Human genetic defects occur in 3000-4000 live births each year in the UK alone. There are many spontaneous abortions which result from genetic abnormalities extreme enough to prevent full term development. Many children are born with a genotype predisposing them to diseases triggered by environmental factors. At birth all babies are screened for PHENYLKETONURIA, while mothers are tested routinely for Rhesus blood group since it is now possible to inject anti-anti-D (not a typing error) which knocks out the mother's anti-D antibodies. Pregnant women considered at risk (ie approaching or over 35) are routinely screened for foetal abnormality due to the increased incidence of non-disjunction defects in women of this age group. It is noteworthy that the meiotic divisions which result in the formation of haploid ova are suspended in mid-division for many years. The longer the suspension then the greater is the chance that one of the satellite chromosomes (at the edge of the equator) will suffer non-disjunction. There is no correlation with paternal age since meiotic suspension does not occur in males.
Amniocentesis in which a small sample of amniotic fluid is withdrawn and the cells in it tested for chromosome number (karyotype analysis), the fluid itself being tested for alpha feto-protein which if at a high level indicates a neural tube defect (Spina bifida). There are now some experimental techniques which allow the genetic screening of single cells removed from embryos at the earliest stages of development. The use of DNA probes to detect the presence of alleles in foetal cells which indicate genetic defects, which are invisible to the other screening techniques, has allowed potential parents to decide whether they wish the pregnancy to be terminated. The main problem with cell screening processes is that until now, they have needed 4 weeks of tissue culture in order to obtain sufficient material for the tests.
Chorionic biopsy (removing a small chunk of the foetal placental material) has improve matters. This technique uses a thin tube inserted through the vagina and into the uterus. A small tissue sample is removed and this is then tested immediately since the cell density of the chorionic tissues is much greater than that of the amniotic fluid. Remember that abortion can only be legally performed below a certain age (28 weeks) and this is under review, also the longer the female is pregnant then the more traumatic the experience can become due to psychological effects.
Many chromosomal aberrations of importance are due to non-disjunction, ie an ovum or sperm is formed with either 2 homologous chromosomes or with none and when fertilisation occurs with a normal gamete trisomy or monosomy results respectively. The other aberrations are translocation effects where a section of chromosome is translocated onto a chromosome, inversion where part of a chromosome becomes detached and rotates and then rejoins the original chromosome. It is possible to have these aberrations in combination. The major defects are listed below:
Downe's syndrome; trisomy of chromosome 21 in full, or in part as the result of translocation of the effective part of chromosome 21 onto another chromosome during meiosis.
This results in the presence of mongoloid eye-shape, squint, broad face, short stature, single palm crease, short crooked 5th finger, low IQ (25-50 is frequent) and a short life expectancy. About 1 in 650 live births have this defect in UK and the probability of having a Down's child increases with respect to the female's age.
Patau's syndrome; Trisomy of chromosome 13. About 1 in 5000 live births makes this rare. the extra autosome causes extreme mental retardation, deafness, hare lip and cleft palate deformity, polydactyly and congenital deformation of most organ systems. Life expectancy is approximately 6 months. It does not correlate very well with the mother's age.
Edward's syndrome; trisomy of chromosome 18. 1 in 3000 live births. Smaller stature than average, front to back skull elongation, low-set ears, receding chin, webbed neck, congenital hip dislocation. Survival time about 35 years.
Turner's syndrome; monosomy of X chromosome (X-). 1 in 3000 live births and present in 20% of spontaneous abortions. Short stature, webbed neck, broad shield like chest, poor secondary sexual characteristics and lack of ovaries although external female genitalia and internal plumbing present.
Klinefelter's syndrome; double X and a Y chromosome (XXY). 1 in 500 male live births. The small testes are unable to produce sperm, penis and ducts are present, other features fall within the normal range: tall, slight mental retardation. The presence of extra X chromosomes has little effect upon the individual apart from causing infertility, a XXX type appears normal but will have a slightly reduced IQ. The reason appears to be that only one X chromosome is switched on in any cell, the other is tightly coiled and can be seen in a Fuelgen stained cell as a Barr body. Presumably if you have extra X chromosomes they are merely switched off. But note that this Barr body effect does have interesting effects upon the female tissues, since it is formed of cells in which one of the two X chromosomes has been randomly switched off forming a tissue mosaic effect. This does not seem important in humans but can affect coat colouration in some mammals.
Also note that X- is female, while XXY is male, hence the Y chromosome carries genes which cause the switching on of male developmental systems.
Diseases can be caused by gene mutations which lead to defective enzymes or reduced amounts of enzymes. The mutation of the base code sequence at a gene locus is called a point mutation and will affect just the single allele which has suffered a code change. The base code sequence affects the sequence of amino acids in the protein manufactured during translation of the allele and this may effect the efficiency or function of the protein.
