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