Genetics, revised edition. Karen Vipond
mentioned in this chapter can be found on the Online Mendelian Inheritance in Man website:
www.ncbi.nlm.nih.gov/omim
Different genetic conditions are allocated a reference number on this site:
• Benign epidermolysis bullosa can be found as #226650.
• Autosomal dominant retinitis pigmentosa is referenced as #268000.
• Albinism is #203100.
1 Sometimes the words gene and allele can be used interchangeably.
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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).