"There's a lot of it about!"

Scarcely a day seems to pass without some reference to genetics in the newspapers. Not since the furore stirred up by the publication of The Origin of Species has Genetics been so prominent in the headlines. Of all sciences which are likely to make changes in our lives in the near future outside the area of microelectronics, no science seems more likely than genetics to have profound effects. At the conclusion of this course, you should understand how genetics is of direct relevance to our lives and you should be able to discuss intelligently newspaper stories which are sometimes poorly written, more usually poorly edited, and are frequently based on over optimism by the researchers concerned. You should also, of course, have received enough information to enable you to study with confidence third year courses in human genetics.

In this course we will attempt to impart some basic principles of the subject (which have not changed since Mendel was rediscovered at the turn of the century) and to show how the techniques of "the new genetics" have revolutionised the subject.

Genetics in the news:

There are a number of headline catching themes, some of which are discussed below.

• DNA fingerprinting

  In 1984 sequences of DNA were discovered which were present at many sites in the genome and which varied in the numbers of copies present at any one location. Human fingerprints though composed of only a few basic elements, lines whorls and loops, are unique to any individual. In the same way, the pattern of variation of these simple DNA elements is sufficient to mark each human individual uniquely (with the exception of identical twins). The added advantage is that any fragment of tissue from which DNA can be extracted, (and this can be as small as a dried drop of blood, or a single hair root) is enough to identify the human from which it originated. A recent high profile trial in which DNA evidence featured was the O.J.Simpson trial. In this case although DNA tests established beyond reasonable doubt the identity of various blood samples, enough questions remained as to how the blood came to be present to allow the defendant to be acquitted. Because the DNA variation is inherited, following the rules of Gregor Mendel which Steve Jones will discuss in lecture 2, it is also possible to use DNA fingerprinting to establish the relationships between individuals. One of the earliest such uses was in an immigration case to prove that a boy desiring entry to the UK was indeed the son of his mother who was resident here.

  Sir Alec Jeffreys, inventor of DNA fingerprinting

   

• Facial features

  "Forensic scientists will be able to predict a criminal's facial features from a hair root at the scene of the crime" - recent news story. Should we believe this headline? In fact, since the work was going on here at UCL, and since I and my family were some of the experimental guinea pigs, I feel fairly confident to report that, as so often, the position has been overstated by journalists in search of a good headline. Nevertheless, studies were underway to try to find measurable components of facial shapes which are controlled by the action of single genes. The type of feature which can be examined is sometimes subtle and can only be revealed by computer imaging techniques. However, some features can be much more obvious such as the prominent cleft in the chins of actors Kirk Douglas, his son Michael, and Michael's son Dylan.

   

  Kirk	Michael	Dylan

  Once such features are found then the genes controlling their appearance can be sought using in the first instance genetic linkage analysis which features in lectures 17 and 18

Normal human variation

Human genetics is concerned with the causes and alleviation of disease. However, an important part of the subject is the study of normal human variation, if only to disprove that there is any such thing as a "true Aryan" genetic type. (That name incidentally only means the descendent of a person who spoke the original Aryan language). There are many traits which are the products of variation in the forms of a single gene present in different individuals. Some examples include:

• “uncombable hair” - wild tangly hair with a triangular cross section and a longitudinal groove
• “woolly hair” - hair which forms tight curls
• ear lobes - attached or unattached
• ability to bend the first joint of the thumb back at a right angle
• ability to curl the tongue into a U section Everybody knows that this is inherited in a very simple way. But everyone is wrong. The evidence is actually very weak and it is quite likely that this is not a genetic trait at all! See the web page by Robert Huskey
• teeth present at birth - King Louis XIV of France was born in this way, much to the distress of his wet nurses it is said.
• colour blindness - there are several forms but the most common, affecting about one male in twelve, is deuteranopia, the inability to distinguish between red and green. It is caused by a missing gene which codes for one of the visual receptor pigments.  A good website test is here.

Genes can affect behaviour. In some cases we can begin to understand why because the gene in question is responsible for the production of a neurotransmitter or receptor. Other cases are so bizarre that we cannot even begin to guess what is the underlying cause.

Examples of "behavioural" genes include:

• Tourette syndrome - This inherited condition is very variable in its severity. The symptoms vary from no more than minor patterns of repetitive behaviour, motor ticks, to the most notorious symptom, an uncontrollable involuntary urge to utter swearwords and obscenities.
• “The jumping Frenchmen of Maine” - These curiously named people are probably all descendants of a French immigrant to America in the 18th century. They have an exaggerated startle reflex (they literally "jump") and are liable to obey any abruptly uttered command however dangerous or foolish it may be. New York neurologist George Beard visited the area around Moosehead Lake in Northern Maine in 1880. One of his subjects was sitting, cutting his tobacco with a knife and Beard startled him by striking his shoulder and shouting “throw it.” “Almost as quick as the explosion of a pistol, he threw the knife, and it struck the beam opposite; at the same time he repeated the order, ‘throw it’ with a certain cry as of terror or alarm” A similar condition known as ‘latah’is found in Malaysia.
• Monoamine oxidase deficiency - Monoamine oxidase is an enzyme which acts to destroy certain neurotransmitters such as dopamine. There is an association between deficiency for this enzyme (because of a gene mutation) and the committal of acts of criminal violence. Inherited genes for bad behaviour such as this one have been attempted as a defence in cases of criminal violence. See the recent Wellcome News report. In Georgia, Stephen Mobley has now been executed after the Georgia Supreme court rejected his appeal based on the the notion that his defence attorneys had been negligent to attempt this strategy for a plea of mitigation rather than one based on an abused childhood in a dysfunctional family.

