16 an introduction to genetic analysisWord格式.docx
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MechanismsofGeneMutation
KeyConcepts
Mutationscanoccurspontaneouslyowingtoseveraldifferentmechanisms,includingerrorsofDNAreplicationandspontaneousdamagetotheDNA.
Mutagensareagentsthatincreasethefrequencyofmutagenesis,usuallybyalteringtheDNA.
Potentiallymutagenicandcarcinogeniccompoundscanbedetectedeasilybymutagenesistestswithbacterialsystems.
BiologicalrepairsystemseliminatemanypotentiallymutagenicalterationsintheDNA.
Cellslackingcertainrepairsystemshavehigherthannormalmutationrates.
Introduction
Thischapterdescribesthemaintypesofmolecularprocessesthatgiverisetothemutantallelesdiscussedinthepreviouschapter.Suchprocessesarerelevantnotonlytoexperimentalgeneticsbutalsohavedirectbearingonhumanhealth.
Molecularbasisofgenemutations
Genemutationscanarisespontaneouslyortheycanbeinduced.Spontaneousmutationsarenaturallyoccurringmutationsandariseinallcells.Inducedmutationsareproducedwhenanorganismisexposedtoamutagenicagent,ormutagen;
suchmutationstypicallyoccuratmuchhigherfrequenciesthanspontaneousmutationsdo.
TounderstandthemechanismsofgenemutationrequiresanalysisatthelevelofDNAandproteinmolecules.PrecedingchaptershavedescribedmodelsforDNAandproteinstructureandhaveconsideredthenatureofmutationsthatalterthesestructures(see,forinstance,Table15-1).
MoleculargeneticstechniquescanbeusedtodeterminethesequenceoflargesegmentsofDNAandthesequencechangesresultingfrommutations.Sequencinghasgreatlyincreasedourunderstandingofthepathwaysthatleadtomutagenesisandhasevenhelpedtounravelthemysteriesofmutationalhotspots—geneticsiteswithapenchantformutating.
Muchworkonthemolecularbasisofmutationhasbeencarriedoutinsingle-celledbacteriaandtheirviruses.However,manymutationsleadingtoinheriteddiseasesinhumansalsohavebeenanalyzed.Weshallreviewsomeofthefindingsofthesestudies.Weshallalsoconsiderbiologicalrepairmechanisms,becauserepairsystemsplayakeyroleinmutagenesis,operatingtolowerthefinalobservedmutationrates.Forexample,inEscherichiacoli,withallrepairsystemsfunctioning,basesubstitutionsoccuratratesof10−10to10−9perbasepairpercellpergeneration.Asageneralprinciple,basesubstitutionsarisebyaperturbationofthenormalpairingofcomplementarybases.
Spontaneousmutations
Spontaneousmutationsarisefromavarietyofsources,includingerrorsinDNAreplication,spontaneouslesions,andtransposablegeneticelements.Thefirsttwoareconsideredinthissection;
thethirdisexaminedinChapter20.
ErrorsinDNAreplication
AnerrorinDNAreplicationcanoccurwhenanillegitimatenucleotidepair(say,A–C)formsinDNAsynthesis,leadingtoabasesubstitution.
EachofthebasesinDNAcanappearinoneofseveralforms,calledtautomers,whichareisomersthatdifferinthepositionsoftheiratomsandinthebondsbetweentheatoms.Theformsareinequilibrium.TheketoformofeachbaseisnormallypresentinDNA(Figure16-1),whereastheiminoandenolformsofthebasesarerare.TheabilityofthewrongtautomerofoneofthestandardbasestomispairandcauseamutationinthecourseofDNAreplicationwasfirstnotedbyWatsonandCrickwhentheyformulatedtheirmodelforthestructureofDNA(Chapter8).Figure16-2demonstratessomepossiblemispairsresultingfromthechangeofonetautomerintoanother,termedatautomericshift.
Mispairscanalsoresultwhenoneofthebasesbecomesionized.Thistypeofmispairmayoccurmorefrequentlythanmispairsduetoiminoandenolformsofbases.
Transitions.
Allthemispairsdescribedsofarleadtotransitionmutations,inwhichapurinesubstitutesforapurineorapyrimidineforapyrimidine(Figure16-3).ThebacterialDNApolymeraseIII(Chapter8)hasaneditingcapacitythatrecognizessuchmismatchesandexcisesthem,thusgreatlyreducingtheobservedmutations.Anotherrepairsystem(describedlaterinthischapter)correctsmanyofthemismatchedbasesthatescapecorrectionbythepolymeraseeditingfunction.
Transversions.
Intransversionmutations,apyrimidinesubstitutesforapurineorviceversa.TransversionscannotbegeneratedbythemismatchesdepictedinFigure16-2.WithbasesintheDNAinthenormalorientation,creationofatransversionbyareplicationerrorwouldrequire,atsomepointinthecourseofreplication,mispairingofapurinewithapurineorapyrimidinewithapyrimidine.AlthoughthedimensionsoftheDNAdoublehelixrendersuchmispairsenergeticallyunfavorable,wenowknowfromX-raydiffractionstudiesthatG–Apairs,aswellasotherpurine–purinepairs,canform.
Frameshiftmutations.
Replicationerrorscanalsolea
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