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Berkeley MCELLBI 140 - Penetrance and expressivity

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Penetrance and expressivity“Cancer Free at 33, but Weighing a Mastectomy”Slide 3Slide 4“Little gene cards” – what if it says, BRCA1-mutant?!“Never ask, for whom the bell tolls”Slide 7Slide 8“Malignancy of somatic cell hybrids” B. Ephrussi et al., Nature (1969) 224:1314Slide 10Beyond Mendel – interactions of gene products in the formation of traits as revealed by highly modified progeny ratios in crossesEpistasis (or: an epistatic interaction between two loci)“For difference determined by one gene…”Slide 14Slide 15How can one tell, if two organisms under study that exhibit mutant phenotypes for a particular trait have a mutation in different genes or in the same gene?Complementation testThe cis-trans test (aka complementation test)OrgoThe cis-trans test, 1949: lozenge (M. Greene)Slide 21Slide 22Slide 23The dataSlide 25Xeroderma pigmentosumWhat was actually doneWait a minuteSlide 29For complete clarityComplementary gene action (9:7)Slide 32Recessive epistasis (9:3:4)Dominant epistasis (13:3)Slide 35Slide 36Slide 37Future e-mailSlide 39“… the stadium capacity is now officially listed as 75,662”Slide 41Slide 42“An SCN9A channelopathy causes congenital inability to experience pain” Nature Dec. 14, 2006So – let’s think about thisProphylactic bilateral mastectomy (and/or oopherectomy) for BRCA1/2 mutation carriersSlide 46A Russian proverb that aptly describes most current cancer treatment modalities“Chemo” drugsSlide 49Penetrance, expressivity, genetic background, and the environmentGenetics of continuous variationSlide 52In a population, phenotypes of individuals for a quantitative trait tend to be normally distributedThe Great Schism (1901-1935)Synthesis: Population GeneticsSlide 56Slide 57Central limit theorem Carl Friedrich Gauss Slide 59“Additive effects of genes”Slide 61Talking to laypeople (and biochemistry majors)MCB140 09-17-07 1Penetrance and expressivity“The terms penetrance and expressivity quantify the modification of the influence on phenotype of a particular genotype by varying environment and genetic background; they measure respectively the percentage of cases in which a particular phenotype is observed when the specific allele of a gene of interest is present and the extent of that phenotype.”MCB140 09-17-07 2“Cancer Free at 33, but Weighing a Mastectomy”The New York Times, Sunday, Sep. 16, 2007Deborah Lindner, 33, did intensive research as she considered having a preventive mastectomy after a DNA test.MCB140 09-17-07 3The New York Times, Sunday, Sep. 16, 2007MCB140 09-17-07 4www.nytimes.comMCB140 09-17-07 5“Little gene cards” – what if it says, BRCA1-mutant?!“The Lindners share a defective copy of a gene known as BRCA1 (for breast cancer gene 1) that raises their risk of developing breast cancer sometime in their lives to between 60 and 90 percent. Only 30,000 of more than 250,000 American women estimated to carry a mutation in BRCA1 or a related gene, BRCA2, have so far been tested.”The New York Times, Sunday, Sep. 16, 2007MCB140 09-17-07 6“Never ask, for whom the bell tolls”MCB140 09-17-07 7Hanahan and Weinberg (2000) Cell 100: 57–70.MCB140 09-17-07 8Knudsen “two-hit” modelMCB140 09-17-07 9“Malignancy of somatic cell hybrids” B. Ephrussi et al., Nature (1969) 224:1314 The studies of Ephrussi et al. and Harris provided compelling evidence that the ability of cells to form a tumor is a recessive trait. They observed that the growth of murine tumor cells in syngeneic animals could be suppressed when the malignant cells were fused to nonmalignant cells, although reversion to tumorigenicity often occurred when the hybrids were propagated for extended periods in culture. The reappearance of malignancy was found to be associated with chromosome losses. Stanbridge and his colleagues studied hybrids made by fusing human tumor cell lines to normal, diploid human fibroblasts. Their analysis confirmed that hybrids retaining both sets of parental chromosomes were suppressed, with tumorigenic variants arising only rarely after chromosome losses in the hybrids. Moreover, it was demonstrated that the loss of specific chromosomes, and not simply chromosome loss in general, correlated with the reversion to tumorigenicity. The observation that the loss of specific chromosomes was associated with the reversion to malignancy suggested that a single chromosome (and perhaps even a single gene) might be sufficient to suppress tumorigenicity. To directly test this hypothesis, single chromosomes were transferred from normal cells to tumor cells, using the technique of microcell-mediated chromosome transfer. It was found that the transfer of a single chromosome 11 into the HeLa cervical carcinoma cell line suppressed the tumorigenic phenotype of the cells. Many studies have now demonstrated that transfer of even very small chromosome fragments will specifically suppress the tumorigenic properties of certain cancer cell lines.MCB140 09-17-07 10Ventura et al (T. Jacks) Nature 445: 661MCB140 09-17-07 11Beyond Mendel – interactions of gene products in the formation of traits as revealed by highly modified progeny ratios in crossesEPISTASIS (“to stand on top of”)MCB140 09-17-07 12Epistasis(or: an epistatic interaction between two loci)1. Pick a trait.2. Find a mutant  phenotype #13. Find a different mutant  different phenotype (#2)4. Cross the two mutants: get not a mix of phenotypes, but instead, either phenotype #1 or #2.The term “epistasis” refers to a phenomenon in which an allele of one gene masks (“stops”) the effects on the phenotype of an allele of a different gene.The discovery of epistatic interactions between gene products is one of the most powerful tools in genetics – it allows the assembly of individual genes into pathways – and understanding of pathways leads to an understanding of mechanism.MCB140 09-17-07 13“For difference determined by one gene…”MCB140 09-17-07 14Fig. 3.7MCB140 09-17-07 15Fig. 3.6MCB140 09-17-07 16How can one tell, if two organisms under study that exhibit mutant phenotypes for a particular trait have a mutation in different genesor in the same gene?MCB140 09-17-07 17Complementation test“Complementation is the production of a wild-type phenotype when two haploid genomes bearing different recessive mutations are united in the same cell.”MCB140 09-17-07 18The cis-trans test(aka complementation test)Edward Lewis (NP 1995)Are two different


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Berkeley MCELLBI 140 - Penetrance and expressivity

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