Ultimately, because almost all genes code for enzyme products, mutant genes give rise to their effects through the altered action of an enzyme. In some of the cases above we can guess what the responsible enzyme might be but in others we have no idea. In the cases below we have a clear understanding of the biochemical defect. In some cases this has led to either a cure or an alleviation.

examples of biochemical deficiencies:

• Phenylketonuria - is caused by the absence of an enzyme which converts phenylalanine to tyrosine. The result is a build up of phenylalanine in the blood to a level where it causes brain damage in infants. Excess phenylalanine is converted into several metabolites and which are excreted into urine where they cause a mousy smell. Understanding the condition has led to a treatment. Patients must be placed on a diet with very little phenylalanine until they are teenagers. The diet must be started within a few weeks of birth, the earlier the better. Everyone born in the UK since the 1950s has been screened within a day or two of birth to test for the presence of this disease. See these notes from a medical genetics lecture
• favism - an abnormal sensitivity to beans which cause a haemolytic anaemia in patients. Even to smell the flowers of the bean may be enough to trigger an attack. This disease is commoner in the Mediterranean region and was known to Pythagoras who exhorted his pupils to avoid beans. It is caused by deficiency for the enzyme glucose-6-phosphate dehydrogenase. Here is a link to a well presented web site to advise people who have this enzyme deficiency.
• Adenosine deaminase deficiency - causes a complete failure of the immune system. It is one of the few diseases which have been successfully treated by gene therapy. Bone marrow cells from patients have been removed, a working gene has been placed into them and the cells have been replaced restoring the immune system. A family with an inherited deficit for this enzyme will be encountered in the "biochemistry quiz". Another well written page can be found here.

Although Online Mendelian Inheritance in Man, OMIM, lists 9530 characteristics for which there is an established gene locus, there are many more characteristics which do not conform to this simple pattern because they are the result of the aggregate effects of several variable genes and also of interaction with the environment.

"The gene for ....... has been cloned!"

We often seem to hear this. Much to my relief (after working on the project for ten years!) I was finally able to utter these words myself in 1997 about the gene TSC1 which is responsible for a genetic disease, Tuberous sclerosis. What is meant by this statement? And how will it help patients? We will go into fuller detail in lectures 7 and 14. For the moment, suffice it to say that when we have identified a mutant gene by "cloning" it, we can often immediately deduce something about its protein product's structure and make a reasonable guess as to its function (see for example the cystic fibrosis story later on). Also, we are able to look for the mutation(s) which may be present in any family with the immediate benefit of being able to detect whether unaffected members of the family are "carriers" for instance or to be able to carry out antenatal or even preimplantation testing of embryos.

The Human Genome Project (HGP) is a huge international effort to find out the complete DNA sequence of the human genome. The project does not stop there, the 3 billion nucleotides has to be annotated and the detailed structure of each gene has to be aligned to the genomic sequence. It has been announced that the entire DNA sequence of the human genome has been completed. This is an exageration but nevertheless is close to the truth. In the next few years more and more "disease" genes are going to be identified based on HGP data. In 1997, the identification both of genes responsible for many cases of breast cancer and the Tuberous sclerosis gene mentioned above were directly aided by the DNA sequence data of the HGP.

Genetics in the near future

One benefit of identifying a genetic disease gene is the potential to offer "gene therapy" - the replacement of the defective gene with a new, functional copy. This is by no means an easy procedure and as yet there have been few successes. However, in the next ten years we will see big advances in our abilities to treat some of the common genetic diseases such as Duchenne Muscular Dystrophy by gene therapy. Gene therapy is also being considered as an approach to fighting cancers and even HIV infection.

A newt can regrow an amputated limb. It would be convenient if humans could also regenerate damaged or missing tissues and organs. The "cloning" of 'Dolly' the sheep from one single cell of adult breast tissue has brought this exciting possibility one step nearer.

The human genome project is going on to consider normal human variation. This may enable us to predict the response of individuals to particular therapeutic drugs. Or to predict those individuals susceptible to drug or alcohol dependency. Or to Alzheimer's disease, or to various forms of cancer.

You should be aware of the potential for harm in the human genome project. A potential exam question: "As well as for beneficial use, our ability to predict individuals at risk of drug dependency or of cancer has potential for misuse. Discuss"