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5.2 Mutations:CreatingVariation Let's look next at the causesof mutations and the different ways mutations can alter DNA. There are many causesof mutations. Radioactiveparticles pass through our bodies every day, for example, and if one of these particles strikes a molecule of DNA, it can damage the molecule's structure. Ultraviolet solar radiation strikes our skin cells and can causemutations to arise as these cells divide. Manv chemicalsalso can interfere with DNA replication and lead to mutation. Whenever a cell copiesits DNA, there is a small chance it may misread the sequenceand add the wrong nucleotide. Our cells have proofreading proteins that can fix most of these errors, but they sometimes let mistakesslip bv. Mutations alter DNA in severaldifferent ways: . Point mutation: A single base changes from one nucleotide to another (also known as a substitution). ' Insertion: A segmentof DNA is inserted into the middle of an existing sequence. The insertion may be as short as a singlebaseor as long as thousandsof bases (including entire genes). . Deletion: A segment of DNA may be deleted accidentally.A small portion of a gene may disappear,or an entire set of genesmay be removed. ' Duplication: A segmentof DNA is copieda secondtime. A small duplication can produce an extra copy of a region inside a gene. Entire genescan be duplicated. In somecases,even an entire genomecan be duplicated. . Inversion: A segmentof DNA is flipped around and inserted backward into its original position. . Chromosome fusion: TWo chromosomes are joined together as one. ' Aneuploidy: Chromosomesare duplicatedor lost, leading to abnormal levelsof ploidy. One way that mutations can give rise to geneticvariation is by altering the DNA within the coding region of a gene (the region that encodesa protein). An alteredcoding region may lead to a protein with a different sequenceof amino acids,which may fold into a different shape.This changecould causethe protein to perform its original activity at a faster or slower rate, or it may acquire a different activity. Pointmutation lnversion TGCATTGCGTAGGC Y TGCATTCCGTAGGC Insertion TGCATTTA6GC Chromosomefusion TGCATTCCGTAGGC A CCGJ Genomeduplication Deletion rGcArrckqrAGGc Y TGCATTTAGGC Geneduplication # iiiliiiltiiliiiitii iiillliiliii!iitn ffffli|tiiiiiiHii.- i i B : t i i r ; fiiill;iiitli!ltfi--^ lilliitlii$itttit ii ffi !-i ii fr it iiii!liiiil!*ji?iH ffiFf:tuxil Figure5.13 DNA canexperience severaldifferentkindsof mutations, suchas pointmutations,insertions, deletions, andduplications. ARrATroN t . 2 M U T A T T o NcsR: E A T T NvG 133 GenesandHeredity in Bacteria andArchaea All livingthings use DNA or RNAto storegeneticinformation.But eukaryotesare differentfrom bacteriaand archaeain the organizationof their DNA as well as in how they replicateDNA and pass it down to their offspring.The name eukaryotepoints to one of the most obviousthings that set eukaryotesapart from other forms of life.In Greek,it means"true kernel,"referringto the nucleusin which eukaryotes keeptheirDNAtightlycoiled.Bacteriaand archaealacka nucleus,and that trait has earnedthem the nameprokaryote,meaning"beforethe kernel." fheword prokaryotecame into use beforethe dawn of molecular systematics. Basedon what is now knownaboutthe relationship of the threedomains,a numberof leadingmicrobiologists argueagainst using the term prokaryote.We know now that archaea are more closelyrelatedto eukaryotes than they areto bacteria,whichmeans that if a cladeincludesarchaeaand bacteria*but not eukaryotesit wouldnot be monophyletic(Pace2OO9).In general,taxonomists avoidgivingnamesto paraphyletic taxa (Chapter4). Criticsargue that usingthe word prokaryotemakesas much senseas mammalogistsgivinga namefor the cladethat includesall mammals-except for rodents.So in this book,we'llavoidusingprokaryoteand simply referto bacteria and archaea. In bacteriaand archaea,a singlecjrcularchromosomefloats within the cell. lt is not constrainedby a nucleus,nor is it tightly spooledaroundhistones.That does not meanthis DNA is simplya loosetangle.Bacteriaand archaeaproduceproteinsthat keepsections of DNA organizedin twisted loops,Likeeukaryotes,bacteria and archaeacan regulategeneexpression by unwindingand winding t h e i rD N A . Like eukaryotes,bacteria and archaea have genetic regulatory regionsupstreamfrom their genes.Transcription factorscan trigger