MCB 140 – GeneticsSlide 2Slide 3Slide 4The complexity of the truth (stay tuned for Prof. Brem’s lecture, #35)A fact, and a problemFive percent of 178,700Slide 8The complexity of the truth, part II (stay tuned for Prof. Brem’s lecture, #31)Slide 10Slide 11Slide 12Slide 13Slide 14Prophylactic bilateral mastectomy (and/or oopherectomy) for BRCA1/2 mutation carriersPeople with insufficient education in genetics AND statistics and not enough time to look at the primary dataA complicated truthLiving With Our Genes D. Hamer and P. Copeland (1998)Gene for starting businessesSlide 20Gene for metaphorsThe God GeneThe problemCancelled health insurance?“Gene Variant Is Linked to Common Type of Stroke” NYT 1/9/07“A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction” Kubo et al. Nature Genetics epub 2007Genetic defense?“That Wild Streak? Maybe It Runs in the Family” NYT 6-15-06Slide 29Ontology vs. epistemologyWhat MCB140 is NOTTwo useful proverbsPart I – “classical genetics”Slide 34“An SCN9A channelopathy causes congenital inability to experience pain” Nature Dec. 14, 2006Section II: key methods in experimental genetics (Prof. Cline)Slide 37Slide 38Slide 39Slide 40Section III: genomics and quantitative genetics (Prof. Brem)What to do so as to do wellQuestions? [email protected], 17-01-07 1MCB 140 – GeneticsMCB140, 17-01-07 2And quite soon, young women will come home from the hospital with their newborn babies in countries with good health systems with little gene cards that will say, ‘Here are your child’s strengths and weaknesses, and if you do the following ten things your baby has a life expectancy of 93 years.’ This is going to happen in the lifetimes, and in the childbearing lifetimes of those young people in this audience.”President Clinton Comes to Cal (Jan. 29, 2002) “I was honored to be president at the time when the International Consortium of Scientists finished the sequencing of the human genome, something which has already yielded the two major variances that are high predictors of breast cancer, something that is leading us very close to unlocking the genetic strains that cause Parkinson’s and Alzheimer’s.MCB140, 17-01-07 3www.genelex.com – listed solely for reference purposes, and does not imply an endorsement of any sort.MCB140, 17-01-07 4Gene Name Area of ActivityAPOC3Heart HealthCETPHeart HealthLPLHeart HealtheNOSHeart HealthMTHFRHeart Health; Vitamin B UseMTRHeart Health; Vitamin B Use MS-MTRRHeart Health; Vitamin B Use CBSHeart Health; Vitamin B UseGSTM1Detoxification; Antioxidant ActivityGSTT1Detoxification; Antioxidant ActivityGSTP1Detoxification; Antioxidant ActivityMnSODHeart Health; Antioxidant ActivitySOD3Heart Health; Antioxidant Activity VDRBone HealthCOL1A1Bone HealthIL-6Heart Health; Inflammation; Bone HealthTNFaInflammation; Bone HealthACEHeart Health; Insulin SensitivityPPAR2Insulin Sensitivitywww.genelex.com – listed solely for reference purposes, and does not imply an endorsement of any sort.“Apolipoprotein C-III gene (APOC3)APOC3 plays an important role in lipid metabolism. It inhibits the break down of triacylglycerol, a lipid, by the enzyme lipoprotein lipase; leading to higher triglyceride levels (hypertriglyceridemia). The polymorphism 3175G is associated with a four-fold risk of hypertriglyceridemia and is linked to an increased risk of heart attack, atherosclerosis and cardiovascular disease.” (emphasis mine – fdu)MCB140, 17-01-07 5The complexity of the truth(stay tuned for Prof. Brem’s lecture, #35)1. SNP2. Haplotype3. Linkage disequlibrium4. “Tags informative for multiple proxies” the very significant scientific problem all of this – put together – creates for using linkage data as a tool for generating “nutrigenomics” guidelines based on a particular individual’s genotype at a particular SNP.For now, read:1. Naukkarinen et al, Curr. Opin. Lipidol. 17(3), p 285–290 (not required); 2. Haga and Willard Nature Reviews Cancer 206 – requiredPubMedMCB140, 17-01-07 6A fact, and a problemFact: what we do is a function of what we know (and many other things, of course).Problem: our knowledge comes in shades of gray, but actions tend to be black-and-white.MCB140, 17-01-07 7Five percent of 178,700 “Germline mutations in BRCA1 confer a 56%-80% lifetime risk for breast cancer and a 15%-60% lifetime risk for ovarian cancer in women.”Dapic V, Monteiro AN. Crit Rev Eukaryot Gene Expr. 2006;16(3):233-52.MCB140, 17-01-07 8Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%.Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.King et al. Science. 2003 Oct 24;302(5645):643-6MCB140, 17-01-07 9The complexity of the truth, part II(stay tuned for Prof. Brem’s lecture, #31)1. QTL2. Epistasis3. Environmental vs. genetic variance4. Norm of reaction 5. Narrow-sense v. broad-sense heritability the very significant scientific problem all of this creates for generating treatment guidelines based on a particular individual’s genotype for a “cancer susceptibility locus.”MCB140, 17-01-07 10www.myriadgenetics.com – listed solely for reference purposes, and does not imply an endorsement of any sort.MCB140, 17-01-07 11MCB140, 17-01-07 12MCB140, 17-01-07 13Forward PCR primer: AAATTATTGAGCCTCATTTATTTTCReverse PCR primer: AAACAAAAGCTAATAATGGAGCNote: the SNP shown is not 185delAG.MCB140, 17-01-07 14A proper description of how this is done:http://www.myriadtests.com/provider/doc/BRACAnalysis-Technical-Specifications.pdfMCB140, 17-01-07 15Prophylactic bilateral mastectomy (and/or oopherectomy) for BRCA1/2 mutation carriers“A study of 139 women with deleterious BRCA1 or BRCA2 mutations who were followed at the Rotterdam Family Cancer Clinic. To reduce their risk of breast cancer, 76 of these women chose to undergo prophylactic bilateral mastectomy, whereas the remaining 63 were followed according to a surveillance protocol consisting of a monthly breast self-examination, a semiannual breast examination by a health care professional, and annual mammography. … No breast cancers were observed in the 76 women who underwent prophylactic bilateral mastectomy, whereas eight were detected in the surveillance group. This study … supports the report by Hartmann et
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