Genetics, revised edition. Karen Vipond
parents
The estimated risk of having an affected child is 75 per cent (Figure 3.10).
Figure 3.10 Estimation of risk from two heterozygous parents
Offspring have a:
• 3 in 4 chance or 75 per cent risk of being affected;
• 1 in 4 chance or 25 per cent risk of being unaffected.
3. Heterozygous x Homozygous recessive: Aa x aa (one affected parent and one unaffected parent) (see Figure 3.11).
Figure 3.11 Heterozygous x homozygous recessive parents
Estimation of risk for this type of mating is 50 per cent (see Figure 3.12).
Figure 3.12 Estimation of risk from heterozygous recessive x homozygous recessive parents
Offspring have a:
• 1 in 2 chance or 50 per cent risk of being affected;
• 1 in 2 chance or 50 per cent risk of being unaffected.
There are thousands of genetic conditions that are monogenic autosomal dominant. Table 3.3 gives some examples of the most common single gene dominant disorders.
Table 3.3 Common monogenic autosomal dominant conditions
| Condition | Chromosome | Gene | Effects |
| Achondroplasia | 4p | FGFR3 | Dwarfism caused by severe shortening of the long bones of the limbs; lumbar lordosis and flattened bridge of the nose |
| Brachydactyly | 9q | ROR2 | Abnormally short phalanges (distal joints) of the fingers and toes |
| Huntington’s disease | 4p | HTT | Progressive brain disorder, involuntary movements and loss of cognitive ability |
| Hypercholesterolaemia | 19p | LDLR | High blood cholesterol leading to increased risk of cardiovascular disease |
| Marfan Syndrome | 15q | FBN1 | Tall stature with elongated thin limbs and fingers; high risk of heart defects |
| Myotonic Dystrophy | 19q | DMPK | Progressive muscle wasting |
| Neurofibromatosis Type 1 | 17q | NF1 | Growth of tumours along nerves in brain and skin; changes in skin colouration; increased risk of hypertension |
| Polycystic Kidney Disease Type 1 | 16p | PKD1 | Fluid-filled cysts on enlarged kidneys and other organs, can lead to kidney failure |
| Polycystic Kidney Disease Type 2 | 4q | PKD2 | Effects are the same as Type 1 but Type 2 has a later onset and symptoms are less severe |
| Porphyria Variegata | 1q | PPOX | Inability to synthesise haem (essential for haemoglobin in red blood cells) |
There are many more dominant traits than recessive traits recognised in humans. The reason for this is that a recessive trait can be ‘hidden’ by carriers whereas a dominant trait is always expressed. An individual with a dominant trait has a higher chance of having an affected child (a 50 per cent risk) compared with carriers of a recessive condition (a 25 per cent risk for two carriers).
| ACTIVITY 3.2 |
a. Autosomal dominant conditions do not appear to ‘skip’ generations in the same way as autosomal recessive conditions. Explain the reasons for this.
b. What is the risk for two heterozygous dominant parents of having a child with the same condition?
c. Could a homozygous dominant affected individual and a homozygous recessive unaffected individual have an unaffected child?
For questions b) and c) you might need to draw a Punnet square (see page 31) to clarify your answers.
Variations in dominant inheritance
The way that dominant and recessive alleles behave is not always so straightforward. There are a few exceptions to the simplistic Mendelian inheritance patterns of dominance, even though the inheritance of these genes still follows Mendelian principles of inheritance.
1. New alterations
Most affected individuals with a dominant condition will have an affected parent. Some alterations in the chromosomal DNA can occur spontaneously either in the egg or sperm, or even early in embryonic development. Individuals may develop certain genetic conditions in this way. These individuals are affected by an altered allele, but their parents are not affected. The altered allele can be inherited by future generations. In some disorders the proportion of cases arising from new mutations is high. For example, 80 per cent of children born with achondroplasia do not have an affected parent but have developed the mutated allele either in early embryonic development or via a new arising mutated allele within the egg or sperm.
2. Late onset
Some autosomal dominant conditions are not expressed phenotypically until adulthood (e.g. Huntington’s disease). This makes it difficult to predict risk when making reproductive choices.
3. Variable expressivity
The severity of symptoms of a dominant condition can vary between members of the same family, especially if the altered allele codes for a protein that is needed for different functions within the body. This makes it sometimes difficult to identify the condition and to track it through the generations of the family. Marfan syndrome has variable expressivity between members of the same family.
4. Incomplete penetrance
Usually a dominant allele will be phenotypically expressed. When an allele is always expressed it is said to be 100 per cent penetrant. There are some dominant conditions that do not follow this rule in that they have reduced penetrance. Retinoblastoma, an eye tumour, is an example of a genetic condition where the altered allele (allele RB on chromosome 13q) has variable penetrance. The susceptibility of developing the tumour is a dominant trait, but 20 per cent of individuals who have the altered allele do not develop the condition. The retinoblastoma gene therefore has an 80 per cent penetrance.
CLASSIFICATION OF GENE ACTION
Dominance usually occurs when a functioning allele is paired with a non-functioning allele. This usually arises from a mutation that alters the DNA structure within the allele, rendering it non-functional. An individual who has two altered alleles will generally display a distinctive phenotype as a result of the missing or altered protein produced by the altered alleles. It is not the lack of function that makes the allele recessive but the interaction of that allele with the alternative allele in the heterozygote. There are three main allelic interactions.
1. Haplosufficiency
This is when a single functional allele is able to encode for a sufficient amount of protein in order to produce a phenotype that is identical to that of the normal phenotype. If each allele encodes for 50 per cent of the amount of protein (100 per cent from both functioning alleles) and the normal phenotype can be achieved with only 50 per cent of the protein, then the functioning allele is considered dominant over the non-functioning allele. For example, the GALT gene on chromosome 9p that normally encodes for an enzyme needed for the breakdown of galactose shows haplosufficiency in the presence of one altered gene.
2. Haploinsufficiency
This is where