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. As doctors you should understand how genetics is of direct relevance to the lives of patients and you will be expected to deliver advice to patients worried or excited by newspaper stories (which are sometimes poorly written, more usually poorly edited, or based on overoptimism by the researchers concerned.)
In this series of lectures I 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.
There are a number of headline catching themes, some of which are discussed below.
In 1985 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. The latest high profile trial in which DNA evidence featured was the O.J.Simpson trial. However, 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. This week we heard in the news of a murderer being convicted because of the DNA evidence obtained from minute bloodstains left on the clothes of his victim - herself a doctor at the Royal Free.
Because the DNA variation is inherited, following the rules of Gregor Mendel which we 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.
"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 is going on here at UCL, and since I and my family are 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 are 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 but can be much more obvious such as the prominent cleft in the chins of actors
Kirk Douglas and his son, Michael.
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 8 and 9
Working in the Galton Laboratory, the first laboratory set up specifically to study human inheritance, and doing research connected with the inheritance of human genetic disease and with the human genome project, I am as guilty as anyone of neglecting the tremendous importance of genetics to agriculture. You may feel that as tomorrow's doctors you too can safely neglect this area. However, as a figure of authority and with your scientific training you are bound to meet from time to time requests for information such as "Is it safe to eat genetically modified food?". In lecture 5 we will consider the techniques of molecular genetics as applied to both human genetics and to agriculture so that even if you lack the detailed information to answer the above question, at least you will understand what processes were involved in creating a "genetically engineered" strain of plants or animals.
Some of the products which have made it to the supermarket shelves include:
Last year Tommy Archer was acquitted in Borchester Crown Court for destroying a field full of genetically modified oilseed rape. Was he right or wrong to fear this crop? (Apologies to those of you who do not follow radio soap opera!) This year true life followed fiction as Lord Peter Melchett was found not guilty on similar charges.
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:
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:
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:
Although Online Mendelian Inheritance in Man, OMIM, lists 8649 characteristics for which there is some evidence of straightforward, single gene inheritance, 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.
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 lecture 5. 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" (defined later) 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. The entire DNA sequence of the human genome is scheduled for completion in 2004 and already useful information is starting to be generated. 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.
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.
We begin with consideration of the mechanics of gene inheritance. You should already be aware that:
It takes many cell divisions to make a person from a single celled egg. In each of those divisions all the genes must be replicated and passed to each daughter cell. For the remainder of this lecture we will concentrate on the process of cell division mitosis and on the structures known as chromosomes.
The act of mitosis can be conveniently divided into four phases.
Chromosomes serve to manoeuvre DNA through the difficulties of cell division where something like two metres of DNA has to be moved through a distance of only about 100 Ám and be separated from a similar amount of DNA moving the other way.
Humans have 23 pairs of chromosomes. Twenty two pairs, the autosomes, are the same in either sex and are numbered from 1 - 22 in order of diminishing size. One pair, the sex chromosomes are either a pair of X chromosomes (in females) or an X and the very much smaller Y chromosome (in males). One complete set of chromosomes i.e. autosomes 1-22 and a sex chromosome is known as a haploid set. Cells which contain two complete sets (i.e. most cells except for mature germ cells) are diploid. Each chromosome contains its own unique sequence of DNA. Consequently, when the chromosomal DNA and its associated histone and non-histone protein is at its most densely packed (i.e. at mitotic metaphase) it adopts a shape which is slightly different from any other chromosome.
Cytogeneticists study chromosomes microscopically. Cells are treated with a drug which prevents the spindle fibres forming. The chromosomes continue to be prepared for mitosis but because the spindle has not formed the division remains blocked and cells accumulate at metaphase. The cells can then be "fixed" i.e. treated with a chemical which denatures proteins causing the structures to be preserved, and then burst open on a microscope slide. After gentle treatment with a very small amount of proteinase, the chromosomes are stained. Each chromosome reveals a characteristic pattern of alternating dark and light bands which reflects in some way its underlying architecture. On the right for example is the ideogram which represents the characteristic banding pattern of chromosome 9.
The "chromosome spread" can be photographed, individual chromosomes cut out and paired and displayed as shown below.
The sum of all the chromosome information is known as a karyotype.
All human chromosomes have two arms, the short arm is referred to as the p arm and the long arm as the q. The position of the primary constriction (another name for the centromere) defines whether the chromosome is metacentric (two substantial arms) or acrocentric (one very tiny arm and one which contains almost all the DNA). The acrocentric chromosomes are numbers 13, 14, 15, 21 and 22. At each end of the chromosome is a telomere, a structure designed to avoid problems with DNA replication right to the end of a linear molecule. Acrocentric chromosome short arms sometimes hardly seem to be attached, they can be linked via a short stalk known as a secondary constriction. The tiny short arm, bobbing about at a distance is known as a satellite.
The following are alternatives, read as many as you want - but at least one!