Chromosomal Aberrations Lecture Notes by Joe Ruhl I. Chromosome Behavior A. Chromosome coiling and condensing II. Anatomy of a Chromosome A. chromosome B. chromatid (sister chromatids) C. centromere (kinetochore) D. p-arm E. q-arm III. Chromosome Classification A. Karyotype – analysis of chromosomes B. Chromosomes are classified by 1. size in descending order 2. similarities in length 3. similarities in centromere location 4. presence or absence of satellites C. metacentric chromosome – centromere in center D. submetacentric chromosome – centromere slightly off center E. acrocentric chromosome – centromere near end F. satellites – round portion of DNA G. match homologous chromosomes H. match the pair of sex chromosomes (XX = female, XY = male) IV. Studying Human Chromosomes A. amniocentesis B. karyotyping 1. Amniotic fluid is centrifuged to concentrate cells. 2. Nutrients are added and cells are stimulated to divide for 3-5 days. 3. Cells are incubated at body temperature. 4. Colcine or colcemid is added to destroy spindle fibers. Cells don’t proceed past metaphase. 5. Cells are washed with saline and dropped onto a microscope slide. 6. Chromosomes are stained to enhance visibility. 7. Chromosomes are photographed through a microscope. 8. Chromosomes are cut out of photograph and karyotyped. V. The Normal Diploid Condition (2N = 46) A. Usually two genes are better than one. B. But mistakes happen. VI. Nature isn’t Perfect A. Aneuploidy (not true multiples) 1. trisomy (2N + 1 = 47) 2. monosomy (2N – 1 = 45) B. Examples of aneuploidy 1. Trisomy 21 (Down Syndrome) 1 in 770 live births a. lowered muscle tone immediately after birth b. IQ usually 25-50 c. Brushfield spots in iris of eye; epicanthal eye folds d. open mouth; protruding tongue e. short, broad hands; single palmar crease f. wide gap between first and second toes g. below average height h. cardiac anomoly in 35-50% of cases i. accounts for 96% of down syndrome cases 2. Monosomy 21 (Al-Aish syndrome) a. extremely rare (about 3 known cases) b. lethal 3. Trisomy 18 (Edwards Syndrome) 1 in 4500 live births a. death usually by 6 months b. mental retardation c. 78% are females d. ears are low set and malformed e. hands – fist clenched, second digit overlapping third, fifth overlapping fourth, single palmar crease. f. “rocker bottom” feet g. 80% have heart malformations h. kidney problems i. more severe than Down Syndrome 4. Trisomy 13 (Patau Syndrome) 1 in 5000 live births a. death usually by 1 month b. marked by mental retardation; incomplete forebrain development c. eye defects (including absence of eyes) d. cleft lip and palate e. polydactyly; clenched fists f. low set, malformed ears g. abnormalities of heart, viscera, and genitalia C. Why don’t we see live births of aneuploids being formed for each of the 22 autosomes? As chromosomes get larger, there is too much repeated information and the deformities are too severe. D. In autosomes, trisomy appears to be less severe than monosomy. Why? More information seems to be better than less information. It is better to have an extra page of instructions rather than one page missing. E. Accidents happen with sex chromosomes too. 1. Turner Syndrome (45, X0) 1 in 3000 female births a. usually short, under 5 feet b. webbing of neck occurs in 50% of cases c. low, irregular hailine at nape of the neck d. broad, flat, shield like chest with widely spaced nipples; little breast development e. external genetalia are juvenile; ovaries reduced to streak of connective tissue; sterile f. aorta defects; 35% have cardiovascular disease g. normal intelligence; mental retardation minimal 2. Klinefelter Syndrome (47, XXY) 1 in 500 male births a. limbs longer than average; patients are tall b. testes underdeveloped; sterile; body hair sparce; breast development in 25% of cases c. diminished IQ in some cases d. less frequent but more extreme variants also occur; they may be 48, XXXY, 49, XXXXY, 48, XXYY, 49, XXXYY 3. Jacobs Syndrome (XYY) 1 in 1000 male births a. tall males, 6 feet or more b. MAY be antisocial, aggressive, violent, psychopathic or criminal in behavior with below average intelligence c. newborn incidence of 1 in 1000 male births suggests that a large proportion of XYY males must exhibit normal behavior and be indistinguishable from normal males F. Major cause of aneuploidy 1. meiotic nondisjunction G. Some causes of nondisjunction 1. late maternal age 2. genes predisposing to nondisjunction 3. radiation 4. chromosomal abnormalities themselves 5. viruses H. Why are anueploids involving sex chromosomes less severe than those involving autosomes? 1. Male XY; Y simply causes maleness 2. Female XX 3. All extra X chromosomes become barr bodies I. Euploidy (true multiples) 1. haploid (monoploid), N – one copy of each chromosome 2. diploid, 2N – two copies of each chromosome (normal) 3. polyploid, 3N or 4N – three or four copies of each chromosome VII. Other Types of Chromosomal Accidents Seen in Humans A. Deletions 1. Caused by: a. irradiation b. chemicals c. drugs d. viral infections 2. Examples: a. Cri-du-chat (B deletion – deletion of #5 p-arm) 1 in 50,000 live births • severe mental retardation; IQ 20 and below • imicrocephaly; “moon face”; low set ears; broad based nose; short neck • defect in larynx causes infant’s cry to sound like the mewing of a cat b. Fragile X syndrome (tandem repeats of X chromosome) • one of the most common causes of mental retardation in males • enlarged testes and ears B. Translocation 1. 14/21 translocation carrier – Phenotypically normal but 25% chance of having a Down Syndrome child 2. 14/21 translocation Down Syndrome – 4% of Down Syndrome cases 3. 21/21 translocation – Phenotypically normal, but 100% chance of having a Down Syndrome child