INTRODUCTION
The richness of nature is its variety. The world around us is teeming with life - immense varieties of trees, flowers, insects, birds, reptiles and mammals not to mention the countless varieties of bacteria and viruses. It can truly be said that variety is the spice of life. Underlying all this variety there is one common plan that forms the basis of all life. Genetics is the study of the basis of life and its infinite and self-perpetuating variety.
We only need to look at the people around us to realise the variation that is so often taken for granted. No two people are exactly alike unless they are identical twins. Some people are taller than others, some are dark skinned, some have blue eyes, some have fair hair and all have particular facial or other differences by which we recognise at a glance one person from another or identify people of different races. Yet these small differences in the facial appearance including the nose, lips, cheeks, ears and eyes are so notoriously difficult to describe. These are all examples of natural variation in humans. Similarly there are variations among cats, dogs, butterflies, roses and all living organisms.
This diversity among living organisms does not apply only to visible external characteristics but even more significantly to the biochemical structure of the molecules of which living organisms are made up. This biochemical diversity accounts for most of the variation observed among human beings, the visible external variations being only a small part of what makes human beings different from one another.
In spite of all this diversity there are also striking similarities. These are most marked among members of the same families indicating that these characteristics are inherited. However, the similarities extend much further. There are obvious similarities among members of the same species; thus all cats have certain common characteristics by which we can identify them as belonging to a particular species. There are also similarities among animals of different species: most animals have a heart, a circulation, and respiratory, excretory, feeding and reproductive organs. At the more fundamental molecular level we can identify similarities in the composition of bacteria, plants, animals and man. All living organisms, including man, are part of one fundamental biological system with an immense and almost infinite degree of variation.
Genetics is the study of this natural variation and how the characteristics of living organisms are transmitted from one generation to another. This is embodied in the genetic material that controls all the stages of development, growth and functioning of organisms. The genetic material is basically the same in all organisms and consists of DNA and RNA, the molecules that contain the secrets of life.
Among the variation that exists among organisms of the same species are characteristics that are deleterious and thus can be considered as diseases. Genetic diseases have always been considered to be among the most interesting variations, especially in man because of their serious implications. They have been predominant in the study of human genetics. From the genetics of disease conditions we are learning more and more about the molecules of the normal human body and the genes that control them. Genetics has been crucial in the understanding of many aspects of life including the molecular biology of cells, developmental mechanisms, ageing and evolution.
In recent years the most significant advance in genetics was the completion of Human Genome Project, which mapped out the complete genetic sequence on the human genome and the genomes of several other organisms. A genome is the total complement of genes present in an organism. The human genome contains the blueprint of human life. It was described by W.J. Clinton, President of the United States of America as "the language in which God created life …. the complexity, the beauty, the wonder of God's most divine and sacred gift.“
It is also the sequence that defines our identities. As pointed out by Richard Aedy (2000) “William Jefferson Clinton was famously caught out by it.” More significantly the Human Genome Project has opened up new avenues for investigating and understanding disease, for
establishing new approaches to treatment and prevention of disease, for the
control of transmission of human life, and for understanding the mechanisms of
normal and abnormal human development, and for gaining important
insights into evolution.
LANDMARKS IN THE HISTORY OF GENETICS
The history of genetics may be divided into three main stages during which evolved the concepts of modern genetics.
1. THE FOUNDATIONS OF GENETICS
This covers the period up to the end of the nineteenth century. Early ideas about the inheritance of characteristics, which existed since the time of Aristotle, were confused and unfounded. Even ideas about conception were based on speculation only. The following are some important persons who proposed new concepts that have become main landmarks in the history of genetics.
REINER DE GRAAF (1641 - 1673), a Dutch scientist who described the "Graafian follicle", recognised that the union of sperm and ovum was essential for conception. Previously it was thought that the sperm alone was necessary for conception, like a seed that was sown in the soil.
PIERRE LOUIS MAUPERTIUS (1720) studied pedigrees of families with polydactyly and albinism and showed that these conditions were inherited in different ways.
JOSEPH ADAMS (1814) an apothecary physician distinguished between different patterns of inheritance and between dominant and recessive characteristics.
GREGOR MENDEL (1822-1844), a Moravian monk of the Augustinian Order and a high school teacher was also a naturalist and a scientist. Like many contemporary scientists he performed experiments on the hybridisation of plants. His experiments performed on pea plants in the monastery garden were simple but were carried out scientifically. They were based on (i) careful selection of the organism to be studied (the pea plant which had many clearly contrasting characteristics); (ii) controlled methods studying only one characteristic at a time and (iii) keeping of accurate numerical records.