dramaticchangesin gene expressionin bacteriaand archaea throughregulatorycascades.Bacteriaand archaeacan alter therr gene expressionin responseto signalsfrom their environment. As a result,some speciescan producesporeswhen conditionsturn stressful. Otherscan producetoxinswhentheysenseothermicrobes competingfor resources. generegulationis lesscomplexin bacteriaand Overall,however, archaeathan it rsin eukaryotes. Bacteriaandarchaealackenhancers (shortregionsof DNAthat helpin transcription), for example,which can be locatedthousandsof basepairsawayfrom genesthey control in eukaryotes. Bacteriaandarchaeahaveself-splicing intronsbut lackthe abundantspliceosomal intronsfound in eukaryotes, which requirea groupof proteinscalledthe splrceosome to removethem from transcripts. Bacteriaandarchaeathus lackthe alternative splicing found in eukaryotes. As a result,they alwaysproducethe same proteinfrom any givengene. Replication in bacteriaand archaeais alsosimpler.They do not performmitosisor meiosis. Theydo not havefull-blownsexualreproduction,in whichmalesand femalesproducegametesthat combine in a new offspring.Instead,bacteriaand archaeatypicallygrow until they are largeenoughto divide.They then build a secondcopy of their circularchromosomeand then the two DNA moleculesare draggedto eitherend of the dividingcell.The two daughtercellsare identicalto the original,exceptfor mutationsthat ariseduringDNA replication. Bacteriaand archaeahavemanyof the same kindsof mutations found in eukaryotes,such as point mutationsand insertions.But theycannotacquiregeneticvariationas a consequence of reproduction the way we see in eukaryotes(i.e.,independentassortmentof As we'llseein Chapter10,this difference chromosomes). can havea majoreffecton how mutationsspreadthroughpopulations. Beneficialmutationsthat increasethe survivalor reproductive rateof bacteriacan sweepquicklythrougha populationof microbes, thanksto naturalselection. As we'llsee in Chapter6, scientistshave used microbesto perform important experimentson evolution, observingnaturalselectionin action.And,as we'llsee in Chapter18, bacteriacan rapidlyevolveresistance antibiotics, turningwhat were once easilytreateddiseasesinto seriousthreatsto publichealth. can spreadso quicklyisthat Onereasonthat antibioticresistance bacteriaare not limitedsimplyto passingdown their genesto their (knownas verticalgenetransfer).lt'salsopossiblefor descendants one individualmicrobeto "donate"DNAto another,througha processcalledhorizontal gene transfer. One way for genesto move from one microbe to another is via plasmids,whicharesmallringletsof DNAthat areseparatefrom the m a i nb a c t e r i a l c h r o m o s o m Uen.d e rc e r t a i nc o n d i t i o n sa.m i c r o b ew i l l translateplasmidgenesand assemblea tube calleda pilus,which linksthe genesto a neighboring cell.The donor cell can then pump B Terminator Promoter Ribosomes NucleoidDNA Plasma membrane DNA template I I Transcription Y g sequence Protein-codin Capsule C e lw l all RNAtranscript tI Translation _ I Y-2 .;e€ Porypeptide@ BoxFigure5.1.1A: Bacteria andarchaea differfromeukaryotes, like humans, in thatthegenetic withinthecellisnotcontained material '134 withina nuclearmembrane. B:Theprocess of geneexpression and regulationis muchsimplerthan in eukaryotes. c H A p r E RF t v ER A w M A T E R T A LH: E R I T A B L E vaRtATtoN AMoNG tNDrvrDUALs i :opy of the plasmidthroughthe pilus,and oftenpumpsa copy of s:'ne of its chromosomalDNAas well.In effect,plasmidsaregenetic ::-asites,usingbacteriaand archaeaas theirhostsandspreadingto -=,vhoststhroughthe piliencodedin theirowngenes.However, they :r also carry genesencodingbeneficialtraits,such as antibiotic -:srstance, whichcan provideadvantages to their hosts, Virusescan alsocarry out horizontalgenetransfer.As they rep:3te, some virusescan accidentallyincorporatehost genes into '-.rr owngenome.Whenthey infecta newhost,theycan insertthose r:res intotheir newhost'schromosome. Inmanycases, genetransferisa deadend.Thedonated horizontal a:res areharmful to the recipientcell,whichdiesor growstoo slowly ': competewith other individuals. But if a microbeacquiresa useful g:re, naturalselectioncan favorit. Evidence for successful horizon:a genetransfercan be found in studieson the spreadof antibiotic ':srstance:the samegeneoftenturnsup in differentspecies.lt'salso :':ssibleto identifycasesof horizontalgenetransferthat occurred - llionsof yearsago by