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The following topics are covered in this chapter:
• autosomal recessive inheritance;
• autosomal dominant inheritance;
• variations in dominance;
• classification of gene action;
• co-dominance;
• multiple alleles;
• lethal alleles.
INTRODUCTION
In Chapter 2 the main principles of inheritance were explained. This chapter focuses on the inheritance of autosomal single gene disorders. Over 10,000 human diseases are due to single gene alterations and, although rare, they affect one per cent of the human population. Single gene disorders are also known as monogenic disorders. Genetic disorders are caused by abnormal genes. Alleles that become altered over time can be passed on to future generations. These altered alleles can result in the production of a non-functioning protein. An altered allele is a mutated allele.
The inheritance pattern of an altered gene depends on whether the gene is situated on an autosome (chromosomes 1 to 22) or on one of the sex chromosomes (XX in females, XY in males), and whether the alleles of that gene are either recessive or dominant. Genetic conditions arising from a single gene can be inherited in one of four ways:
1. autosomal recessive;
2. autosomal dominant;
3. X-linked recessive;
4. X-linked dominant.
Only the inheritance patterns of genes on the autosomal chromosomes will be explained in this chapter. X-linked inheritance is discussed in Chapter 4.
When the DNA coding within a gene becomes altered in any way, the resulting gene product may also be affected. The production of an altered or non-functioning gene can give rise to a genetic condition that affects health and development. These altered or mutated genes can be inherited in a recessive or dominant fashion.
AUTOSOMAL RECESSIVE INHERITANCE
Two copies of the altered allele must be present for an individual to be affected by a recessive disorder. That individual would be classified as homozygous recessive for that disorder. Heterozygous individuals who only possess one altered allele and a normally functioning allele will not display the effects of the altered allele in their phenotype but are classified as carriers of the altered allele. Carriers are not affected by the recessive allele but are able to pass that affected allele on to the next generation. Individuals need both alleles to be in the recessive form for the expression of the recessive phenotype.
Most individuals carry a small number of recessive alterations within their genes that cause no symptoms. Recessive diseases are single-gene disorders arising from two malfunctioning alleles (mutant alleles) and appear in homozygous individuals. Most affected individuals have two heterozygous parents who are unaffected because they have one altered and one normal allele and are carriers of the disorder.
Rules of autosomal recessive inheritance
• Both males and females are equally affected.
• Gene expression can ‘skip’ several generations as carriers do not express the gene.
• Affected children can be born to non-affected parents.
• If both parents are affected, all children will also be affected.
• Affected individuals with homozygous non-affected partners will usually have normal children.
Inheritance patterns
Affected individuals (homozygous recessive) are produced via one of three different types of mating:
1. Two heterozygous parents: Aa x Aa (both parents are carriers) (see Figure 3.1).
Figure 3.1 Two heterozygous parents
Key: A = normal allele, a = affected recessive allele
This is by far the most common type of mating that produces an affected offspring. The estimation of risk for an affected offspring from this type of mating is 25 per cent.
Figure 3.2 Estimation of risk from two heterozygous parents
Offspring have a:
• 1 in 4 chance or 25 per cent risk of being an unaffected non-carrier (AA);
• 1 in 2 chance or 50 per cent risk of being a carrier (Aa);
• 1 in 4 chance or 25 per cent risk of being affected (aa).
2. Recessive Homozygote x Heterozygote aa x Aa (affected parent with a carrier parent) (see Figure 3.3).
Figure 3.3 Recessive homozygote x heterozygote parent
The estimation of risk for an affected offspring from this type of mating is 50 per cent (Figure 3.4).
Figure 3.4 Estimation of risk from a recessive homozygote and heterozygote parent
Offspring have a:
• 1 in 2 chance or 50 per cent risk of being a carrier;
• 1 in 2 chance or 50 per cent risk of being affected.
3. Two recessive homozygotes: aa x aa (both parents are affected) (see Figure 3.5).
Figure 3.5 Two recessive homozygote parents
The estimation of risk for an affected offspring from this type of mating is 100 per cent (Figure 3.6).
Figure 3.6 Estimation of risk from two homozygote parents
Offspring have a:
• 1 in 1 chance or 100 per cent risk of being affected.
Affected individuals who are homozygous recessive are usually the offspring of one of the above three matings.
There are thousands of autosomal monogenic recessive conditions. Table 3.1 contains a few examples of the most common conditions.