Mendel interpreted the results of his experiments and deduced two main principles known as Mendel’s laws of inheritance. The first law, also known as the principle of segregation, was that each characteristic was determined by a pair of "factors" (now termed genes) and each parent transmitted only one of the pair to the offspring. These two factors separated or segregated during the process of meiosis.
Mendel’s second law, or the principle of independent assortment, was that different characteristics were inherited independently of one another. These laws were later shown to apply to all organisms and formed the basis of classical genetics. However, several other factors, which are not included in these principles and at times even contradict them, are now known to control the inheritance of characteristics.
CHARLES DARWIN (1809 - 1882) was a medical doctor from Edinburgh but pursued his career as a naturalist who travelled around the world on a voyage of exploration, studying the similarities and differences in the characteristics of related organisms living in different natural habitats. He published his famous works "The Origin of Species by Natural Selection" and "The Descent of Man" as well as other publications. Although he was a contemporary of Mendel, and both of them studied characteristics of organisms, their works were not known to one another.
FRANCIS GALTON (1822 - 1911) first cousin of Charles Darwin and born in the same year as Gregor Mendel started his career as a medical student but later changed his mind and graduated in mathematics. He became interested in the inheritance of physique, mental abilities and special talents. He combined his interest in inheritance with mathematics and studied mathematically the frequency distributions of human characteristics in populations. He also performed studies on twins.
FRIEDRICH MIESCHER (1869) discovered that the cell nucleus was composed of a mixture of substances, which he called nuclein, and that the major component was deoxyribose nucleic acid (DNA)
2. THE GROWTH OF GENETICS
The significance of Mendel's laws was not recognised by his contemporaries but became evident 35 years later, just after the turn of the twentieth century. At this time other important events marked the progress of genetics:
SIR ARCHIBALD GARROD (1857-1936), a physician, made important contributions to the chemistry of diseases especially porphyria, cystinuria and alkaptonuria, noting their recurrence among sibs in the same family and the effect of consanguineous marriage. He introduced the term "inborn errors of metabolism" and the concept of "one gene, one enzyme" and thus opened the way to biochemical genetics, which became one of the most important aspects in the development of genetics.
THEODOR BOVERI and WALTER S. SUTTON in 1903 independently proposed the chromosome theory of inheritance, stating that the chromosomes carried the "hereditary factors" proposed by Mendel and that their behaviour during cell division provided an explanation for their segregation during meiosis.
In the twentieth century the fruit fly, Drosophila was the organism most extensively used in the study of genetics. It was extremely useful because it was easily bred in the laboratory, reproduced very rapidly (about 20 times in one year) and produced thousands of offspring that could be analysed. Besides, it had only four chromosome pairs that were exceptionally large in the salivary glands and showed a pattern of transverse bands on which individual genes could be localised.
THOMAS HUNT MORGAN is one of the most famous of the hundreds of scientists who worked on Drosophila. He described sex-linked characteristics that were manifest in the male flies. He is best known for proposing methods for estimating distances between genes located on the same chromosome through the phenomenon of recombination. The unit of gene distance, the centimorgan, is named after him. Morgan’s work opened up the important field of gene mapping.
Advances in human genetics did not parallel the great advances in the genetics of Drosophila since the beginning of the twentieth century. This was mainly due to (1) the inability to perform breeding experiments in man; (2) the very long generation time and (3) the small size and relatively large number of human chromosomes, which made their microscopic examination very difficult. However, several hundreds of human genes were known to exist through the visible characteristics they produced.
In the 1950s two great advances completed the phase of growth of classical genetics and paved the way for a new era of genetics.
J. D. WATSON and FRANCIS H. C. CRICK in 1953 proposed the molecular structure of DNA, which explained how the molecule could replicate itself and how the same molecule could represent an almost infinite variety of different genes. From then the gene could be visualised as a structural entity and was no longer an invisible hereditary particle that could be identified only by its effects on the characteristics of an organism. The discovery of the molecular structure of DNA thus paved the way for the study of the gene itself and the direct analysis of DNA in the new era of molecular genetics that was to follow.
TIJO and LEVAN devised a technique for the study of human chromosomes and established that the human chromosome number was 46. Earlier techniques were suitable for organisms that had few chromosomes but not for human chromosomes, which were small and numerous. This was immediately followed by the discovery of chromosomal abnormalities and marked the beginning of human cytogenetics. It was one of the most important advances that brought human and medical genetics into prominence.
3. THE NEW GENETICS
A new era of genetics began in the 1970s with the development of three new techniques, which together enabled the direct analysis and manipulation of genes. At this stage studies on DNA were performed mainly on bacteria as they had a very short generation time and very simple DNA. Most of the new discoveries arose from the study of bacterial genetics.
HAMILTON SMITH discovered that bacteria produced "restriction endonucleases", enzymes that had the ability to cut open the DNA molecule at specific sites.
ED SOUTHERN at Edinburgh University developed a technique by which specific genes could be isolated from the whole complement or genome of DNA. The process was called Southern blotting.
STANLEY COHEN at Stanford University developed the use of plasmids, which are naturally occurring circular loops of DNA capable of entering bacterial cells, as vectors for carrying foreign DNA into bacterial cells.
These three techniques of cutting, isolating and inserting genes form the basis of recombinant DNA technology, popularly called genetic engineering. They also formed the basis of modern genetic technology.
We are now on the threshold of a new era that promises the treatment of genetic diseases.
SOME BASIC DEFINITIONS
The genetic material is contained within the nucleus of all cells. It consists of extremely fine thread-like structures composed of DNA and associated proteins. Within it is stored the genetic information, a whole library of genes which constitute the genome.
These thread-like structures become visible as chromosomes during cell division as they gradually coil up and become thick and prominent.
For the purpose of analysis the
chromosomes can be arranged as a karyotype. They are
classified in order of decreasing size and according to their pattern of
bands. Chromosomes occur in pairs.
There are 23 pairs of chromosomes: 22 pairs of autosomes and one pair of sex chromosomes.
The sex chromosomes are XX in females and
XY in males.
The Y chromosome is much smaller than the X chromosome. It carries the genes responsible for the male sexual characteristics. The X chromosome carries genes that are not related to sex and are equally important in both males and females.
The genetic material is made of DNA. The DNA molecule consists of two spirally arranged chains in which each unit consists of a sugar (deoxyribose), a phosphate group and a nitrogenous base. The base can be Adenine, Guanine, Thymine or Cytosine (A,G,T or C).
A gene is a segment of DNA that carries a genetic message. One gene carries instructions for the synthesis of one protein or enzyme. Enzymes are the functioning units of the cell.
The g
enes are situated on the chromosomes.
A locus is the point on a chromosome at which a gene is situated.
Genes occur in pairs that occupy corresponding loci on a pair of chromosomes.
The genes at a locus are called alleles.
An individual is homozygous if the two alleles are identical e.g. AA or aa.
An individual is heterozygous if the two alleles are different e.g. Aa.
A A A a a a
Homozygous Heterozygous Homozygous
The genotype of an individual indicates the type of alleles present (heterozygous or homozygous).
The phenotype of an individual indicates the identifiable characteristics present in an individual. These may be visible or biochemical characteristics. Examples of phenotypic characteristics are eye colour, height, blood group.
A dominant characteristic is one that manifests itself in heterozygotes (i.e. only one gene is required for its manifestation in the phenotype).
A recessive characteristic is one that appears only in homozygotes (i.e. two identical alleles are required for its manifestation in the phenotype).
An X-linked gene is one that is situated on the X chromosome. An X-linked recessive characteristic is usually manifest in males while females are carriers of the gene. An X-linked dominant characteristic is manifest in both sexes.
The following is an example of an inherited trait for brown or blue eyes.
|
ALLELES |
B - gene for brown eyes b - gene for blue eyes |
||
|
GENOTYPE |
B B Homozygote |
B b Heterozygote |
b b Homozygote |
|
PHENOTYPE |
Brown eyes |
Brown eyes |
Blue eyes |
“Brown eyes” is the dominant characteristic because it appears in the heterozygote (Bb). “Blue eyes” is the recessive characteristic because it appears only in the homozygote (bb).
It is possible to work out how genes are inherited by constructing a Punnett square.
In this example both parents were heterozygous. The phenotypes of the offspring were 3 brown : 1 blue eyes. The genotypes of the offspring were 1 dominant homozygote (BB) : 2 heterozygote : 1 recessive homozygote (bb)
The inheritance of the phenotype can be illustrated as a pedigree.
The following pedigree shows inheritance of eye colour.
Males are represented by squares, females by circles.
The arrow indicates the propositus or proband i.e. the individual with a particular characteristic through whom the family came to be investigated. In this case the propositus was a boy with blue eyes.
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