performinglarge-scalecomparisonsof DNA - bacteriaandarchaea,In a numberof cases,scientistshavefound genesin species thatareunlike theircloserelatives butarehomologousto genesfoundin distantly relatedclades. Thesestudiesindicatethathorizontalgene transfer hasbeena majorelement ofevolution.InE.coli,Iorexample, 80 percent of allthegenesin itsgenome genetransferat somepointsincethe showevidence of horizontal (Dagan lastcommonancestor of bacteria andMartin2007).As we genetransferis promptingscientists sawin Chapter4,horizonlal to revise theirconcepts of species andof theoverall shapeof thetree of life. Compared to bacteria andarchaea, eukaryotes appearto have genetransfer. experienced relatively littlehorizontal Thereare a numberof possible explanations for thisdifference. Oneis opportunity:thecomplexity DNAreplication of eukaryotic maynotafford theopportunity to takeup foreigngenes.In bacteriaandarchaea, a contiguous setofgenesmayforma functional unit,called anoperon, inwhichtheyareallcontrolled bythesameupstream regulatory elements.Theentireoperoncanbe inserted intoa newhost,whereit maybe ableto providea usefulfunction.Eukaryotes lackoperons, genesarelesslikely however, sothatforeign to beusefulina newcell. Vertical gene transfer: The process of receivinggeneticmaterialfrom an parentce,@ ancestor. A Horizontal genetransfer: Any process in whichgeneticmaterialis transferred o'n"!'-l',=t="j.1-1 W to anotherorganismwithoutdescent. Plasmids:Molecules of DNA,found mostoftenin bacteria, that canreplicateindependently of chromosomal DNA. Y @@ /\ Plasmid ldentical daughter cells Horizontal 9ene transfer / \ ffi@ Cellsaregenetically identical to ancestors, exceptfor an acquired pointmutation. Box Figure 5.1.2 Bacteriareproduceby dividingin two. As they preparefor the division,they separate the two strandsof DNA CellscarryDNAof ancestors aswellasDNAacquired genetransfer. by horizontal and add a new strandto eachone,creatingtwo new DNA molecules,whicharetypicallyidenticalto the originalone.On rare occasions,however,genescan be passedfrom one bacteriumto another,througha processknownashorizontalgenetransfer. GA R t A T t O N 5 . 2 M U T A T T O N SC: R E A T T N V 135 .t t1 i1 14 I tl. !.frl r genescanhavephenotypic Figure5.14 Pointmutationsin humanprotein-coding effectsthat rangefrom the benign(e.g.,eyecolor)to the severe. Shownherearea varietyof striking(but genethat replaces rare)mutations.Forexample, a mutationin the FGFR3 the aminoacidproline with serineat position380 is responsible for albinism(A;Oettingand King1993);a singleC-to-T (B;Wanget a1.2007); transitionin the IMBRl geneleadsto triphalangeal thumb polydactyly a m i s s e n sm e u t a t i o ni n e x o nX I Vo f t h e G l 1 3g e n e r, e p l a c i ntgh e a m i n oa c i dp r o l i n ew i t h s e r i n el ,e a d : (C);a missense to Greig'scephalopolysyndactyly substitutionin the K/f proto-oncogene replacing t h e a m i n oa c i da r g i n i n w e i t hg l y c i n e at position 7 9 5l e a d st o p i e b a l d i s (mD ;S d n c h e z - M a ret itna l . 2 0 0 3 ) a; m u t a t i o ni n t h eA C V Rg1e n es u b s t i t u t i nt g e i t h h i s t i d i n ae t p o s i t i o ' h e a m i n oa c i da r g i n i nw 2 0 6 r e s u l t isn f i b r o d y s p l a soisas i f i c a npsr o g r e s s i (vEa ;S h o r ee t a 1 . 2 0 0 6a) ;n da p o i n tm u t a t i o ni n progeriasyndrome(F;Eriksson the LaminA genecausesHutchinson-Gilford et al.2OO3). Cis-actingelements:Stretchesof D N Al o c a t e dn e a ra g e n e - e i t h e r ( a d j a c e nt ot i m m e d i a t eu l yp s t r e a m the promoterregion),downstream, or i n s i d ea n i n t r o n - t h a ti n f l u e n cteh e expression of that gene.Cisregions oftencodefor bindingsitesfor oneor moretransposable factors. Trans-acting elements:Sequences of DNAthat arelocatedawayfrom the focalgene(e.g.,on anotherchromosome).Thesestretches of DNAgener, i c r o R N Ao,r a l l yc o d ef o r a p r o t e i nm Mutations can also have important effects without altering the product of a gt'n' Instead, they can simply change how much of a protein is made, or they can chan,. the timing or location of its production. These changes in levels o/gene expres\r,, can alter the behavior of cells or tissues and can have profound consequences 1, evolution as an additional component of heritable variation. Mutations can alter ger . expression by affecting where, when, or how much a gene is transcribed. For exanrpl. mutations