One aspect of clinical genetics which makes it somewhat different to other branches of medicine is that results affecting one individual have ramifications extending to both the close family and to more distant relatives. But this is seen also in reverse; our ability to make predictive diagnoses of risk of affected offspring in a marriage will depend on our knowledge not just of the immediate families from which prospective parents are drawn but also of the populations.
Some genetic diseases are present at a much higher frequency in one population rather than another. For instance in the Boer population of South Africa the disease porphyria variegata is much more common than in either the Dutch population from whom the Boers are descended or the surrounding African populations. This interesting disease (which is an example of haploinsufficiency) is familiar to those of us who have seen the film 'The Madness of King George' (whose retrospective diagnosis was made in 1966). In South Africa it occurs at a frequency of 1 in 375 in the white population. The mutation responsible has been discovered and has been shown to be the same in almost all cases. All of these can trace their descent to one couple Gerrit Jansz and his wife, Ariaantje Jacobs who were some of the first settlers in the 17th Century. This is a classic example of the founder effect. Approximately forty founding families have now expanded until their one million descendants represent one third of the modern white population in the country. The defective gene originally present in either Gerrit or Ariaantje has similarly increased in frequency, as it has not seriously interfered with the ability to leave descendants. There has been some selection against the defective gene and during this time it has decreased slightly in relative frequency (from about 1 gene in 160 to about 1 gene in 250 in the one million descendants who trace their lineage back to the founders.)
A similar situation can be seen in Finland which was mostly settled only from the 17th Century. Today a number of distinct mutations which are rare elsewhere in Europe are present at a high frequency in the Finnish population. An example is one type of familial colon cancer, another example is in one form of Batten disease. The high incidence of Huntington's Disease in the Venezuelan population living around Lake Maracaibo is another example. All affected people are descendants of a Portuguese sailor who married a local woman in the 19th Century.
Many conditions which we recognise as genetic diseases are actually present in certain populations because, either presently or in the not too far distant past, they actually conferred a survival advantage on their carriers. In most cases the disease is manifested in the homozygote whereas the heterozygote is at an advantage. Malaria has been a powerful selective force. In countries where malaria is endemic are found high frequencies of many such mutations, for example the sickle cell mutation in the beta globin gene, the thalassemia mutations affecting either alpha or beta globin genes and favism (glucose-6-phosphate dehydrogenase deficiency).
In the case of a dominant and a recessive allele at a locus, it is not immediately obvious what will happen to their frequencies in the population as generations go by. Do we expect the recessive allele to diminish in frequency? Also, there will be three genotypes, homozygotes for each of the alleles and the heterozygotes. What will be their relative frequencies?
The answer was provided by a physician, Weinberg and a mathematician, Hardy in 1908. They recognised that, provided certain conditions were met, the allele frequencies (sometimes rather misleadingly called the gene frequencies) would remain constant from one generation to the next and that no matter what the relative frequencies of the genotypes in the starting population, in all subsequent generations these too would be fixed at certain values determined by the allele frequencies. The conditions are listed in the box.
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In practice these conditions are impossible to fulfil exactly because:
The Hardy-Weinberg equilibrium can be stated thus:
| Genotype | frequency |
| AA | p2 |
| Aa | 2pq |
| aa | q2 |
The Hardy Weinberg equilibrium can be used to estimate genotype and gene frequencies from limited data.
| Population | Frequency of M allele | Frequency of N allele |
| UK (Somerset) | 0.49 | 0.51 |
| Japan (Kyoto) | 0.35 | 0.65 |
a) What frequency of MN heterozygotes would you expect to find in the Somerset population?
b) What frequency of NN homozygotes would you predict in Kyoto?
Show your reasoning.
| Genotype | number of adults | number of infants |
| 1,1 | 33 | 44 |
| 1,2 | 67 | 45 |
| 2,2 | 0 | 11 |
Which of these results fits those predicted by the Hardy Weinberg equilibrium equations? (Show your working.) Suggest a possible explanation why the other might not.
The use of DNA evidence in both criminal and civil trials has been called into question for one of two reasons, either the poor quality control and procedures of the forensic laboratory concerned or the lack of proper control data from the population from which the DNA sample has been drawn. The former is none of our concern here but the latter is highly relevant.
What is a DNA fingerprint? Essentially, it is an attempt to examine the alleles present at sufficient polymorphic loci in a DNA sample to be able to give a unique identity to that sample. Sometimes this can be done by examining a single Southern blot if the probe recognises many loci simultaneously (which is where the term fingerprint came into the jargon).
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The aim of this small section is to introduce the idea of cancer as a genetic disease. Although probably a relatively small proportion of all cases of cancer are caused by the inheritance of faulty genes, all cases of cancer are caused by mutation of one (more often several) genes. In addition, for all types of cancer there exist a small and instructive proportion of cases in which the mutation was inherited.
Cancer is caused by the loss of control of cell division. Many cells need to divide for tissue growth or maintenance but this ability must be strictly regulated. When the regulation breaks down and a cell is able to divide unchecked then cancer is the result. The cause of the breakdown is mutation
Most examples of oncogenes were discovered by molecular virologists working in the 1970s and 80s. They were studying RNA viruses which had the property of transforming cells which they infected from a normal to a cancerous state. The viruses had aquired copies of host genes (protooncogenes) which had mutated (into oncogenes). The normal roles of the genes were varied. Some were growth factors involved in the normal stimulation of cells to divide. Some were growth factor receptor proteins which would now stimulate their targets even without binding external growth factors. Some were themselves transcription factors, directly stimulating other genes.
Tumour suppressor genes act normally to prevent cells dividing. If they are inactivated by mutation then cell division may be triggered. It is always necessary to inactivate both copies of a tumour suppressor gene. Sometimes one copy is lost through an inherited mutation. In this case every cell in the body will have only one active copy of the gene. It will not be an infrequent event that the second copy be removed because of a second somatic mutation event (remember for instance that loss of a chromosome occurs at a frequency of 1 in 100 cell divisions). Patients will show multiple tumours caused by many such second events. There are many examples of inherited genes of this type such as retinoblastoma and the breast cancer genes BRCA1 and BRCA2. The concept of the first (rare) event which must be followed by a second (much more frequent) event to initiate a cancer was first put forward by Knudsen in 1972.
The topics include:
Reading: