Genetic probes are mainly used in antenatal diagnosis of genetic disorders, and in investigating whether people with a family history of a genetic disorder carry the defective gene themselves.
Genes carry, in coded form, the detailed speci?cations for the thousands of kinds of protein molecules required by the cell for its existence, for its enzymes, for its repair work and for its reproduction. These proteins are synthesised from the 20 natural AMINO ACIDS, which are uniform throughout nature and which exist in the cell cytoplasm as part of the metabolic pool. The protein molecule consists of amino acids joined end to end to form long polypeptide chains. An average chain contains 100–300 amino acids. The sequence of bases in the nucleic acid chain of the gene corresponds in some fundamental way to the sequence of amino acids in the protein molecule, and hence it determines the structure of the particular protein. This is the genetic code. Deoxyribonucleic acid (see DNA) is the bearer of this genetic information.
DNA has a long backbone made up of repeating groups of phosphate and sugar deoxyribose. To this backbone, four bases are attached as side groups at regular intervals. These four bases are the four letters used to spell out the genetic message: they are adenine, thymine, guanine and cystosine. The molecule of the DNA is made up of two chains coiled round a common axis to form what is called a double helix. The two chains are held together by hydrogen bonds between pairs of bases. Since adenine only pairs with thymine, and guanine only with cystosine, the sequences of bases in one chain ?xes the sequence in the other. Several hundred bases would be contained in the length of DNA of a typical gene. If the message of the DNA-based sequences is a continuous succession of thymine, the RIBOSOME will link together a series of the amino acid, phenylalanine. If the base sequence is a succession of cytosine, the ribosome will link up a series of prolines. Thus, each amino acid has its own particular code of bases. In fact, each amino acid is coded by a word consisting of three adjacent bases. In addition to carrying genetic information, DNA is able to synthesise or replicate itself and so pass its information on to daughter cells.
All DNA is part of the chromosome and so remains con?ned to the nucleus of the cell (except in the mitochondrial DNA). Proteins are synthesised by the ribosomes which are in the cytoplasm. DNA achieves control over pro-tein production in the cytoplasm by directing the synthesis of ribonucleic acid (see RNA). Most of the DNA in a cell is inactive, otherwise the cell would synthesise simultaneously every protein that the individual was capable of forming. When part of the DNA structure becomes ‘active’, it acts as a template for the ribonucleic acid, which itself acts as a template for protein synthesis when it becomes attached to the ribosome.
Ribonucleic acid exists in three forms. First ‘messenger RNA’ carries the necessary ‘message’ for the synthesis of a speci?c protein, from the nucleus to the ribosome. Second, ‘transfer RNA’ collects the individual amino acids which exist in the cytoplasm as part of the metabolic pool and carries them to the ribosome. Third, there is RNA in the ribosome itself. RNA has a similar structure to DNA but the sugar is ribose instead of deoxyribose and uracil replaces the base thymine. Before the ribosome can produce the proteins, the amino acids must be lined up in the correct order on the messenger RNA template. This alignment is carried out by transfer RNA, of which there is a speci?c form for each individual amino acid. Transfer RNA can not only recognise its speci?c amino acid, but also identify the position it is required to occupy on the messenger RNA template. This is because each transfer RNA has its own sequence of bases and recognises its site on the messenger RNA by pairing bases with it. The ribosome then travels along the chain of messenger RNA and links the amino acids, which have thus been arranged in the requisite order, by peptide bonds and protein is released.
Proteins are important for two main reasons. First, all the enzymes of living cells are made of protein. One gene is responsible for one enzyme. Genes thus control all the biochemical processes of the body and are responsible for the inborn di?erence between human beings. Second, proteins also ful?l a structural role in the cell, so that genes controlling the synthesis of structural proteins are responsible for morphological di?erences between human beings.... genetic code
The options for individuals would include taking no action; modifying their behaviour; or taking some form of direct action. For those at risk of having an affected child, where prenatal diagnosis is available, this would involve either carrying on with reproduction regardless of risk; deciding not to have children; or deciding to go ahead to have children but opting for prenatal diagnosis. For an adult-onset disorder such as a predisposition to ovarian cancer, an individual may choose to take no action; to take preventive measures such as use of the oral contraceptive pill; to have screening of the ovaries with measures such as ultrasound; or to take direct action such as removing the ovaries to prevent ovarian cancer from occurring.
There are now regional genetics centres throughout the United Kingdom, and patients can be referred through their family doctor or specialists.... genetic counselling
Already genetic engineering is contributing to easing the problems of diagnosis. DNA analysis and production of MONOCLONAL ANTIBODIES are other applications of genetic engineering. Genetic engineering has signi?cantly contributed to horticulture and agriculture with certain characteristics of one organism or variant of a species being transfected (a method of gene transfer) into another. This has given rise to higher-yield crops and to alteration in colouring and size in produce. Genetic engineering is also contributing to our knowledge of how human genes function, as these can be transfected into mice and other animals which can then act as models for genetic therapy. Studying the effects of inherited mutations derived from human DNA in these animal models is thus a very important and much faster way of learning about human disease.
