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Unformatted text preview: Ploidy: number of chromosome sets Ploidy: When good cells go bad... bad...
Ploidy, Mutation, & Cancer Ploidy, Diploid: having sets of two (pairs) Haploid: having sets of one (like gametes) Euploid: "true" (correct) ploidy Euploid: true" Aneuploid: not true ploidy Aneuploid: Polyploid: multiple sets of chromosomes Polyploid: Meiosis yields normal gametes unless ... A small fraction of aneuploids are viable, because they suffer from gene imbalance. The major observations of aneuploidy in humans occur with chromosomes 21, 22, (13, 18, 15,) and the sex chromosomes. The most common syndromes are: Trisomy 21 (Down's), Klinefelter's (Down' Klinefelter' (XXY), Turner's (XO), Jacob's (XYY). Turner' Jacob' ... a "non-disjunction" yields non- disjunction" aneuploid gametes. Complete nondisjunction leads to polyploid gametes ... ... and empty ones. The union of a diploid gamete and a haploid gamete yields a triploid zygote. Some organisms tolerate this, but they are sterile because nearly all gametes are aneuploid. aneuploid. Useful examples inc. bananas, some apples, grass carp. 1 When TWO diploid gametes unite, the result is a "tetraploid", which produces euploid tetraploid" (diploid) gametes, but cannot mate with the parental species (makes triploid zygotes). This mechanism of "instant speciation" has speciation" been very important in plant evolution. It has also been extremely important in crops, and can be forced in the lab with colchicine (e.g., rye + wheat = Triticale). Triticale). In plant evolution (in wild & and early crops) this has occurred in hybrids of closely related species ("allopolyploidy", "amphidiploidy"). (" allopolyploidy" amphidiploidy" Examples include: ferns; coffee, cotton, wheat. Many autotetraploids (& above) have been bred as crops (e.g., potato). Polyploids produce more gene product and have larger cells. Animal examples inc. amphibians, fish, invertebrates, and even a mammal. Mutations at the DNA level: level: "Somatic" mutations are not passed on to Somatic" offspring. These include cancers. "Germline" mutations are passed on to Germline" offspring (evolutionarily important). Mutation is very rare. Typical rates are about 10-9 per nucleotide, 10-6 per locus. Mutations in noncoding DNA are mainly harmless but very useful (below). The majority of mutations in coding sequences are, not surprisingly, deleterious. 75% (441/576) of mutations to codons change the amino acid. There are two kinds of "point mutations": mutations" insertion/deletions, and substitutions (already discussed rearrangements). "Indels" Indels" occur in regions of repeating sequences. Top is a fingerprint -type indel; indel; bottom is a frameshift mutation. Most transitions appear to result from tautomeric shifts from the "keto" forms at keto" exactly the right moment. These induce base-pairing basemismatches (A bonds to C, G bonds to T). 2 Transitions (AG, TC) (A T vastly outnumber transversions. transversions. ~~~~~~~~~~~~ Cancers are caused by environmental mutagens: ionizing radiation UV light (pyrimidine (pyrimidine dimers) dimers) numerous chemicals (T. 18.3, p. 156) 40% of all US cancers are lung & colorectal, due mainly to smoking & meat consumption. Cancer is the 2nd biggest killer (1 in 4 deaths). About 40% of people get some form of cancer. Cancer = uncontrolled cell growth, caused by mutations in genes that control cell growth. T. 18.2, p. 154; Y2K Lung (= others) Breast+Prostate Colorectal Lymphoma Thousands 157 (<5 pre-smoking) pre73 = 41+32 56 49 (ca. auto deaths) Stage G1 S G2 M C The cell cycle: What happens Checkpoint? General growth (growth) DNA synthesis Division growth Mitosis Cytokinesis (DNA repl.) repl.) (ready to split) - Two main categories of controls: "Proto-oncogenes" Proto- oncogenes" stimulate cell division mutations typically dominant e.g., growth factor receptors "Tumor suppressors" suppressors" prevent cell division mutations typically recessive e.g., p53 (F. 11.22, p. 59; 18.22, p. 165) Mechanisms include signaling by accumulation & destruction of proteins (e.g., cyclin/Cdk). cyclin/Cdk). 3 Something like half of all cancers have mutations in p53 (stands for "protein of weight 53"). 53" When p53 finds damaged DNA, it halts accumulation of cyclins & calls for repair. If repair fails, it initiates selfselfdestruct sequence! Experiments show that BPDE from tobacco smoke causes mutations in 3 particular regions of the p53 gene; DNA sequences from lung cancers show the same mutations in the same 3 places. Applying weak concentrations of BPDE to lung cells causes G T transversions at the same three codons (157, 248, 273). Denissenko et al. 1996. Science 274: 430-432. 430- Smoking is bad for you. Very, very bad for you. Much research is focussed on understanding and fixing the biochemical mechanisms that have broken down in cancerous cells: 1) Overproduction of receptors for cell growth factors can be treated with "monoclonal antibodies". antibodies" 2) Angiogenesis is the secretion of proteins which encourage capillary growth; chemicals that bind to these proteins "starve" the tumor. starve" Many genes that control cell growth can be corrupted to initiate cancer. It may take more than one mutation in such genes to make a cell cancerous (e.g., above). Inheriting one of a set of such mutations is the basis of cancer "predisposition" genes, like BRCA-1 & -2. predisposition" BRCA- 4 ...
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- Spring '08