Genetic disease is a common cause of illness and even death. Approximately 3% of babies are affected by a genetic disease. Genetic diseases can be considered to be caused by chromosomal defects or single or multiple gene defects. One per cent of children admitted to hospitals suffer from chromosomal defects, 5–10% from single gene defects and 35–45% from multi-gene defects. Chromosomal defects are relatively common, with 15% of all conceptions affected, and if severe they usually result in miscarriage.
Chromosome structure
Human cells are diploid, i.e. there are two copies of each chromosome. They are the result of an 8000-fold condensation of chromatin during mitosis. The human genome consists of 23 pairs of chromosomes: 22 pairs of autosomes and a pair of sex chromosomes, XX for a female and XY for a male. The chromosome content of a cell is known as the karyotype. Each cell in an individual contains the same genome, known as the genotype. The expression of certain genes in different tissues refers to the phenotype.
Cytogenetic analysis shows that humans contain metaphase chromosomes (Figure 17.1).
Sources of genetic variation
- During reproduction the fertilisation of an ovum of one individual by the sperm of another.
- Human genes are inherited according to Mendelian laws. Offspring inherit one chromosome from each parent.
- During meiosis crossing-over of DNA between two chromatids occurs.
Mutations
A mutation is any permanent heritable change in DNA sequence. A mutagen is an agent that increases the mutation rate. There are two major types of mutation.
Chromosomal defects
During cell division the following changes in chromosome structure or content can occur.
- Gain of a whole set of chromosomes to form a tetraploid.
- Changes in the number of copies of a single chromosome arising from non-disjunction during meiosis, a failure to separate chromosomes correctly; the resulting cells are aneuploid, e.g. the gain of a chromosome results in a triploid cell. Triploidy is deleterious to the cell. Down syndrome results from the presence of three copies of chromosome 21. Fewer than 30% of Down fetuses survive to birth (Figure 17.2). For trisomy 18 (Edward’s syndrome) and trisomy 13 (Patau syndrome) fewer than 10% survive to birth. Sex chromosomes are an exception to this. Aneuploidy is usually much less severe if a cell contains 47XXX, 47XXY, or 47XYY. This is as a result of the inactivation of all but one X chromosome in a somatic cell during the early stages of embryogenesis (known as the Lyon hypothesis) or the small number of genes on the Y chromosome.
Changes in chromosome structure can occur (Figure 17.1).
- Triplet repeat sequences occur in normal chromosomes. For example, the normal myotonin gene contains between five and 35 copies of a CTG sequence. The number of these repeats can increase during meiosis (Figure 17.3). In patients suffering from myotonic dystrophy, the number of these repeat sequences increases to greater than 50 and may be over 1000. A similar situation occurs in a number of other diseases, including Huntington’s disease. It is possible to estimate in which generation a future offspring will inherit sufficient triplet repeats to be affected by the disease. This phenomenon is known as anticipation.
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