55-213 Lecture 13 notes.pdf

Lecture 13 2013-01-10 2:29 PM Personalized)Genomics)&)23andme:$ • The$concept$of$personalized$genomics$is$to$give$physicians$more$information$so$that$ they$can$give$you$better$care$ • Hopefully,$as$the$price$gets$cheaper,$everyone$will$be$able$to$have$it$ • Disease$risk:$ o Start$off$with$bad$news$in$red$ o Confidence:$number$of$stars$out$of$4$ o Shows$your$risk$and$average$risk$ o For$the$professor,$average$risk$is$17.8%$while$his$is$23.1%$ o Decreased$risk$=$green$bar$ o Increased$risk$=$red$bar$ o In$a$different$region,$CC$means$decreased$risk$$ o Then$you$see$good$news$in$green$he$gene$is,$but$only$its$location$ • Carrier$status$ • Drug$response$ o Exploding$area$of$researching$ o Physicians$have$known$for$a$logn$time$that$certain$populations$react$ adversely$to$drugs$ o It$comes$down$to$different$alleles$in$the$population$that$affect$the$ metabolism$of$these$drugs$ o Every$drug$that$we$take,$be$it$caffeine$or$codeine,$gets$broken$down$by$ enzymes$in$our$system$"$metabolism$ o Depending$on$the$various$alleles$of$those$enzymes,$there$will$be$an$impact$ on$your$response$to$that$drug$ o Ex:$Fluorouracil$toxicity$ ! The$main$drug$in$chemotherapy$(see$last$lecture)$ ! People$can$die$from$a$lethal$dose$of$it$ ! DPYD*2A$mutation$causes$you$to$react$adversely$to$it$ o Ex:$caffeine$metabolism$$ ! Tells$you$how$fast$you’re$able$to$metabolize$caffeine$$ • Traits:$ o Ex:$muscle$performance$ ! Tells$you$if$you’re$a$likely$sprinter$(see$last$lecture)$ ! Mutation$in$a$gene$called$alpha$actonin,$which$controls$muscle$fiber$ formation$ ! Those$that$have$the$mutation$are$more$likely$to$be$sprinters$or$ athletes$in$short$endurance$types$of$sport$ ! However,$if$you$have$the$wild$type$version,$you’re$generally$better$in$ longer$endurance$sports$such$as$cycling$and$long$distance$running$ ! Professor$has$CC$genotype,$meaning$2$working$copies$of$alpha[ actinin,$which$is$present$in$most$world[class$sprinters$ o Ex:$malarial$resistance$ o Ex:$lactose$intolerance$ o Ex:$Types$of$ear$wax$(wet$or$dry)$ o Ex:$Asparagus$metabolite$detection$ ! When$people$eat$asparagus,$normally$their$pee$smells$ ! Some$people$can$smell$it$and$most$others$can’t$$ $ Ancestry:)(continued)from)last)lecture)$ • Where$do$you$(and$your$family)$come$from?$ • Obtain$haplogroup$information$–$how$is$this$obtained?$ o Y$chromosome$(paternal)$ o Mitochondrial$(maternal)$–$women$can$get$the$Y$chromosome$data$from$ their$brother$and$father$ • Ancestry$haplogroups$and$human$evolution:$ o See$23andme$YouTube$video$ o All$humans$are$descended$from$Africa$about$200$000$years$ago$ ! Sounds$like$a$long$time,$but$in$evolutionary$terms,$its$not$a$long$time$ at$all$ o Thus,$were$all$connected$and$share$some$genes$to$some$extent$ o Migration$out$of$Africa$50$–$100$000$years$ago$and$displaced$other$human$ species$(Homo$erectus$and$Neanderthals)$ ! Some$of$them$mated$with$humans,$which$explains$why$we$share$ some$of$our$genes$with$Neanderthals$ o Humans$migrated$all$over$the$world$–$DNA$changes$over$that$time$were$ conceAncestry haplogroups and human evolution: o Thus,$when$we$look$at$DNA$now,$we$can$discover$where$those$populations$ came$from$ http://www.youtube.com/watch?v=wZpox7_7k1c> o Example:$Haplogroup$R$originated$in$Southwest$Asia$about$30$000$years$ago$ and$then$split$over$time$ ! It$split$into$different$lineages$ ! AlR1$(Europe$and$Asia)$d from Africa about 200,000 years ago ! R2$(Southwest$Asia$and$India)$ ! MiIts$like$a$genetic$signature$00 years ago and displaced other ! huBut$then$what$happened,$is$that$the$DNA$changed,$it$mutated$and$ the$populations$became$smaller$and$more$distinct.$The$changes$were$ Humans migrated all over world (DNA changes over that timeult$was$ were concentrated in different populations) # R1b$(Europe,$Balkans)$ # The$more$specific$R1b1b2$(Western$Europe$–$50%$of$western$ European$men$have$it,$happened$12$000$years$ago)$ $ R1b (Europe-Balkans) $ R1 (Europe and Asia) R1b1b2 (West Europe- $ $ 50% men-12000yrs ago) $ R2 (Southwest Asia and India) $ o If$you$share$a$genetic$signature$in$your$DNA,$you$can$extrapolate$back$to$ know$where$you$came$from$ • Finding$family$relatives:$ o 23andme$relative$finder$database:$ ! Can$find$relatives$connected$via$haplogroups$and$DNA$similarity$ ! Haplogroups$only$give$paternal$and$maternal$lineages;$therefore$your$ father’s$mother$would$not$show$a$relationship,$even$though$she$is$ related$to$you$(when$looking$only$at$haplotypes)$ ! Thus,$haplogroups$are$good,$but$not$great.$This$is$why$23andme$looks$ at$the$rest$of$your$DNA$(chromosomes$and$SNP$data),$and$matches$it$ to$a$database$to$find$who$is$similar$in$order$to$show$relatives$ ! Use$autosomal$genetic$markers$(SNP$sequences$at$certain$ chromosomal$sites)$ rd th # For$example:$can$find$3 $to$6 $cousins$ ! The$databases$are$still$relatively$small,$but$hopefully$by$the$end$of$ this$year$there$will$be$a$million$people$as$a$part$of$the$database$ • See$ancestry$figure$ o In$terms$of$haplotypes,$its$pretty$clear$that$the$professor$has$European$ ancestry$ o His$father:$R1b1b2a1a2f*$"$an$Irish$haplotype$ ! Half$of$all$Irish$males$have$this$haplotype$ ! Not$found$at$all$in$the$Americas$$ o His$mother:$H1N$"$a$Western$Europe$haplotype$ $ Great- Gr$at- grandfather grandmother grandfather grandmother grandfather grandmother (British)Xr (British)er (British) X(British) (Swiss) X (Swiss) (German) X (German) $ Grandfather Grandmother Grandfather Grandmother (British) X (British) (Swiss) X (German) $ $ $ Father Mother $ (British) X (Swiss) $ R1b1b2a1a2f* H1N