Lethal alleles
Many so called dominant mutations are in fact semidominant, the phenotype of the homozygote is more extreme than the phenotype of the heterozygote. For instance the gene T (Danforth's short tail) in mice. The normal allele of this gene is expressed in the embryo. T/+ mice develop a short tail but T/T homozygotes die as early embryos. Laboratory stocks are maintained by crossing heterozygotes, T/+ x T/+
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|
V
T/T T/+ +/+
1 : 2 : 1 ratio at conception
0 : 2 : 1 ratio at birth
Incomplete or semi- dominance
Incomplete dominance may lead to a distortion of the apparent ratios or to the creation of unexpected classes of offspring. A human example is Familial Hypercholesterolemia (FH). Here there are three phenotypes: +/+ = normal, +/- = death as young adult, -/- = death in childhood. The gene responsible codes for the liver receptor for cholesterol. The number of receptors is directly related to the number of active genes. If the number of receptors is lowered the level of cholesterol in the blood is elevated and the risk of coronary artery disease is raised.
Codominance
If two or more alleles can each be distinguished in the phenotype in the presence of the other they are said to be codominant. An example is seen in the ABO blood group where the A and B alleles are codominant.
The ABO gene codes for a glycosyl-transferase which modifies the H antigen on the surface of red blood cells. The A form adds N-acetylgalactosamine, the B form adds D-galactose forming the A and B antigens respectively. The O allele has a frameshift mutation in the gene and thus produces a truncated and inactive product which cannot modify H. A phenotype people have natural antibodies to B antigen in their serum and vice versa. O phenotype individuals have antibodies directed against both A and B. AB individuals have no antibodies against either A or B antigens.
| Genotype | Phenotype | red cell antigens | serum antibodies |
| AA | A | A | anti-B |
| AO | A | A | anti-B |
| BB | B | B | anti-A |
| BO | B | B | anti-A |
| AB | AB | A and B | neither |
| OO | O | neither | anti-A and anti-B |
Codominance is the normal case for alleles which are revealed by direct study of an individual's DNA, see for example lecture 9, "restriction fragment length polymorphism" (RFLP).
Silent alleles
In a multiple allele system, it is sometimes not obvious that a silent allele exists. This can give confusing results. Consider for example:
A/A x A/B (phenotype A crossed to phenotype AB)
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|
V
A/A : A/B
1 : 1
and compare with
A/O x A/B (phenotype A crossed to phenotype AB)
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|
V
A/A : A/O : A/B : B/O
1 : 1 : 1 : 1
It would be important not to lump together these two different sorts of crosses but when there are only small numbers of offspring (which is the case in most human matings) some offspring classes may not be represented in a family and it may not be obvious which type of mating you are examining.
Epistasis
This occurs where the action of one gene masks the effects of another making it impossible to tell the genotype at the second gene. The cause might be that both genes produce enzymes which act in the same biochemical pathway.
If the product of gene1 is not present because the individual is homozygous for a mutation, then it will not be possible to tell what the genotype is at gene2. The Bombay phenotype in humans is caused by an absence of the H antigen so that the ABO phenotype will be O no matter what the ABO genotype. A soap opera example of this is given on page 89 (figure 5.4) in Lewis.
Pleiotropy
Mutations in one gene may have many possible effects. Problems in tracing the passage of a mutant allele through a pedigree can arise when different members of a family express a different subset of the symptoms. In the case of Tuberous sclerosis, an autosomal dominant condition affecting about 1 in 6000 people in the UK, symptoms can include any subset of:
- small depigmented patches on the skin
- a disfiguring facial rash
- kidney cysts
- heart tumours
- mild to severe mental subnormality
- autism
among others.
Lewis gives the interesting example of Tourette syndrome which may cause strange behavioural problems.
Pleiotropy can occur whenever a gene product is required in more than one tissue or organ.
Genetic heterogeneity
This is the term used to describe a condition which may be caused by mutations in more than one gene. Tuberous sclerosis again provides a good example of this, the identical disease is produced by mutations in either of two unrelated genes, TSC1 on chromosome 9 or TSC2 on chromosome 16. In such cases, presumably both genes act at different points in the same biochemical or regulatory pathway. Or perhaps one provides a ligand and one a receptor.
variable expressivity
The degree to which a disease may manifest itself can be very variable and, once again, tuberous sclerosis provides a good example. Some individuals scarcely have any symptoms at all whereas others are severely affected. Sometimes very mild symptoms may be overlooked and then a person may be wrongly classified as non-affected. Clearly this could have profound implications for genetic counselling.
Incomplete Penetrance
This is an extreme case of a low level of expressivity Some individuals who logically ought to show symptoms because of their genotype do not. In such cases even the most careful clinical examination has revealed no symptoms and a person may be misclassified until suddenly he or she transmits the gene to a child who is then affected.
One benefit of gene cloning is that within any family in which a mutant gene is known to be present, when the gene is known, the mutation can be discovered and the genotype of individuals can be directly measured from their DNA. See lecture 5. In this way diagnosis and counselling problems caused by non-penetrance can be avoided. The degree of penetrance can be estimated. If a mutation is 20% penetrant then 20% of persons who have the mutant genotype will display the mutant phenotype, etc.
Anticipation
In some diseases it can appear that the symptoms get progressively worse every generation. One such disease is the autosomal dominant condition myotonic dystrophy. This disease, which is characterized by a number of symptoms such as myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding and ECG changes, is usually caused by the expansion of a trinucleotide repeat in the 3'untranslated region of a gene on chromosome 19. The severity of the disease is roughly correlated with the number of copies of the trinucleotide repeat unit.
| Number of CTG repeats | phenotype |
| 5 | normal |
| 19 - 30 | "pre-mutant" |
| 50 - 100 | mildly affected |
| 2,000 or more | severely affected |
The "premutant" individuals have a small expansion of the number of trinucleotide repeats which is insufficient to cause any clinical effect in itself but it allows much greater expansions to occur during the mitotic divisions which precede gametogenesis. Mildly affected individuals can again have gametes in which a second round of expansion has occurred.
Germline Mosaicism
If a new mutation occurs in one germ cell precurser out of the many non-mutant precursers, its descendent germ cells, being diluted by the many non-mutant germ cells also present, will not produce mutant offspring in the expected Medelian numbers.
Phenocopies
An environmentally caused trait may mimic a genetic trait, for instance a heat shock delivered to Drosophila pupae may cause a variety of defects which mimic those caused by mutations in genes affecting wing or leg development. In humans, the drug thalidomide taken during pregnancy caused phenocopies of the rare genetic disease phocomelia, children were born with severe limb defects.