Tay Sachs disease; A gene on chromosome 15 is involved in the formation of the enzyme hexosaminidase A. In the homozygous recessive condition this enzyme is modified and "gangliocides" accumulate in nervous tissue causing severe damage. The symptoms are blindness, paralysis, severe mental retardation and eventually death at age 2 or 3. The baby appears quite normal for the first 8 months or so. It can be detected by denaturing the enzyme extracted from skin or blood cells and assaying the degree of denaturing at different heat levels. The mutant form is much more sensitive to heat.
Sickle cell anaemia; This codominant allele causes the production of a modified haemoglobin (the 6th codon is altered from CTT to CAT). The modified Haemoglobin (HbS) is unable to carry oxygen and the homozygote suffers from chronic anaemia (often dying), the heterozygote has a 50/50 mix of HbN and HbS and suffers from mild anaemia. It is thought that the high frequency of this allele in some world regions is due to the increased malarial resistance of the heterozygote (HbN HbS) which outweighs its deleterious effects.
Phenylketonuria (PKU); a chromosome 12 allele which controls the production of the enzyme phenylalanine hydroxylase. If the recessive homozygous condition occurs then phenylalanine cannot be broken down into tyrosine and builds up in the blood and tissues. It is excreted in the urine, but it will damage the nervous system, (an IQ of <40 is common), the brain size is reduced (microcephaly), and muscular hypertonicity may cause "tailor's posture" in which arms are drawn in to the body and the legs are tightly crossed. If detected early the diet can be modified to restrict phenylalanine intake to between 35-50 mg per kilogram of body mass during the first year of life with a reduction to 20-25 mg per kilogram as the child grows older. Phenylalanine is an essential amino acid in man. The Guthrie test is used to detect the defect. A small blood drop is taken and placed on a bacterial plate containing a growth inhibitor. Phenylalanine antagonises the inhibitor allowing bacteria to grow so that blood samples with high phenylalanine content produce plates with bigger bacterial colonies (a bioassay technique). Heterozygotes have slightly higher phenylalanine levels than homozygous dominants (normals) on average. A gene probe has recently been developed to detect heterozygotes and homozygous recessive foetuses.
Cystic fibrosis; found in about 1 in 2000 live births per year in the U.K. A chromosome 7 recessive allele causing the production of a thick mucus which blocks the lungs and pancreas and results in these organs becoming increasingly fibrous. The prognosis, with regular treatment consisting of exercises to remove mucus from the lungs, is that the individual may survive into adulthood, but most do not reach this stage. The blockage of the pancreas requires the oral intake of pancreatic extract to enable digestion of food. The failure of the mucous to liquify adequately is caused by the failure of a chloride pumping protein in the cell membranes of the epithelial cells in the repiratory tract. Without adequate amounts of chlorine the mucous remains thick and coagulates.
Galactosaemia; probably a chromosome 9 recessive allele. Very rare condition, about 4 live births per annum in the U.K. The enzyme galactose-1-phosphate uridyltransferase is improperly made in the homozygous recessive and this results in the inability to convert galactose-1-phosphate into glucose-1-phosphate. The galactose sugar from the mother's milk therefore acts as a toxin due to its high tissue levels and the severe malnutrition occurring complicates the condition. The individual shows very poor growth, mental retardation, the liver becomes grossly enlarged and death can result. Rapid diagnosis can prevent the worst effects of the disease, but even a few days of normal feeding can cause irreversible brain damage and therefore it needs to be detected early and this can be done since the transferase enzyme can be assayed from foetal cells. The treatment is to provide a galactose free diet.
Haemophilia; an X chromosome recessive allele which results in the non-production of clotting factor VIII when in the homozygous condition. Male offspring are most often affected (sex-linked) and the absence of female haemophiliacs is thought to be due to a lethal effect in homozygous recessive females which results in spontaneous abortion.
Red green colour blindness; This is often stated as being a simple sex-linked recessive condition. However, there are a number of forms of red-green colour defects which are thought to be due to mutation at very closely linked loci on the X chromosome. The two main types are protan and deutan and the different levels of effect in each type are thought to be due to a number of allelic forms at each locus. The protan type have defective red vision due to the absence or very low levels of red photosensitive pigment, while deutans have problems with greens, although green photosensitive pigment is present and it seems that the brain is unable to use the information sent to it from the green cones. A carrier mother may produce deutan, protan and normal sons which seems to indicate that there are indeed two separate loci operating.
Blue-yellow colour vision deficiency; (tritanopia) is a very rare autosomal mutant with a frequency of 0.004% in Europeans. An even rarer autosomal mutant is responsible for complete monochromatism (light intensity only).
Achondroplastic dwarfism; (also called chondrodystrophy) a dominant allele causing cartilage tissue to develop incorrectly and preventing normal growth.
Albinism; a recessive allele which causes the failure of melanin production, probably controlling one of the enzymes at the start of the melanin production pathway. It is quite common in Africa but possibly because it is more obvious to casual observation.
Note that the recessive traits are often rare but may have a relatively high gene frequency due to the heterozygous component of the population; for example if a trait is present at a frequency of 1 in 4000, then using Hardy-Weinberg:
This doesn't seem many but consider that it is 124 times greater than the number of recessive homozygotes and we can see that it is going to be difficult to completely remove this deleterious allele from the population.