Table 3.1 Common autosomal monogenic recessive conditions
| Condition | Chromosome | Gene | Effect |
| Adenosine Deaminase Deficiency | 20q | ADA | Severe combined immunodeficiency |
| Batten Disease | 16p | CLN3 | Progressive disorder resulting in neuronal death within the brain |
| Congenital deafness | 11p | USH1C | Deafness |
| Cystic Fibrosis | 7q | CFTR | Defective chloride ion transport leading to thickened mucus production |
| Galactosaemia | 9p | GALT | Developmental delay as a result of inefficient metabolism of galactose |
| Gaucher Disease | 1q | GBA | Build-up of fatty deposits on liver, spleen, lungs and brain; anaemia and joint problems |
| Hereditary Haemochromatosis | 6p | HFE | Iron overload due to too much iron being absorbed from the small intestine |
| Maple syrup urine disease | 7q | DLD | Metabolic disorder leading to seizures, failure to thrive and developmental delay |
| Oculocutaneous Albinism | 11q | TYR | Lack of pigment in hair, skin and eyes |
| PKU | 12q | PAH | Increased levels of phenylalanine leading to brain damage |
| Sickle Cell Anaemia | 11p | HBB | Abnormal haemoglobin. Sickle-shaped red blood cells, which lead to the blocking of small blood vessels |
| Spinal Muscular Atrophy | 5q1120 | SMN1IGHMBP2VAPB | Progressive loss of function of motor neurones leading to atrophy of muscles |
| Tay-Sachs | 15q | HEXA | Build-up of fatty deposits in the central nervous system, leading to death |
Additional risks
Everyone carries several ‘faulty’ recessive genes that have no impact on their health. There are many different forms of faulty genes within a population but, because genes are inherited from parents and grandparents, family members will have more similarity within their genes and shared ‘faulty’ genes.
Consanguinity
The risk of developing an autosomal recessive genetic condition is increased in offspring of consanguineous relationships. The term consanguinity derives from the Latin prefix con-, meaning ‘together’, and the word sanguis which means ‘blood’. It describes the marital relationship between two individuals who share a common ancestor. The most common form of consanguinity is the marriage between first cousins, which is encouraged in some cultures.
The children of unrelated parents are at low risk of inheriting two copies of the same faulty or altered allele. The risk of having a child with a birth defect is between 2 and 3 per cent, some of which will be due to a genetic condition. Children of parents who are blood relatives have an increased risk of having a genetic defect. The risk is doubled for parents who are cousins (5 to 6 per cent). The risk of inheriting the same faulty gene from both parents is increased the closer the relationship is between the parents (i.e. the more genes that they have in common) (see Table 3.2).
Table 3.2 Relationships between blood relatives
| Relationship to each ot her | Brothers/sisters Parent/child | Uncles/aunts Nephews/niecesGrandparentsHalf-brothersHalf-sisters | First cousins Half-unclesHalf-auntsHalf-nephewsHalf-nieces |
| Relationship type | First-degree relatives | Second degree | Third degree |
| Proportion of genes that they have in common | Half 50 per cent | Quarter 25 per cent | Eighth 12.5 per cent |
The risk of having an affected child is much higher than 5 to 6 per cent in some families, because parents who are first cousins might also have grandparents who are themselves related.
| ACTIVITY 3.1 |
a. A child who has a recessive genetic condition has two unaffected parents. If the child’s genotype for this disorder is bb, what are the genotypes of the parents?
b. Why do recessive conditions appear to ‘skip’ generations?
AUTOSOMAL DOMINANT INHERITANCE
Autosomal dominant single gene disorders occur in individuals who have a single altered copy of the disease-associated allele. An alteration in only one of the alleles within a gene is enough to cause the disorder. The mutated disease-causing allele can be inherited from either parent.
Alleles encode for the production of a specific protein. When one allele is altered, in that the specific protein is no longer produced, the remaining functioning allele will still continue to encode for the specific protein. In autosomal dominant disorders, the amount of protein being encoded for by the functioning allele is not enough for the body to function normally. In these cases the faulty allele causes a problem for the individual as it is dominant in its effect over the functioning normal allele.
In individuals who possess both alleles in an altered form (homozygous dominant), the disease symptoms are generally more severe. Dominant disease allele homozygotes are quite rare as many conditions appear lethal in the homozygous dominant form.
Rules of autosomal dominant inheritance
• Both males and females are equally affected, and can transmit to both sons and daughters.
• Most affected individuals will have an affected parent. The disease does not ‘skip’ generations.
• In affected families, where one parent is affected, the risk of transmitting the trait to the offspring is 50 per cent.
• If both parents are unaffected, none of the children will be affected.
Inheritance patterns
Affected individuals, who possess a dominant allele, are produced via one of three different types of mating.
1. Two homozygous dominant parents: AA x AA (both parents are affected) (see Figure 3.7).
Figure 3.7 Two homozygous dominant parents
Key: A = dominant affected allele, a = recessive normal allele.
The estimation of risk of an affected offspring is 100 per cent (see Figure 3.8).
Figure 3.8 Estimation of risk from two homozygous dominant parents
Offspring have a:
• 1 in 1 chance or 100 per cent risk of being affected.
2. Two heterozygous parents: Aa x Aa (both parents are affected) (see Figure 3.9).
Figure 3.9 Two heterozygous 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 a single functioning allele is unable to produce enough protein. Essential levels of protein must be over 50 per cent in cases of haploinsufficiency. The phenotype in haploinsufficiency resembles the homozygote for the non-functioning allele. This is rare in humans as deficiency usually results in a case of incomplete dominance.