Genetic engineering is a scienti?c procedure that could have profound implications for the human race. Manipulating heredity would be an unwelcome activity under the control of maverick scientists, politicians or others in positions of power.... genetic engineering
Genetic screening is proving to be a controversial subject. Arguments are developing over whether the results of such screenings should be made available to employers and insurance companies – a move that could have adverse consequences for some individuals with potentially harmful genetic make-ups. (See GENES; GENETIC DISORDERS.)... genetic screening
Dominant genes A dominant characteristic is an e?ect which is produced whenever a gene or gene defect is present. If a disease is due to a dominant gene, those affected are heterozygous – that is, they only carry a fault in the gene on one of the pair of chromosomes concerned. A?ected people married to normal individuals transmit the gene directly to one-half of the children, although this is a random event just like tossing a coin. HUNTINGTON’S CHOREA is due to the inheritance of a dominant gene, as is neuro?bromatosis (see VON RECKLINGHAUSEN’S DISEASE) and familial adenomatous POLYPOSIS of the COLON. ACHONDROPLASIA is an example of a disorder in which there is a high frequency of a new dominant mutation, for the majority of affected people have normal parents and siblings. However, the chances of the children of a parent with the condition being affected are one in two, as with any other dominant characteristic. Other diseases inherited as dominant characteristics include spherocytosis, haemorrhagic telangiectasia and adult polycystic kidney disease.
Recessive genes If a disease is due to a recessive gene, those affected must have the faulty gene on both copies of the chromosome pair (i.e. be homozygous). The possession of a single recessive gene does not result in overt disease, and the bearer usually carries this potentially unfavourable gene without knowing it. If that person marries another carrier of the same recessive gene, there is a one-in-four chance that their children will receive the gene in a double dose, and so have the disease. If an individual sufferer from a recessive disease marries an apparently normal person who is a heterozygous carrier of the same gene, one-half of the children will be affected and the other half will be carriers of the disease. The commonest of such recessive conditions in Britain is CYSTIC FIBROSIS, which affects about one child in 2,000. Approximately 5 per cent of the population carry a faulty copy of the gene. Most of the inborn errors of metabolism, such as PHENYLKETONURIA, GALACTOSAEMIA and congenital adrenal hyperplasia (see ADRENOGENITAL SYNDROME), are due to recessive genes.
There are characteristics which may be incompletely recessive – that is, neither completely dominant nor completely recessive – and the heterozygotus person, who bears the gene in a single dose, may have a slight defect whilst the homozygotus, with a double dose of the gene, has a severe illness. The sickle-cell trait is a result of the sickle-cell gene in single dose, and sickle-cell ANAEMIA is the consequence of a double dose.
Sex-linked genes If a condition is sex-linked, affected males are homozygous for the mutated gene as they carry it on their single X chromosome. The X chromosome carries many genes, while the Y chromosome bears few genes, if any, other than those determining masculinity. The genes on the X chromosome of the male are thus not matched by corresponding genes on the Y chromosome, so that there is no chance of the Y chromosome neutralising any recessive trait on the X chromosome. A recessive gene can therefore produce disease, since it will not be suppressed by the normal gene of the homologous chromosome. The same recessive gene on the X chromosome of the female will be suppressed by the normal gene on the other X chromosome. Such sex-linked conditions include HAEMOPHILIA, CHRISTMAS DISEASE, DUCHENNE MUSCULAR
DYSTROPHY (see also MUSCLES, DISORDERS OF – Myopathy) and nephrogenic DIABETES INSIPIDUS.
If the mother of an affected child has another male relative affected, she is a heterozygote carrier; half her sons will have the disease and half her daughters will be carriers. The sister of a haemophiliac thus has a 50 per cent chance of being a carrier. An affected male cannot transmit the gene to his son because the X chromosome of the son must come from the mother; all his daughters, however, will be carriers as the X chromosome for the father must be transmitted to all his daughters. Hence sex-linked recessive characteristics cannot be passed from father to son. Sporadic cases may be the result of a new mutation, in which case the mother is not the carrier and is not likely to have further affected children. It is probable that one-third of haemophiliacs arise as a result of fresh mutations, and these patients will be the ?rst in the families to be affected. Sometimes the carrier of a sex-linked recessive gene can be identi?ed. The sex-linked variety of retinitis pigmentosa (see EYE, DISORDERS OF) can often be detected by ophthalmoscopic examination.
A few rare disorders are due to dominant genes carried on the X chromosome. An example of such a condition is familial hypophosphataemia with vitamin-D-resistant RICKETS.
Polygenic inheritance In many inherited conditions, the disease is due to the combined action of several genes; the genetic element is then called multi-factorial or polygenic. In this situation there would be an increased incidence of the disease in the families concerned, but it will not follow the Mendelian (see MENDELISM; GENETIC CODE) ratio. The greater the number of independent genes involved in determining a certain disease, the more complicated will be the pattern of inheritance. Furthermore, many inherited disorders are the result of a combination of genetic and environmental in?uences. DIABETES MELLITUS is the most familiar of such multi-factorial inheritance. The predisposition to develop diabetes is an inherited characteristic, although the gene is not always able to express itself: this is called incomplete penetrance. Whether or not the individual with a genetic predisposition towards the disease actually develops diabetes will also depend on environmental factors. Diabetes is more common in the relatives of diabetic patients, and even more so amongst identical twins. Non-genetic factors which are important in precipitating overt disease are obesity, excessive intake of carbohydrate foods, and pregnancy.
SCHIZOPHRENIA is another example of the combined effects of genetic and environmental in?uences in precipitating disease. The risk of schizophrenia in a child, one of whose parents has the disease, is one in ten, but this ?gure is modi?ed by the early environment of the child.... genetic disorders
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