enzyme produces pigment; at more centrally located body areas, it cannot function. This leaves a pattern of dark pigmentation on the tail, ears, nose, feet, and scrotum, with no pigmentation at other areas.

Multiple-Gene Phenomena

Few genes act completely independently, and biochemistry can be used to explain gene interactions. One simple interaction can be seen in fruit-fly eye pigmentation. There are two separate biochemical pathways to make pigment. One produces the red pteridines, and the other produces the brown omochromes. If b is an allele that cannot code for an enzyme necessary to make red pigments, a bbr⁺r⁺ fly would have brown eyes. If r is an allele that cannot code for an enzyme necessary to make brown pigment, a b⁺b⁺rr fly would have red eyes. When mated, the resulting progeny would be b⁺br⁺r. They would make both brown and red pigments and have the normal brick-colored eyes. Interbreeding these flies would produce some offspring that were bbrr. Since these offspring make neither brown nor red pigments, they would be white-eyed.

Another multigene phenomenon that is seen when looking at the genes of enzymes that are in the same is epistasis. Consider the following pathway in dogs:

colorless → brown → black

The a⁺ allele codes for the enzyme that converts colorless to brown, but the a allele cannot, and the b⁺ allele codes for the enzyme that converts brown to black, but the b allele cannot. The phenotype of an organism that is aab⁺b⁺ depends only on theaa genotype, since an aa individual produces no brown and the b⁺b⁺ enzyme can make black only by converting brown to black. The cross a⁺ab⁺b × a⁺ab⁺b would be expected to produce the normal 9a⁺‗b⁺‗ (black) : 3a⁺bb‗ (brown) : 3aab⁺‗ (white) : 1aabb (white) phenotypic ratio of the classic dihybrid cross, but this is more appropriately expressed as 9 black : 3 brown : 4 white ratio. (The symbol “‗” is used to indicate that the second gene can be either dominant or recessive; for example, A‗ means that both AA and Aa will result in the same phenotype.) Other pathways give different epistatic ratios, such as the following pathway in peas:

white → white → purple

If A codes for the first enzyme, B codes for the second enzyme, and a and b are the nonfunctional alleles, both AAbb and aabb are white. Their progeny when they are crossed, AaBb, is purple because it has both of the enzymes in the pathway. Interbreeding the AaBb progeny gives a ratio of 9 purple to 7 white.

Human pigmentation is another case in which many genes are involved. In this case, the various genes determine how much pigment is produced by nonalbino individuals. Several gene loci are involved, and the contributions of each allele of these loci is additive. In other words, the more functional alleles one has, the darker the pigmentation; the fewer one has, the lighter. Since many of the genes involved for skin, eye, and hair color are independent, ranges of color in all three areas are seen that may or may not be the same. In addition, there are genes that code for enzymes that produce chemicals that modify the expression of the pigment genes (for example, to change blue eyes to gray, convert hazel eyes to green, or change brown hair to auburn). This gives rise to the great diversity of pigmentation in humans. To these many possible expression patterns at the biochemical level, add the effect of the environment, and it is clear why such great variation in phenotypic expression is possible.

Key Terms

• allelea form of a gene at a specific gene locus; a locus in an individual organism typically has two alleles
• biochemical pathwaythe steps in the production or breakdown of biological chemicals in cells; each step usually requires a particular enzyme
• genotypethe genetic characteristics of a cell or organism, expressed as a set of symbols representing the alleles present
• heterozygousa genotype in which a locus has two alleles that are different
• homozygousa genotype in which a locus has two alleles that are the same
• phenotypeexpressed or visible characteristics of a genotype; different genotypes often are expressed as different phenotypes but may have the same phenotype

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