genetics, human

genetics, human Surely, people must always have been curious about how physical traits and aspects of character are passed down from generation to generation. But, until the middle of the nineteenth century, thoughts about heredity were extremely confused. Indeed, throughout the medieval period in Europe, all organisms were thought to grow from replicas created by God at the beginning of the universe. In these terms, Eve literally contained within her ovaries the whole of the rest of the human race, generation after generation of miniatures packed one inside the other, each waiting for an act of fertilization. Even after the discovery of sperm this ‘pre-formation hypothesis’ was not discarded, and some held that an individual was pre-formed in the sperm, and simply nurtured by the mother. Towards the end of the nineteenth century, anatomists found that they could see thread-like objects, which could be stained with coloured dyes, inside dividing cells. They called these structures chromosomes, and later suggested that they might carry heritable information from cell to cell. At about the same time, based on a series of breeding experiments on ornamental plants, Gregor Mendel formulated the concept that later became known as the gene — a unit of heredity, passed from generation to generation in a way that follows simple mathematical laws. These disparate observations were finally unified during the middle of the twentieth century with the discovery that genetic information carried by chromosomes resides in the double helix of deoxyribonucleic acid (DNA), first described by Francis Crick and James Watson. DNA has the remarkable property of self-replication — it copies itself faithfully each time a cell divides. It was soon clear that genes consist of lengths of DNA, and that their major function is to direct the synthesis of proteins, ensuring that the structure of proteins is always the same and that they are made in the right amount in the right place at the right time.

Proteins are made up of 20 different amino acids, and the extensive differences in their structures — from the fluid haemoglobin of our blood to the tough keratin of our skin — reflect differences in the number and order of amino acids in their constituent peptide chains. The information responsible for selecting and arranging the amino acids in these peptide chains is encoded by the order of the four bases that make up each strand of the DNA helix — adenine (A), guanine (G), cytosine (C), and thymine (T). Each individual amino acid is represented by a unique three-letter ‘word’, spelled out by a particular sequence of three bases in the gene. Even more remarkable, the code is the same throughout almost all of the animal kingdom.

In recent years it has been feasible to isolate human DNA, cut it into pieces, and insert these into bacterial cells, where they grow and multiply. In this way, it has been possible to prepare ‘libraries’ containing most of a person's genes (the ‘genome’), to isolate individual genes, and to examine their structure and function.

The human genome

Normal human cells (except eggs and sperm) have 46 chromosomes, arranged in pairs, one member of each pair coming from each parent. Twenty-two pairs are called autosomes and the other pair are the sex chromosomes, designated X and Y. Females have two X chromosomes (one from the mother, the other from the father) while males have one maternal X and one paternal Y sex chromosome. ‘Germ cells’ (sperm and eggs) are unusual in having only 23 unpaired chromosomes, each of which is created by a process in which maternal and paternal chromosome pairs become closely wound round each other in the germinal cells that give rise to the eggs and sperm. The closer together a pair of genes are on the same chromosome the less chance they will have to cross over from one to another. Hence the number of crossovers is a measure of the distance between genes. Indeed, many years ago it was realized that if two different genes are on the same chromosome, and particularly if they are close together, they will tend to be inherited together. They are then said to be linked.

Through studies of individual families, and later by generating genetic markers by analysing DNA itself, geneticists have been able to obtain a ‘linkage map’ of the human chromosomes, assigning many different genes to particular chromosomes. In essence, this looks like a road map in which the towns (genes) are clearly marked, although it tells us nothing about the state of the roads (DNA) in between. Early in the new millennium, as part of the Human Genome Project, this work will be extended, and the complete sequence of all the bases that make up the 30–40 000 genes of the human genome will be worked out.

Mutations and human diversity

Occasionally, during cell division, when new strands of DNA are synthesized, a different base is inserted, by mistake, into a gene. This is called a mutation. Without this slight imperfection in the mechanism of DNA replication we would still be swimming round in the primeval soup. For, while many mutations, or polymorphisms, are neutral (that is, the slight changes in the proteins produced have no effect on the function of the organism), others may be beneficial. Although it is still a topic of some controversy, there is general agreement that this is the way in which Darwinian evolution has occurred; the occurrence of mutations occasionally leads to changes in organisms that enable them to adapt better to their current environments, or to new ones. While this may not be the only mechanisms for the gradual emergence of different species there is compelling evidence that it has been a major force behind human evolution. The existence of polymorphisms, and our new-found ability to analyse DNA with ease, are providing major insights into the origins of human beings, the ways in which different races have evolved, and, indeed, the whole basis of human diversity. As well as the DNA that resides in the nuclei of our cells, our mitochondria, the chemical dynamos that energize the cell, have their own DNA. Since mitochondrial DNA is all derived from our mothers, it is of particular value in tracing our evolutionary past in a direct line.