may cause a transcription factor to bind more strongly than it did befor Or they may prevent a specific transcription activator protein from binding, so tl).. the gene no longer can be expressed in a particular kind of tissue. Transcription factors, hormones, and other regulatory molecules are themseh' o t h e rd i f f u s i b lm e o l e c u lteh a tt h e n encoded in genes,which means mutations that alter their genes ultimately can a11,. the genes they regulate. As a result of these interactions, a gene can be affecteil : a mutation that is far away from the gene itself. (Nearby elements that affect gt.: expression are cis-acting elements; faraway ones are trans-acting elements.) Mutations, as we'll see in later chapters, are required for evolution to occur. I.] it's important to bear in mind that they're extremely rare. To measure just how olt, \nfluencesexpress\onof \he foca\ gene mutations occur, scientists can erther run experiments onpopu\ations 136 c H A p r E RF r v ER A w M A T E R t a L H : E R I T a B L vEA R l a r r o N A M o N G r N D r v r D U A L s o{ ce\\s or ma, Table5.3 Themanywaysmutations caninfluence expression of a gene. Location of Mutation Type of Mutation Consequencefor Gene Action Coding Region insertion, Substitution, deletion,duplication. Altersthe product of the gene, andthus its functionor activity. cis-Regulatory insertion, Substitution, deletion,duplicationthat altersthe bindingaffnity of promoters,activators, repressors, erc. Altersthe timing,location, or levelof expression of the gene. Regions trans-Regulatory Regions Mutationto codingregions Altersthe bindingaffnity and factor. thus the activityof a promoter, of trans-acting activator,repressor, etc. Mutationto cis- or transregulatory regionsof factors. trans-acting Physiological Pathways(e.g., hormones) Altersthe developmental or environmental contextin which the geneis expressed. Alterswhere,when,or to what extentinhibitory, activating, or facothertrans-acting regulatory tors areexpressed. Altersthe timing,location, or Mutationsalterwhere, levelof expression when,or how muchan enof the gene. docrinesignalis produced. Altersthe developmental or environmental contextin which the geneis expressed. surveysof living populations.In 2008,for example,Michael Lynch and his colleagues at Indiana University rearedcoloniesofyeast (Lynchet al. 2008).From a singleancestor, Lynch and his colleaguesrearedhundreds of geneticallyidentical populations of yeast.They then allowed these lines to reproducefor 4800 generations.After selecting someof the descendants, the scientistssequencedall 12 million basepairs of DNA in eachcell'sgenome. Each time a yeast cell divides, the scientistsfound, each site in its DNA has a 0.00000003percent chanceof undergoing a point mutation. This probability is so low that a typical yeast cell may not acquirea single point mutation in its whole genome. But in a population of millions of yeast cells,point mutations will arise in thousands of individuals in eachnew generation. Lynch'sexperiments also showed that different kinds of mutations occur at different rates.The investigatorsfound that each gene has a roughly one-in-a-million chanceof being lost or duplicatedeachtime a cell divides.Duplicationsand deletions are rare, in other words, but they're also about a thousand times more likely than point mutations. Estimating mutation ratesin multicellular organismslike humans is a more complicated matter, for severalreasons.First, all of our genes are present in duplicate tdiploidy), and this meansthat many mutations that arisein one of the chromosomes rvill be hidden or masked by a functional copy of the same gene on the sister chromosome. Second,not all mutations that arise in our bodies are transmitted to our offspring.Any individual cell in our body has a chanceof mutating as it divides.If it's a skin cell,the skin cellsthat descendfrom it will continue to carry that mutation. But this lineageof cells will come to an end when we die. Such mutations are known as somatic mutations becausethey occur in the "soma," or body. If, on the other hand, a mutation arisesin the line of cells that gives rise to sperm or egg cells, it may be passedon to ofispring. And those offspring, in turn, may pass the mutation down to their own descendants.These mutations are known as germ- Somaticmutations:Mutationsthat affectcellsin the body("soma")of an organism. Thesemutationsaffect all the daughtercellsproducedby the affectedcell and can affectthe phenotypeof the individual. In animals, somaticmutationsarenot oassed downto offspring. ln plants,somatic mutationscanbe passeddownduring vegetative reproduction. Germ-linemutations:Mutationsthat affectthe gametes(eggs,sperm)of an individual andcanbetransmittedfrom parentsto offspring.Becausethey can be passedon, germ-linemutationscreate the heritablegeneticvariationthat is relevantto evolution. 