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Lecture 10

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Department
Biological Sciences
Course
55-213
Professor
Hubberstey
Semester
Winter

Description
Lecture 10 2013-02-07 8:07 PM Introduction:(where(do(our(genes(come(from?! • We!all!have!common!ancestors!that!go!way!back!!!genes!also!have!ancestors!! • Exons!are!thought!to!be!the!building!blocks!of!genes! • Exons!make!a!particular!string!of!amino!acids! • Exons!are!separated!by!introns! • When!you!look!at!gene!structure!of!every!species!(mammals,!frogs,!birds),!the! introns!occur!in!the!exact!same!positions!! o This!implies!that!when!the!gene!evolved!in!the!ancestral!organisms,!the! evolution!worked!really!well! o The!gene!went!along!with!the!species!as!it!evolved( ( Intron(position(is(conserved:( • Intron!positions!are!usually!conserved!in!related!genes! • Introns!are!found!in!the!same!positions!relative!to!the!exons,!however!the!length!of! introns!can!vary!widely! o Example:!globin!genes!(alpha!and!beta)! • In!mammals,!frogs!and!birds,!introns!occur!in!same!position!but!have!different! lengths! • See!figure!4.4!!!globin!genes!vary!in!intron!lengths!but!have!the!same!structure! ! ! ! ! ! ! ! ! ! ! ! ! ! o Number!underneath!shows!variation!in!exon!sizes! o Exon!length!highly!conserved! o Number!on!top!shows!variation!in!intron!sizes! o Intron!length!has!a!lot!more!variation!in!it! o Exon!2!in!all!mammals!have!not!changed!at!all.!This!implies!that!it!is!a!very! important!exon.!Any!changes!to!it!!!you’ll!probably!be!dead.!! o Exon!3!has!a!little!bit!of!variation! o Intron!2!has!quite!a!big!difference!in!nucleotide!length!(5001900)! • Position!is!conserved,!but!length)is!not!! • Why?!Because!introns!don’t!code!for!anything,!there’s!really!no!selective!pressure! • Exons!code!for!protein.!Thus,!any!changes!to!the!coding!region!theoretically!has!a! much!higher!risk!of!mutation!than!a!change!to!introns.!! • There!are!specific!sequences!within!the!intron!(usually!at!the!exon/intron! boundaries!in!green)!that!are!very!critical!to!tell!the!cell!to!splice!out!the!introns!and! fuse!the!exons!together! • If!you!move!exon!around,!you!change!reading!frame!of!protein!!!it’s!a!big!deal!! • This!is!why!it’s!believed!that!the!ancestral!genes!that!took!up!the!introns!won’t!be! changed.!You!can!change!the!length!of!the!intron,!but!changing!the!position!of!the! intron!is!a!much!more!serious!consequence!to!the!overall!gene!structure!and! function! • What!about!mutations!within!an!intron?! o You!could!get!insertions!put!in!without!having!any!major!effect! Intron(structure:( • Mutations!within!introns!may!be!silent! o They!don’t!really!have!an!effect!on!gene!function!!!all!it!does!is!change! sequence! • However,!there!are!some!mutations!within!introns!that!can!have!very!serious! effects.!These!are!found!in!the!splicing!sequences!(shown!in!green,!between! into Very!dramatic!effect! • Mutations!that!affect!splicing!can!affect!protein!function! o Frameshift!mutations!can!result! o Frameshift!mutations!are!usually!very!bad!for!a!cell!and!a!gene! o Genes!involved!in!human!disease!were!thought!to!be!disturbed!by!splicing! mutations!mutations that affect splicing can affect protein function o 15%!of!human!diseases!are!caused!by!mutations!in!introns!that!affect! splicing!! ▯frameshift mutations can result • Our!introns!are!sometimes!huge!compared!to!exons.!If!you!look!at!our!genome,!the! majority!of!it!codes!for▯15% of human disease are caused byxons!(surprisingly)! • In!eukaryotes,!introns!are!generally!longer!than!exons! • Some!eukaryotes!have!very!few!introns!