3. Incomplete dominance
With a small number of alleles there is a lack of complete dominance. A heterozygous individual will have an intermediate phenotype compared with the two different homozygous individuals. The phenotype of the heterozygote becomes an intermediate or a ‘blend’ of the two different alleles. A simple example of incomplete dominance in humans can be seen with the gene for curly hair. An individual who has inherited a curly hair allele from one parent and a straight hair allele from the other parent will have wavy hair. In humans the ‘blend’ of the curly hair allele and the straight hair allele gives rise to wavy hair.
Most genes that display patterns of incomplete dominance have arisen from alleles in which a ‘loss of function’ has occurred. In a gene composed of one functioning allele and a non-functioning allele, only half the required amount of protein is encoded for by that gene. The genetic condition of familial hypercholesterolaemia demonstrates incomplete dominance in that individuals with one faulty or non-functioning allele will have raised blood cholesterol levels, while individuals who have two non-functioning alleles will have much higher cholesterol levels.
| ACTIVITY 3.3 |
The straight hair allele (s) and the curly hair allele (c) show incomplete dominance in humans. Individuals with straight hair are homozygotes (ss), as are individuals who have curly hair (cc). Heterozygotes for this trait have wavy hair as they have one straight hair allele and one curly hair allele (sc). Note that the two different traits are represented by different letters.
a. Complete a Punnet square for a mating between a curly hair individual and a wavy hair individual.
b. What is the predicted offspring from this mating?
c. Is it possible for these individuals to have a straight hair child with each other?
d. Complete a Punnet square to determine the possible genotypes of the offspring of two wavy hair individuals.
e. Could two wavy hair parents have a child with straight hair?
f. Could the same wavy hair parents have a child with curly hair?
Whether an allele is classified as dominant or incomplete dominant depends on the individual’s phenotype. However, the phenotype can be measured in different ways. Take, for example, the genetic condition of Tay–Sachs disease. Tay–Sachs disease is a degenerative condition that affects the nervous system. Affected individuals are born healthy but start to lose acquired skills at around the age of six months, gradually becoming blind, paralysed and unaware of their surroundings. It is a lethal condition with an average life expectancy of around five years. Affected individuals have two altered alleles in the HEXA gene on chromosome 15. A functioning HEXA gene is vital for development of the nervous system. Without the specific enzyme that this gene encodes for, fatty deposits build up in the brain, which then leads to neuronal damage. An affected individual has two non-functioning HEXA alleles. A heterozygote individual who has one functioning copy of the gene will be able to produce half the normal amount of the HEXA protein, which is enough to prevent damage from occurring. Heterozygotes are therefore carriers of Tay–Sachs disease. The healthy functioning copy of the HEXA allele is therefore classified as dominant to the non-functioning HEXA allele as the heterozygote individual displays no symptoms of the condition. However, if enzyme levels were measured, only half the usual amount of the HEXA enzyme protein would be discovered. In Tay–Sachs disease half the enzymatic levels are sufficient for health. At the biochemical level, the heterozygous individual displays incomplete dominance but complete dominance at the whole body level.
All the examples so far have demonstrated one allele being dominant or recessive over its partner allele. There are some conditions in which different versions of the same allele demonstrate equal dominance to each other. This is called co-dominance.
CO-DOMINANCE
Co-dominance is quite similar to incomplete dominance, in that neither of the two alleles is dominant or recessive to each other. However, there is no ‘blending’ in the offspring as both allelic products are expressed. Both parental traits are expressed in the offspring with co-dominant alleles. The biggest difference between incomplete dominance and co-dominance is that in co-dominance both alleles still encode for a functioning protein. The different proteins may have a slightly different function.
Most co-dominant alleles are thought to have arisen from a ‘gain in function’ mutation, where the alteration to the DNA structure within the allele has resulted in a different functioning protein being encoded for.
The MN blood group
An example of a co-dominant gene in humans is the gene that encodes for the MN blood group. The MN system is a type of blood grouping that is formed by the presence of specific antigens on the surface of the red blood cells. Two co-dominant alleles were originally identified for this blood group, termed M and N. The MN system is under the control of the MN gene located on chromosome 4. As both M and N alleles are co-dominant to each other there are three possible genotypes and phenotypes that can arise from the MN blood grouping system (see Table 3.4).
Tale 3.4 The MN blood grouping system
| Genotype | Phenotype |
| MM | MM blood group |
| NN | NN blood group |
| MN | MN blood group |
There is distinct expression of both alleles in the MN blood group system, which is a characteristic of co-dominant inheritance.
| ACTIVITY 3.4 |
In which of the following does the ‘blending’ of traits occur – incomplete dominance or co-dominance?
MULTIPLE ALLELES
