As with many great scientific breakthroughs, the true situation has proved to be more complicated than the initial insight suggested. There are many examples of exceptions to simple Mendelian genetics. In general, the extensions to Mendel’s laws can be classified in two groups, depending on whether a trait is encoded by a single gene (monogenic inheritance) or by many genes, known as multifactorial inheritance.
In the single-gene inheritance group, there are three major extensions.
First, dominance is not always complete. In incomplete dominance, the hybrid phenotype is intermediate between the phenotypes of both true-breeding parents. In co dominance, neither allele is dominant, with the F1 hybrid showing traits from both true-breeding parents. These relationships are schematically depicted in Figure 1.
Fig1. Dominance relationships between alleles. (A) Different dominance relationships between pairs of alleles are revealed by the phenotype of the heterozygote. Variations in dominance relationships do not detract from Mendel’s law of segregation; rather, they reflect differences in the way in which gene products control the production of phenotype. (B) In this example of incomplete dominance, the petal color of the F1 heterozygote Pp is unlike that of either homozygote parent. The phenotypic ratios in F2 are an exact reflection of the genotypic ratios. The explanation for this behavior lies in the biochemistry of pigment production. p does not encode a functional enzyme for pigment production, hence a white color of the petals results. Conversely, the PP homozygote produces a double dose of the enzyme and hence a bright pink color is seen.
Second, a gene may have more than two alleles. There are numerous examples of such genes, including those that determine human blood groups and the genes that code for human histocompatibility antigens, which are cell surface proteins that participate in proper immune responses. The latter proteins are encoded by three genes, each with between 20 and 100 alleles; each allele is co-dominant with every other allele at the molecular level. The most extreme example known to date is the olfactory genes, which have ~1300 alleles, only one of which is expressed. This monoallelic gene expression is strictly regulated by mechanisms that remain largely unknown. Usually, cells express both alleles of a gene.
Third, one gene may contribute to several visible characteristics; this phenomenon is known as pleiotropy, from the Greek pleion, meaning more, and tropi, meaning to turn or convert. A classic example of pleiotropy is found in sterile males among the aboriginal Maori people of New Zealand. These men are sterile and have respiratory problems. The gene’s normal dominant allele specifies a protein needed in both cilia and flagella; in men who are homozygous for the recessive allele, cilia and flagella do not function properly, affecting their abilities to both clear mucus from their respiratory tract and produce motile sperm.
In multifactorial inheritance, two or more genes can interact to determine a single trait and each type of interaction produces its own signature of phenotypic ratios. In this group, there are three major extensions to Mendel’s laws.
First, novel phenotypes can emerge from the combined action of the alleles of two genes. The genes either complement each other or are epistatic to each other. In complementation, a wild-type offspring is produced from crosses between strains that carry different homozygous recessive mutations in different genes; the phenotype of the two homozygous parents is the same, that is, they are not distinguishable by appearance. Complementation, or reversal to the wild-type phenotype, can occur only if the mutations occur in different genes, so that for each of the two genes in the genome, the offspring carries one wild-type, dominant allele that complements the mutated allele of the same gene. In epistasis, one gene’s alleles mask the effects of another gene’s alleles. Biochemically, this situation arises when several genes participate in succession in a single biochemical pathway. The inactivity of a gene at the beginning of the pathway will hide the fact that subsequent genes may be expressed.
Second, a given genotype does not always produce the same phenotype: phenotype often depends on penetrance and expressivity. Penetrance describes how many members of a population with a particular genotype show the expected phenotype. Penetrance can be complete or incomplete. A frequently cited example of incomplete penetrance concerns the disease retinoblastoma: only 75% of people carrying a mutant allele for the retinoblastoma protein develop the disease. Expressivity refers to the degree or intensity with which a particular genotype is expressed in a phenotype. In some people who have retinoblastoma, only one eye is diseased. It is important to understand that chance can affect penetrance and expressivity. For example, in the case of retinoblastoma, every cell carries the inherited mutation in one allele of the retinoblastoma gene, but a second chance event is needed for the disease phenotype to appear. Damaging radiation or errors in DNA replication in retinal cells provide the second hit, creating a mutation in the second copy of the retinoblastoma gene within one or more cells. Such situations gave rise to the two-hit hypothesis for the origin of cancer proposed by Alfred Knudson in 1971.
Third, there are also quantitative traits that vary continuously over a range of values. Good examples are height or skin color in humans. These traits are polygenic and show the additive effects of a large number of genes and their alleles on the phenotype.
Here we mention the concept of modifier genes, which have secondary, more subtle effects on a trait. We also introduce the concept of allele frequency within a population. This is the percentage of the total number of gene copies in a population comprised of any one allele. The most prevalent allele, the one with the highest frequency in a population, is defined as the wild-type allele. In evolution, new alleles appear as a result of mutations.
Finally, it is now clear that the environment can affect the phenotypic expression of a genotype. When environmental agents cause a change in phenotype that mimics the effects of a mutation in a gene, this is known as phenocopying. A painful example of this phenomenon was the effect of the sedative drug thalidomide. If taken by pregnant women, this drug produced a phenocopy of a rare dominant trait called phocomelia, which disrupts limb development in the fetus.
Perhaps the most significant exception to the laws of Mendelian inheritance is the fact that Mendel’s second law is not generally correct. There are many cases in which genes are linked, and discovery of this led to the second great advance in classical genetics.
