Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function

A fundamental genetic difference between experimental organisms is whether their cells carry a single set of chromosomes or two copies of each chromosome. The former are referred to as haploid; the latter, as diploid. Complex multi-cellular organisms (e.g., fruit flies, mice, humans) are diploid, whereas many simple unicellular organisms are haploid. Some organisms, notably the yeast Saccharomyces, can exist in either haploid or diploid states. Many cancer cells and the normal cells of some organisms, both plants and animals, carry more than two copies of each chromosome. However, our discussion of genetic techniques and analysis relates to diploid organisms, including diploid yeasts.

Since diploid organisms carry two copies of each gene, they may carry identical alleles, that is, be homozygous for a gene, or carry different alleles, that is, be heterozygous for a gene. A recessive mutant allele is defined as one in which both alleles must be mutant in order for the mutant pheno-type to be observed; that is, the individual must be homozy-gous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutant allele are observed in a heterozygous individual carrying one mutant and one wild-type allele (Figure 9-2).

Whether a mutant allele is recessive or dominant provides valuable information about the function of the affected gene and the nature of the causative mutation. Recessive alleles usually result from a mutation that inactivates the affected gene, leading to a partial or complete loss of function. Such recessive mutations may remove part of or the entire gene from the chromosome, disrupt expression of the gene, or alter the structure of the encoded protein, thereby altering its function. Conversely, dominant alleles are often the consequence of a mutation that causes some kind of gain of function. Such dominant mutations may increase the ac

▲ FIGURE 9-2 Effects of recessive and dominant mutant alleles on phenotype in diploid organisms. Only one copy of a dominant allele is sufficient to produce a mutant phenotype, whereas both copies of a recessive allele must be present to tivity of the encoded protein, confer a new activity on it, or lead to its inappropriate spatial or temporal pattern of expression.

Dominant mutations in certain genes, however, are associated with a loss of function. For instance, some genes are haplo-insufficient, meaning that both alleles are required for normal function. Removing or inactivating a single allele in such a gene leads to a mutant phenotype. In other rare instances a dominant mutation in one allele may lead to a structural change in the protein that interferes with the function of the wild-type protein encoded by the other allele. This type of mutation, referred to as a dominant negative, produces a phenotype similar to that obtained from a loss-of-function mutation.

aSome alleles can exhibit both recessive and dominant properties. In such cases, statements about whether an allele is dominant or recessive must specify the phenotype. For example, the allele of the hemoglobin gene in humans designated Hbs has more than one phenotypic consequence. Individuals who are homozygous for this allele (HbVHb) have the debilitating disease sickle-cell anemia, but heterozygous individuals (Hbs/Hba) do not have the disease. Therefore, Hbs is recessive for the trait of sickle-cell disease. On the other hand, heterozygous (Hbs/Hba) individuals are more resistant to malaria than homozygous (Hba/Hba) individuals, revealing that Hbs is dominant for the trait of malaria resistance. I

A commonly used agent for inducing mutations (muta-genesis) in experimental organisms is ethylmethane sul-fonate (EMS). Although this mutagen can alter DNA sequences in several ways, one of its most common effects is to chemically modify guanine bases in DNA, ultimately leading to the conversion of a G • C base pair into an A • T base pair. Such an alteration in the sequence of a gene, which involves only a single base pair, is known as a point mutation. A silent point mutation causes no change in the amino acid sequence or activity of a gene's encoded protein. However, observable phenotypic consequences due to changes in a protein's activity can arise from point mutations that result in substitution of one amino acid for another (missense mutation), introduction of a premature stop codon (nonsense mutation), or a change in the reading cause a mutant phenotype. Recessive mutations usually cause a loss of function; dominant mutations usually cause a gain of function or an altered function.

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