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3.5Genetic Mutations and Dominance/Recession

As shown in section 2, traits found in human bodies are mostly dominant traits and recessive traits are seldom observed. Individuals with dominant traits constitute the majority of a population and are called “wildtype.” Let us now understand how dominant and recessive traits are determined. This topic will be explained in greater detail in Chapters 610. Genes that determine traits contain information on protein structure. Although this is an oversimplification, the specific protein formed on the basis of the information possessed by a specific gene determines a specific trait in an organism. The observable characteristics determined by specific genes are called the phenotypes of the genes.

Fig. 3-3 Loss-of-function and Phenotypes

The various abnormalities that occur in genes are called “mutations.” Let us consider what happens when the wild-type gene A is mutated to the mutant-type gene a. As a result of mutation, the protein encoded by the gene might lose its functions. This is called loss-of-function due to a genetic mutation. On the other hand, mutation might lead to loss of the gene, and thus, the protein might not even be formed. Loss of the function of the protein encoded by the wild-type gene may have various negative effects, both morphological and functional, on the phenotype. However, in the cells of an individual carrying both the “normal” (wild-type) gene A and mutant gene a (heterozygous), the normal protein is encoded by gene A and therefore the phenotype often expressed is basically normal (wild-type phenotype) (Fig. 3-3). If the genotype is AA, then the wild-type phenotype is certainly expressed. However, the wild-type phenotype is also expressed, if the genotype is Aa. This shows that gene A is dominant over gene a and gene a is recessive to gene A. A mutant phenotype is only expressed when the genotype is aa, i.e., the recessive phenotype appears only in homozygotes. When both parents have the genotype Aa, then the phenotype in both parents is wild-type. However, if offspring carrying the aa genotype are born, then they will exhibit a recessive trait (Fig. 3-3). Moreover, the phrases dominant and recessive only represent the differences in which traits are expressed in heterozygotes, and they do not necessarily define a trait as being superior or inferior.

The phrases wild-type and mutant are used for both genotypes and phenotypes. A is used to represent a wild-type genotype, and a is used to represent a mutant genotype. Wild-type refers to the phenotype of an individual (cell) with the AA or Aa genotype, while mutant refers to the phenotype of an individual (cell) with the aa genotype.

The effect of a genetic mutation varies according to mutation type, degree of loss of function, and importance of the relevant protein. If the gene is critical for survival, then individuals with a loss-of-function mutation may die during development and might not even be born (embryonic lethality). With regard to human genetic disease, individuals experience a comparatively large influence of the functional loss due to a recessive gene (e.g., phenylketonuria or muscular dystrophy). Thus, when the mutant phenotype is disadvantageous to survival, the wild-type phenotype accounts for the majority of the population and the mutant phenotype is exceedingly rare. In contrast, if the resulting change to the protein encoded by the mutated gene does not have any problematic effects, then the presence of the mutation may go unnoticed. Moreover, although brown eyes and curly hair are dominant over green eyes and straight hair, these traits are totally unrelated to any advantage or disadvantage to survival. The ABO blood type was also formed by genetic mutation, but it caused no change in the advantage to survival. Thusss, mutations in genes that have little impact on survival often lack an overwhelming majority (wild-type) for any trait. When the lesser trait represents more than 1% of the population, it is called “polymorphism” instead of mutation.

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Phenylthiocarbamide and Bitterness

At the beginning of the 20th century, Arthur Fox noticed that some individuals taste bitterness and some are completely unable to taste bitterness (the ratio of the former to the latter was 3:1) on tasting phenylthiocarbamide (PTC). This is one of the first inherited human traits to be reported; however, for a long time the reasons for this trait were unclear.
Bitterness is perceived by a group of receptors generally called T2RX (where X is a number; there are total 25 receptors) in humans. For example, human T2R16 responds to any bitter substance that has a certain structure attached to sugar. Each of the 25 receptors shows a slightly different reactivity to different bitter substances, and the brain is able to discern different bitter tastes. Research has shown that the receptor of PTC is T2R38. This receptor may also be activated by bitter molecules with the structure N-C=S (commonly found in the Brassicaceae). T2R38 is a protein that consists of 333 amino acids, but sensitivity to PTC is determined by the difference in only three amino acids of these 333 amino acids. When the N terminus of this protein is composed of amino acids proline, alanine, and valine at positions 49, 262, and 296, respectively, the individual perceives bitterness (the individual is referred to as the PAV type, the initials of the amino acids), whereas when the amino acids at these locations are alanine, valine, and isoleucine, the individual does not perceive bitterness (the individual is referred to as the AVI type, the initials of the amino acids). A heterozygous individual with one each of PAV and AVI genes has a significantly lower sensitivity to PTC than an individual with two PAV genes, and thus, the individual exhibits an intermediate type of the trait. PTC sensitivity is therefore an example of a dominant inherited trait that actually exhibits incomplete dominance.

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Maternal Inheritance Incongruous with Mendel’s Laws

Mitochondria found in cells are known to show maternal inheritance. This is because mitochondria found in sperm do not penetrate into the egg during fertilization, and even if they do accidentally penetrate it, the egg is provided with a mechanism to immediately decompose them. Therefore, all mitochondria in the fertilized egg are of maternal origin.
This fact can be used to trace an individual’s ancestry. Mitochondria contain circular DNA (see Chapter 24). By tracing mutations in 16,569 base pairs, the ancestry of a modern man has been traced to a single woman who lived in Africa 150,000 to 200,00 years ago (male ancestry can be determined by tracing the Y chromosomes found only in males). Moreover, because mitochondrial DNA of a child and the maternal grandmother is the same, parental testing becomes possible.
In addition, mitochondrial DNA has a higher frequency of errors than nuclear DNA. This is believed to be caused by factors such as greater number of DNA replications and the fact that mitochondrial DNA is more frequently exposed to reactive oxygen species. Mutations in mitochondrial DNA may result in extremely severe diseases of the brain and muscles, which are collectively termed mitochondrial myopathy (mitochondrial neuromuscular disorders). If a female has such a disorder, it may be inherited by all her offspring. This is because the female’s mitochondria, regardless of whether the child is male or female, are always inherited. However, spindle transfer (nuclear DNA transplantation) technology could be used to avoid these disorders (Column Fig. 3-1). Avoiding these genetic diseases is no longer in the realm of science fiction. By removing the nucleus from the female’s egg, transplanting it in a denucleated egg of another female, and then fertilizing it with the father’s sperm, one can conceive a child free of genetic diseases.

Column Fig. 3-1 Treatment of Mitochondrial Neuromuscular Diseases with Nuclear Transplantation

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