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Lecture 4

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Department
Biological Sciences
Course
55-213
Professor
Hubberstey
Semester
Winter

Description
Lecture 4 2013-01-24 4:25 AM Bodily%Functions:% • Each$cell$needs$to$replicate$6$billion$times$with$no$error$ $ Beneficial%Mutations:% • Some$mutations$provide$benefit$for$survival$ • Examples:$CCR5$and$cystic$fibrosis$ A)%CCR5Δ32%mutation$$ • The$mutation$that$some$of$us$have$is$called$CCR5Δ32$mutation.$ • The$normal$gene$encodes$for$chemokine$receptor$5$–$a$neurological$compound$ released$upon$infection$that$also$codes$some$of$our$cells.$It$also$plays$a$role$in$viral$ infections.$In$the$CCR5Δ32$mutation,$the$receptor$becomes$non$functional.$$ • It$turns$out$this$mutation$isn’t$as$rare$as$initially$thought.$ • CCR5$gene$"$encodes$chemokine$receptor$5$ • CCR5Δ32$mutation$"$non$functional$ • Found$that$patients$homozygous$for$CCR5Δ32$were$resistant$to$HIV$infection$ (mostly$of$European$origin)$ • HIV$uses$receptor$to$infect$white$blood$cells$ • Why$does$this$mutation$exist$in$the$population?$th o The$theory$is$because$of$the$plague$in$14 $century$Europe$ o Because$society$was$swamped$by$plague,$anybody$who$was$slightly$resistant$ to$the$infecthon$was$going$to$survive$and$propagate$the$delta$mutation.$$ • Bubonic$plague$(14 $century$Europe)$caused$by$bacteria$ o CCR5Δ32$leads$to$plague$resistance$when$you$have$2$copies$of$it$ (controversial$idea)$ o But$for$sure,$the$allele$protected$some$against$the$plague.$It$can$also$protect$ against$small$pox$and$Nile$virus.$$ • Disease$causing$genes$with$benefits$depending$on$gene$allele$copy$number$(homo$ vs.$heterozygous)$ • There$are$many$examples$where$being$a$heterozygous$carrier$for$a$mutation$may$ confer$a$selective$advantage$(vs.$having$a$homozygous$mutation,$thus$having$a$ disease)$ • Most$known$example:$sickle$cell$anemia$ o Homozygous$mutation$"$you$get$sickle$cell$anemia$ o Heterozygous$mutation$"$you’re$protected$against$malaria$aka$selective$ advantage$ B)%Cystic%Fibrosis:% • Most$common$mutation$in$Caucasian$populations,$especially$of$European$origin$ • Homozygous$recessive$alleles$for$CFTR$mutation$ • Causes$mucus$to$form$in$lungs$and$intestines$ • The$gene$controls$a$pump$on$epithelial$cells;$when$it$is$disturbed,$it$causes$mucus$to$ form$in$lungs$and$intestines.$The$result$is$that$bacteria$are$allowed$to$grow$and$ harbor$in$the$lungs,$causing$lung$infections.$ • When$you’re$a$heterozygote$carrier:$$ o One$copy$of$recessive$allele$provides$resistance$to$diarrhea$(caused$by$ cholera)$and$resistance$to$tuberculosis$ • If$you$look$at$the$history$of$Europe,$those$2$diseases$were$absolutely$epidemic$in$the$ last$1000$years.$$ • Those$with$a$heterozygote$carrier$of$cystic$fibrosis$thus$had$a$selective$advantage$ • Tuberculosis$was$responsible$for$20%[email protected]$ % Mutation%and%Population%Questions:$ • What$has$to$occur$in$the$population$for$beneficial$mutations$to$be$successful$and$ become$heritable?$ o Selective$advantage$$ • Why$are$serious$mutations$not$generally$observed$in$the$population?$ o Because$they’re$deleterious$at$the$early$stage$of$development.$ o The$majority$of$successful$zygotes$formed$don’t$make$it$to$term$(aka$ majority$of$pregnancies$fail)$ ! Naturally,$60%$of$pregnancies$don’t$make$it$to$term$ o Why?$Mutations$occur$that$disrupt$the$developmental$pathway$so$seriously$ that$the$fetus$can’t$survive$ $ Types%of%Mutation:%Point%Mutation% • Point$mutation:$change$in$single$base$pair$(AT$into$CG,$or$CG$into$AT)$ o Transition:$replaces$pyrimidine$with$pyrimidine$and$purine$with$purine$ o Transversion:$purine$replaced$by$pyrimidine$and$vice$versa$(A$to$C,$or$G$to$T)$ • Mutations$can$be$induced$by$chemical$modification$of$bases$or$incorporation$of$ base$analogs$into$DNA.$This$is$where$exposure$to$chemicals$in$your$lifetime$can$ affect$the$mutation$rate.$For$example,$cigarettes$have$many$mutagens.$On$the$ bright$side,$physicians$have$taken$advantage$of$mutations$that$look$very$similar$to$ our$DNA$in$attempts$to$stop$diseases$like$cancer.$ • See$figure$1.26$"[email protected]$Nitrous$acid$deaminates$cytosine$to$uracil.$You$can$go$ [email protected][email protected]$eventually$in$one$cell,$but$the$other$one$will$remain$unaffected$(will$ [email protected])$ • See$figure$1.27$"[email protected][email protected][email protected]$through$analogs$ • $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ Uses%of%Base%Analogs:% • As$mentioned,$physicians$have$utilized$chemotherapy$based$analogs$for$many$years.$ This$is$because$it$was$shown$that$cancer$cells$can$take$these$up$very$rapidly,$and$are$ so$incorporated$into$their$DNA,$that$the$cancer$cell$can’t$keep$up,$leading$to$ apoptosis.$ • Chemotherapy$([email protected]):$cancer$cells$take$up$analogs$and$blocks$division$ and$DNA$replication$ • Examples:$ o Purine$analog:$mercaptoguanine$ o Pyrimidine$analog:$fluorouracil$ • Eventually,$cancer$cells$die$but$the$problem$is,$normal$cells$die$too.$ o Causes$side$effects$of$chemotherapy$ o Targets$actively$dividing$normal$cells$(e.g.$hair,$skin,$epithelial)$ • Cancer$cells$divide$much$faster$than$normal$cells.$ • This$technique$triggers$cells$that$divide$fast.$What$normal$cells$divide$fast?$Intestinal$ cells,$hair$follicle$cells,$bone$marrow$cells,$etc$ • A$cancer$patient$is$thus$given
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