One of 2 or more different forms of a gene that occupies a specific position on a chromosome (see gene; inheritance).
Gene therapy is currently used to treat disorders caused by a fault in a single recessive gene, when the defect can remedied by introducing a normal ALLELE. Treating disorders caused by dominant genes is more complicated. CYSTIC FIBROSIS is an example of a disease caused by a recessive gene, and clinical trials are taking place on the e?ectiveness of using LIPOSOMES to introduce the normal gene into the lungs of someone with the disorder. Trials are also underway to test the e?ectiveness of introducing tumour-suppressing genes into cancer cells to check their spread.
Gene therapy was ?rst used in 1990 to treat an American patient. Eleven European medical research councils (including the UK’s) recommended in 1988 that gene therapy should be restricted to correcting disease or defects, and that it should be limited to somatic cells. Interventions in germ-line cells (the sperm and egg) to e?ect changes that would be inherited, though technically feasible, is not allowed (see CLONING; HUMAN GENOME).... gene therapy
Genes fulfil these functions by directing the manufacture of proteins. Many proteins have a structural or catalytic role in the body. Others switch genes “on” or “off”. The genes that make these regulatory proteins are called control genes. The activities of control genes determine the specialization of cells; within any cell some genes are active and others idle, according to its particular function. If the control genes are disrupted, cells lose their specialist abilities and multiply out of control; this is the probable mechanism by which cancers form (see carcinogenesis; oncogenes).Each of a person’s body cells contains an identical set of genes because all the cells are derived, by a process of division, from a single fertilized egg, and with each division the genes are copied to each offspring cell (see mitosis; meiosis). Occasionally, a fault occurs in the copying process, leading to a mutation. The gene at any particular location on a chromosome can exist in any of various forms, called alleles. If the effects of an allele mask those of the allele at the same location on its partner chromosome, it is called dominant. The masked allele is recessive. (See also genetic code; inheritance.)... gene
HLA incompatibility causes the immune response, or rejection reaction, that occurs with unmatched tissue grafts. Strong associations between HLA and susceptibility to certain diseases – notably the AUTOIMMUNE DISORDERS such as rheumatoid arthritis, insulin-dependent diabetes, and thyrotoxicosis – have been described. Certain HLA antigens occur together more frequently than would be expected by chance (linkage disequilibrium), and may have a protective e?ect, conferring resistance to a disease. (See IMMUNITY.)... hla system
(See also inheritance; genetic disorders.)... homozygote
Sometimes during cell division chromosomes may be lost or duplicated, or abnormalities in the structure of individual chromosomes may occur. The surprising fact is the infrequency of such errors. About one in 200 live-born babies has an abnormality of development caused by a chromosome, and two-thirds of these involve the sex chromosomes. There is little doubt that the frequency of these abnormalities in the early embryo is much higher, but because of the serious nature of the defect, early spontaneous ABORTION occurs.
Chromosome studies on such early abortions show that half have chromosome abnormalities, with errors of autosomes being three times as common as sex chromosome anomalies. Two of the most common abnormalities in such fetuses are triploidy with 69 chromosomes and trisomy of chromosome 16. These two anomalies almost always cause spontaneous abortion. Abnormalities of chromosome structure may arise because of:
Deletion Where a segment of a chromosome is lost.
Inversion Where a segment of a chromosome becomes detached and re-attached the other way around. GENES will then appear in the wrong order and thus will not correspond with their opposite numbers on homologous chromosomes.
Duplication Where a segment of a chromosome is included twice over. One chromosome will have too little nuclear material and one too much. The individual inheriting too little may be non-viable and the one with too much may be abnormal.
Translocation Where chromosomes of different pairs exchange segments.
Errors in division of centromere Sometimes the centromere divides transversely instead of longitudinally. If the centromere is not central, one of the daughter chromosomes will arise from the two short arms of the parent chromosome and the other from the two long arms. These abnormal daughter chromosomes are called isochromosomes.