Harmful mutations

Unfortunately, not all mutations are simply neutral or even beneficial; occasionally they cause disease, because they affect some vital process in the body. Inherited diseases due to single defective genes usually follow Mendelian patterns of inheritance. Some are said to be ‘dominant’ because they occur with the inheritance of a single defective gene on only one of the pair of chromosomes. Others are ‘recessive’ — it is necessary to inherit the mutant gene from both parents to have the disease. ‘Carriers’, or ‘heterozygotes’, are individuals who have a recessive disease gene on only one of the pair of chromosomes, and who therefore are not affected by the disease but can pass it on their children if they mate with a partner who is also a carrier. Yet other diseases are sex-linked; that is, they are carried on the X chromosome and, if recessive, are not expressed in females (who have two X chromosomes) but may be transmitted to a son to whom the mother passes down an X chromosome bearing the mutant gene.

Although there are over 4000 single-gene (monogenic) disorders, most are very rare because they produce such severe disorders that they usually prevent reproduction, and therefore cannot disseminate within a population. However, a few monogenic diseases — the inherited anaemias, sickle cell anaemia and thalassaemia, for example — are extremely common. This is because carriers are made more resistant to malaria by the presence of the mutation in their cells. Therefore they tend to survive slightly longer than non-affected individuals in malarious countries, and hence have more children. In this way, the frequency of the disease increases until it reaches an equilibrium, at which it is balanced by the loss from the community of severely affected homozygotes (those who have received the defective gene from both parents). This kind of interaction may explain why cystic fibrosis, a disease that affects the lung and bowel, is so common in European populations: the mutation may have made carriers resistant to one or more of the severe infections that swept through Europe in the past, possibly cholera.

Many of the common diseases of Western society — heart attacks, stroke, diabetes, and dementia, for example — are the result of complex interactions between our genetic make-up and the environment. These diseases do not run predictably through families like single-gene disorders, but there may be a familial tendency, which probably reflects the action of several different genes combined with the effects of lifestyle. Other common diseases, cancer in particular, also reflect interactions between our genes and environments.

Many cancers result from the acquisition of mutations in a family of genes called oncogenes, which normally serve important housekeeping functions for our cells. They tell the cells how and when to divide, identify those with damaged DNA and either ensure that it is repaired or programme the potentially harmful cells to die, and regulate how they interact with their fellow cells. Cancer appears to be due to the acquisition of mutations in these genes; the frequency with which this occurs may be related both to exposure to environmental mutagens such as tobacco smoke, and to chemical agents that are by-products of our metabolism.

Other genetic defects are responsible for congenital malformation and for mental retardation. Sometimes these conditions result from major chromosomal abnormalities, involving either their numbers or structure. However, many malformations of this type can be traced to the action of single mutant genes — an observation that is providing clues about the mechanisms that control human development.

Manipulating the human genome

Our new-found ability to analyse human DNA, which has led to the discovery of the mutations that cause many monogenic diseases, means that they can be identified in carriers and appropriate counselling and advice can be given. It is also now possible to diagnose most of these diseases prenatally by chorionic villus sampling — removing and genetically analysing a tiny amount of tissue from round the fetus between 9 and 13 weeks of pregnancy. This allows prenatal diagnosis, and gives the mother the option of termination of a pregnancy if the fetus has a particularly severe condition. Soon it may be feasible to correct genetic disease or alter the genetic machinery of cells in a way that may be used to treat cancer or other acquired diseases. The treatment of single-gene disorders can, in principle, be approached by either germ-cell gene therapy (in which a ‘good’ gene is injected into a fertilized egg and therefore distributes among all the cells of the body, including future germ cells) or somatic-cell therapy (in which the gene is inserted into a particular cell population in the body of one individual — the stem cells of the bone marrow for example). Although germ cell gene therapy offers the prospect of eliminating disease from a family for all future generations, it is currently not permitted because of the possible risk of making damaging errors to the genes. On the other hand, somatic-cell gene therapy poses no major ethical problems beyond those of any form of tissue or organ transplantation. Human genes can also be inserted into cultured cells or whole animals (a process called transgenesis) in order for the recipient cells or animals to produce molecules of therapeutic value — insulin to treat diabetes, or clotting factors to treat haemophilia, for example.

Biological determinism and the future

The remarkable developments in human genetics over the last half of the twentieth century led to the notion that most of people's mental achievements, personality traits, and behaviour can be explained by their genetic make-up, shaped in the past by Darwinian evolution. Much of this thinking ignores the important role of the environment in making us what we are. But because it carries such conviction, and because it is assumed that we will gradually learn how to manipulate our genetic make-up, this view is causing considerable concern about the possible resurgence of the eugenics movement — a philosophy for the ‘betterment’ of mankind by selective breeding, which stimulated the study of human genetics at the end of the nineteenth century. Although it will be a long time before we know the relative role of nature and nurture in shaping human beings, there is little doubt that our ability to modify the human genome will increase dramatically during the new millennium, and society will be faced with the dilemma of deciding how far it wishes to shape its destiny in this way.

D. J. Weatherall

Bibliography

Bodmer, W. and and McKie, R. (1994). The book of man. Little, Brown and Co, London.
Bowdler, P. J. (1989). The Mendelian revolution. Johns Hopkins University Press, Baltimore.
Jones, S. (1993). The language of the genes. Harper Collins, London.
Lewin, B. (1997). Genes VI. Oxford University Press, Oxford.
Raskó, I. and and Downes, C. S. (1995). Genes in medicine. Chapman and Hall, London.

See also evolution, human; gene therapy; heredity.