5 . 2 M U T A T T o N sc:R E A T T NvGA R r A T r o N 137 line mutations. Even though somatic mutations sometimes drastically reduce the performance and fitness of an individual (e.g.,many cancers,as we seein Chapter 18, are the result of somatic mutations), they are not heritable. Heritable variation within populations arises becauseof the gradual accumulation of germ-line mutations. Until recently scientists could make only very indirect estimatesof the germ-line mutation rate in humans. One common method was to study the rate of diseasesthat are caused by a mutation of a single gene. But improvements in DNA sequencing have made it possible for scientists to make far more precise estimates.In 2010,Leroy Hood of the Institute for SystemsBiology in Seattleand his colleaguessequencedthe entire genomes of tvvo human siblings and their parents. They searchedthe genomes of the children for mutations that their parents did not carry. All told, they identified 70 new mutations in eachchild {Roachet al. 2010). KeyConcepts for evolution byadding in levels of geneexpression canhaveprofound consequences Changes genetic another component to heritable variation. Geneticchangesin geneexpression arisewhen mutationsoutsideof the codingregionsaffectwhere, when,or how mucha geneis transcribed. i 5.3 Heredity Allele:One of severalalternative formsof the DNA sequence of the samelocus. Meiosis:A form of celldivisionthat in whichthe occursonly in eukaryotes, numberof chromosomes is cut in half. Meiosisgivesriseto gametesor sporesand is essential for sexual reproduction. Genetic recombination:Theexchange ofgeneticmaterialbetweenpaired chromosomes duringmeiosis. Recombinationcanform newcombinations of allelesand is an importantsourceof heritablevariation. 138 Once new mutations arise,organismscan passthem down, along with their unmutated DNA, to their offspring. Bacteria and archaeareproduce by dividing and making a new copy of their genomefor eachdaughtercell (Box 5.1).In sexuallyreproducing, multicellular eukaryotes,on the other hand, heredity is more complex.For one thing, only germJine cells can pass on genes to offspring. For another, the development of sex cells introduces new genetic variation, so that sexually reproducing organisms producegeneticallyunique offspring insteadof clones. One reasonthat parentsdo not producefamilies of identical children is that each parent'sown paired chromosomesare not identical.One chromosomemay have one version of a gene (an allele) while the other chromosomehas an allelewith a slightly different DNA sequence.Differencesbetweenthe chromosomesin eachpair generate variation among the gamete cells that are produced, so that no tvvo sperm or egg cells are identical. Gametesof sexually reproducing organismsare produced through a distinctive Meiosis can generatea stunning kind of cell division known as meiosis (Figure5.'15). amount of geneticvariation. During the final stageof meiosis,each pair of chromo' somes separates,so that only a single copy ends up in each daughter cell. Which copy' endsup in eachcell occursrandomly,and it occursrandomly for eachof the different chromosomal pairs. This means that a single sperm cell may inherit the maternal copy of one chromosome,but the paternal copy of another. Humans have 23 pairs of chromosomes,and the independentassortmentof eachseparatechromosomecan result in many different combinationsof maternally inherited and paternally inher ited genes. In addition, each pair of chromosomes may cross over during meiosis and exchange segments of DNA in a process known as genetic recombination. By the time these chromosomes are packed into gamete cells, many of them have alreadr' been rearranged so that they differ from either of the parental chromosomes.Recom bination also can creategeneticvariation among the different gametesproduced br an individual. Consequently,the processesof independent assortment and recombi nation can, through the rearrangement of alleles, generate a