Molecular genetics and the skin
Recent and rapid advances in genetics have had an impact on our understanding of skin diseases. The Human Genome Project has now mapped all human genes, of which there are about 35 000. Genetics has been found to be more complicated than the original Mendelian concept, and common conditions such as atopy occur as a result of a complex interaction between multiple susceptibility genes and the environment. An average pregnancy carries a 1% risk of a single gene disease and a 0.5% risk of a chromosome disorder, but genetically influenced traits, e.g. atopy, are much more common.
The human chromosomes
The human genome comprises 23 pairs of chromosomes that are numbered by size (Fig. 1). Chromosomes are packets of genes with support proteins in a large complex. The karyotype is an individual’s number of chromosomes plus their sex chromosome constitution, i.e. 46XX for females and 46XY for males. The phenotype is the expression at a biological level of the genotype, e.g. blue eyes or atopy.
Molecular methods
DNA sequence variations can be identified by the consequent change in polymerase chain reaction (PCR) amplification product size (Fig. 2), loss or gain of restriction endonuclease cutting, or sequence analysis. In recent years, DNA sequencing has become a high-throughput technology that has led to the concept of ‘whole genome sequencing’ studies of healthy versus controls. As this technique is so powerful, smaller numbers are required.
Fig. 2 Agarose gel electrophoresis, showing migration of DNA after cutting with enzymes, screening for mutations in a keratin gene.
Molecular techniques can be used to:
detect small amounts of DNA, e.g. of human papilloma virus within a skin cancer
sequence DNA from a ‘candidate’ section of an individual’s chromosome and compare the base sequences with family members similarly affected by a disorder, thus mapping a specific gene polymorphism characteristic for that disease (Table 1)
sequence the entire genome of an individual
identify the repertoire of genes that have been transcribed as a measure of the protein profile of the cell.
Chromosome site | Disease or characteristic |
---|---|
1p34 | Porphyria cutanea tarda: enzyme (p. 46) |
2q31 | Ehlers–Danlos syndrome: collagen III (p. 93) |
3p21.3 | Dystrophic epidermolysis bullosa: collagen VII (p. 91) |
4, 4p | Red hair colour, psoriasis (Psors3 gene) |
6p21.3 | Psoriasis (Psors1 gene: 30% of susceptibility) |
9p21 |