These changes have important bearings on heredity, as the e?ect of a gene depends not only upon its nature but also upon its position on the chromosome with reference to other genes. Genes do not act in isolation but against the background of other genes. Each gene normally has its own position on the chromosome, and this corresponds precisely with the positon of its allele on the homologous chromosome of the pair. Each member of a pair of chromosomes will normally carry precisely the same number of genes in exactly the same order. Characteristic clinical syndromes, due to abnormalities of chromosome structure, are less constant than those due to loss or gain of a complete chromosome. This is because the degree of deletion, inversion and duplication is inconstant. However, translocation between chromosomes 15 and 21 of the parent is associated with a familial form of mongolism (see DOWN’S (DOWN) SYNDROME) in the o?spring, and deletion of part of an X chromosome may result in TURNER’S SYNDROME.
Non-disjunction Whilst alterations in the structure of chromosomes arise as a result of deletion or translocation, alterations in the number of chromosomes usually arise as a result of non-disjunction occurring during maturation of the parental gametes (germ cells). The two chromosomes of each pair (homologous chromosomes) may fail to come together at the beginning of meiosis and continue to lie free. If one chromosome then passes to each pole of the spindle, normal gametes may result; but if both chromosomes pass to one pole and neither to the other, two kinds of abnormal gametes will be produced. One kind of gamete will contain both chromosomes of the pair, and the other gamete will contain neither. Whilst this results in serious disease when the autosomes are involved, the loss or gain of sex chromosomes seems to be well tolerated. The loss of an autosome is incompatible with life and the malformation produced by a gain of an autosome is proportional to the size of the extra chromosome carried.
Only a few instances of a gain of an autosome are known. An additional chromosome 21 (one of the smallest autosomes) results in mongolism, and trisomy of chromosome 13 and 18 is associated with severe mental, skeletal and congenital cardiac defects. Diseases resulting from a gain of a sex chromosome are not as severe. A normal ovum contains 22 autosomes and an X sex chromosome. A normal sperm contains 22 autosomes and either an X or a Y sex chromosome. Thus, as a result of nondisjunction of the X chromosome at the ?rst meiotic division during the formation of female gametes, the ovum may contain two X chromosomes or none at all, whilst in the male the sperm may contain both X and Y chromosomes (XY) or none at all. (See also CHROMOSOMES; GENES.)... sex chromosomes
Genes are organized into chromosomes in the cell nucleus. Genes controlling most characteristics come in pairs, 1 from the father, the other from the mother. Everyone has 22 pairs of chromosomes (called autosomes) bearing these paired genes, in addition to 2 sex chromosomes. Females have 2 X chromosomes; males have an X and a Y chromosome.
Most physical characteristics, many disorders, and some mental abilitiesand aspects of personality are inherited. The inheritance of normal traits and disorders can be divided into those controlled by a single pair of genes on the autosomal chromosomes (unifactorial inheritance, such as eye colour); those controlled by genes on the sex chromosomes (sex-linked inheritance, such as haemophilia); and those controlled by the combination of many genes (multifactorial inheritance, such as height).
Either of the pair of genes controlling a trait may take any of several forms, known as alleles. For example, the genes controlling eye colour exist as 2 main alleles, coding for blue and brown eye colour. The brown allele is dominant over blue in that it “masks” the blue allele, which is called recessive to the brown allele. Only 1 of the pair of genes controlling a trait is passed to a child from each parent. For example, someone with the brown/blue combination for eye colour has a 50 per cent chance of passing on the blue gene, and a 50 per cent chance of passing on the brown gene, to any child. This factor is combined with the gene coming from the other parent, according to dominant or recessive relationships, to determine the child’s eye colour. Certain genetic disorders are also inherited in a unifactorial manner (for example, cystic fibrosis and achondroplasia).
Sex-linked inheritance depends on the 2 sex chromosomes, X and Y. The most obvious example is gender. Male gender is determined by genes on the Y chromosome, which is present only in males. Any faults in a male’s genes on the X chromosome tend to be expressed outwardly because such a fault cannot be masked by the presence of a normal gene on a 2nd X chromosome (as it can in females). Faults in the genes of the X chromosome include those responsible for colour vision deficiency, haemophilia, and other sex-linked inherited disorders, which almost exclusively affect males.
Multifactorial inheritance, along with the effects of environment, may play a part in causing certain disorders, such as diabetes mellitus and neural tube defects.... inheritance
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