staggering number of possiblegametegenotypes. This rich mixing of alleles occurs in the formation of gametes of both the male and the female. Sexualreproduction brings the chromosomalforms of each parenr c H A p r E RF r v ER A w M A T E R T a LH: E R I T a B L vEa R t a r l o N A M o N G l N D t v t D U A L S Father Chromosomes areduplicated. Chromosomes are duplicated crossover Chromosomes of DNA. segments andexchange of homologous Segregation chromosomes of Segregation sisterchromatids Haploid gametes f \ likehumans, organisms, Figure5.15 Amongsexuallyreproducing Duringthe malesandfemalescombinetheir gametesto reproduce. crossoverancl eachpairof chromosomes productionof gametes, onlyone copyfrom of DNA.Eachgametereceives segments exchange a unique carries each child a result, As eachoairof chromosomes. parents. her of his or DNA of the combination 5.3 HEREDTTY 139 lrlr Figure5.16 Independent assortment occursduringmeiosisin eukaryotic gametes and produces organisms with a mixtureof maternaIand paternalchromosomes. Alongwith independent chromosomalcrossover, geneticdiversity increases assortment of by producingnovelcombinations alleles. together, creating yet another combination of alleles. Consequently,when Maternalcopies a human sperm cell fertilizes an egg, the chromosomescombine to produce a new set of 23 pairs. But this new set is drawn from a rich pool of genetic variants reflecting millions of possible combinations of allelesinherited from both the father and the mother. The particular combination that fuses to form the new diploid offspring indi' vidual is literally one in a million, and it is not likely to happen twice. This is why sibling offspring from the same parents always differ in their inherited characteristics.(An exception to that rule, of course,is identical twins who developfrom a single fertilized egg.) The best estimate of the differences between our paired chromo. somes comes from Craig Venter, a genome-sequencingpioneer. In 2007 he and his colleaguespublished the complete sequenceof his own genome (Levy et aL.2007).They compared each pair of chromosomes,tallying up the differences.The researchersidentified Novelcombinations of alleles 3.2 million placeswhere a single nucle otide in one chromosomedid not match the correspondingnucleotidein its partner. The scientistsalso found about a million segmentsof DNA on one chromosomethat were missing from its partner,or that had been inserted. @@ @)@ KeyConcept recombination, meiosis Because of chromosomes andgenetic can of theindependent assortment generate genetic extraordinary diversity amonggametes. Genotype:Thegeneticmakeupof an individual. Althougha genotypeinc l u d e sa l lt h e a l l e l e os f a l lt h e g e n e si n that individual, the term is oftenused to referto the specificallelescarriedby gene. an individual for any particular Phenotype:An observable, measurablecharacteristic of an organism. A phenotypemaybe a morphological structure(e.g.,antlers,muscles), a (e.g.,learning), process developmental process a physiological or performance trait (e.g.,runningspeed), or a behavior (e.g.,matingdisplay). Phenotypes can producedby evenbe the molecules genes(e.9.,hemoglobin). f4O 5.4 TheLinkbetweenMostPhenotypes ls Complex andGenotypes Scientistsdraw a distinction between the genetic material in an organism and the traits that the geneticmaterial encodes.The geneticmakeup of an organism is knor.r'n as its genotype, and the manifestation of the genotype is known as the phenotype. Organismsdo not inherit a phenotype; they inherit genes,which together constitute a genotype,which gives rise to a phenotype. Understanding how phenotypesemergefrom genotypesis no easytask. A trait does not come with a label on it, detailing all the genesthat helped to build it and the specificrole played by each of the genes.Instead,scientistsrely on a variety of methods to explore how genesand gene expressioncontribute to the formation oi organismalphenotypes.Thesemethods range from controlled breeding experiment' to detailed genetic mapping studies-even to perturbations of expressionof focal developmentalgenes(Chapter10 describesmany of thesemethods in greaterdetailr The traits that Mendel studied in his peas (Box5.2) have relatively simple, dis crete, alternative phenotypic states.The peas were either wrinkled or smooth, for L :E R I T A B T E c H A p r E RF r v ER A w T T A T E R T A H vARtATtoN At oNG tNDtvtDUALs