(e.g.!yeast)!ffect splicing o 90%!of!yeast!genes!have!no!introns!whatsoever! • Summary!picture:! o If!you!get!▯in eukaryotes, introns are generally longer than exonsave!an!effect! on!gene! o Imore!deleterious!effect!es have very few introns (e.g. yeast)l!have!a!much! PROGERIA # ( exon1 * intron *▯1 in 8 million births ( Progeria(Disease:( • Only!140!cases!recorded!in!all!of!medical!literature!auses premature and rapid ageing of cells • Thus,!incredibly!rare!disease! • Causes!premature!and!rapid!ageing!of!cells! ▯ death usually by age 15 • Death!usually!by!age!15! • It!progresses!very!rapidly!from!the!onset!of!birth! • Mostly!die!of!arteriosclerosis,!hardening!of!arteries,!stroke,!etc!ne for progeria was discovered in 2003 • Dominant!defective!gene!for!Progeria!was!discovered!in!2003! o Found!in!Human!Genome!Project! Single nucleotide mutation o Mutations!in!this!gene!definitely!cause!this!disease! o You!could!actually!change!the!gene!in!mice!and!they!will!show!ageing!and!die! A prematurely! Nuclear protein which causes proper nuclear structure o Its!dominant!:!1!copy!of!it!!!you!get!the!disease! o Dinovel!mutation!! o Usually!not!hereditary!because!the!kids!don’t!live!! long!enough!to!have!kids!of!their!own! o Single!nucleotide!mutation! o Lamin!A! o Lines!the!inner!nuclear!membrane!of!the!nucleus! o Nstructure!tein!which!causes!proper!nuclear!! o Nucleus!shape!is!messed!up!because!the!Lamin!is!! o impaired!! o Non!circular!shape!of!nucleus!!!see!picture! • Lamin!A!mutation:!Gly608Gly!which!is!a!C1T!transition!! : Gly608Gly which is a C ▯T transition o CG!base!pair!changed!to!an!AT!base!pair ! o GGC!codon!changed!to!GGU!codon! changesGGC codon to aGGU o Specific!RNA!sequences!determine!splice!sites! o These!2!codons!code!for!Glycine!!!this!is!why!it!took!such!a!long!time!to!find!ites this!gene!! o How!does!it!change!the!function!of!the!protein!without!changing!the!amino! acid?!This!was!the!riddle!that!was!hard!to!figure!out!! " RNA!splicing!!! " See!picture!(right)! ! Progeria: !plice sequences ! ! PreLamin A * ! Exon 11 ! Exon 12 ! 50 amino acids deleted ! ! Progerin ! • This!mutation!occurs!in!an!exon,!not!an!intron!!So!how!can!it!affect!splicing?!?! o If!the!sequence!looks!kind!of!like!a!splice!site!(but!its!not)!and!you!change!the! nucleotide!to!make!it!look!exactly!like!a!splice!site!!!probRNAsplicing o Splice!sites!are!normally!20!nucleotides!in!length!! o See!picture!(left)!!!Yellow!star!is!where!single!mutation!occurs!(wobble! position)!–!its!nowhere!near!an!intron,!but!amazingly,!it!creates!a!splice!site! o Before!mutation,!yellow!star!is!just!a!bunch!of!nucleotides.!However,!after! you!change!the!one!nucleotide,!it!becomes!a!splice!site!and!the!cell!doesn’t! recognize!it!as!a!normal!codon.!! o Picking!up!this!extra!splice!site!means!that!the!cell!splices!earlier!than!usually! (a!piece!of!exon!11!disappears,!exon!12!remains!intact)! " You!essentially!get!a!deletion,!due!to!a!single!base!pair!change!which! then!changes!the!splicing!of!that!particular!gene.!! " 50!amino!acids!are!deleted! " This!creates!a!protein!now!called!Progerin! " If!your!cells!are!producing!Progerin!(even!if!you!only!have!1!copy,! since!its!dominant),!you!will!have!the!disease!! " A!very!minimal!amount!is!enough!to!make!the!cell!completely!ignore! the!wild!type!amount!!!disease!! " Thus,!the!mature!mRNA!is!missing!a!whole!piece,!so!it!can’t!make!the! Glycine! • From!studies!conducted!on!the!elderly,!it!has!been!seen!that!as!you!age,!this! mutation!occurs!in!somatic!cells.!This!is!potentially!a!result!of!normal!aging.!The! protein!progerin!and!the!mutation!was!found!in!some!of!the!DNA!of!the!elderly! people.!
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