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In that case,referenceto the gorilla sequencecan be be used to sort out which of the few differencesbetween human andchimp DNA sequenceswasinherited from our common ancestorsome6 millionyearsago (seeFigure4-76).For an ancestorthat hasproduced a largenumber ofdifferent organisms alive today, the DNA sequencesof many speciescan becompared simultaneouslyto unscramblethe ancestralsequence,allowing scientists to trace DNA sequencesmuch farther back in time. For example,fromthe complete genome sequencesof 20 modern mammals that will soon beobtained,it shouldbe possibleto deciphermost of the genomesequenceof the100million year-oldBoreoeutherianmammal that gaverise to speciesasdiverseas dog, mouse,rabbit, armadillo and human (seeFigure4-77).MultispeciesSequenceComparisonsldentifylmportantDNASequencesof UnknownFunctionThe massivequantity of DNA sequencenow in databases(morethan a hundredbillion nucleotide pairs) provides a rich resourcethat scientistscan mine formany purposes.We have alreadydiscussedhow this information can be usedtounscramblethe evolutionarypathwaysthat haveled to modern organisms.Butsequencecomparisonsalsoprovide many insightsinto how cellsand organismsfunction.
Perhapsthe most remarkable discoveryin this realm has been theobservationthat, althoughonly about I.5% of the human genomecodesfor proteins, about three times this amount (in total, 5%of the genome-see Table4-1,p. 206)has been stronglyconservedduring mammalian evolution.This massofconservedsequenceis most clearly revealedwhen we align and compareDNAsynteny blocks from many different species.In this way, so-calledmultispeciesconseruedsequencescan be readily identified (Figure 4-83).
Most of the noncoding conservedsequencesdiscoveredin this way turn out to be relativelyshort, containing between 50 and 200 nucleotide pairs.The strict conservationgene(cystichumanCFTRfibrosistransmembraneconductanceregulator)190,000nucleotidepairs,t3'intronexonT---------------rt i t j'.
r i i' t r i t li 'i i 't i i r t r | l t r ' i i t i ' i t i i l i + t t i l l i i i t i i i l t t i i t lr*.}}+iF)+i*.,+iF++ *chimpanzeeorangutanbaboonmarmosetlemurrabbithorsecatdogmouseopossumchicken\100%Fugu,L['I10-0nucleotide pairs1O OOO nr rrlonfidanrir<rSOVoFigure4-83 The detection ofmultispeciesconservedsequences.Inthis example,genome sequencesforeachofthe organismsshownhavebeencomparedwith the indicatedregionofthe humanCFTRgene,scanningin25 nucleotideblocks.Foreachorganism,the percentidentity acrossits syntenicsequencesis plotted in green.Inaddition,a computationalalgorithmhas beenusedto detect the sequenceswithin thisregionthat are most highly conservedwhen the sequencesfrom all of theorganismsaretaken into account.Besidesthe exon,three other blocksofmultispeciesconservedsequencesareshown.The function of most suchsequencesin the humangenomeis notknown/Cor rrfcsv of Frir f) Grcen )HOW GENOMESEVOLVEimplies that they have important functions that have been maintained by puriffing selection.
The puzzle is to unravel what those functions are. Some of theconserved sequence that does not code for protein codes for untranslated RNAmolecules that are known to have important functions, as we shall see in laterchapters. Another fraction of the noncoding conserved DNA is certainlyinvolved in regulating the transcription of adjacent genes,as discussedin Chapter 7. But we do not yet know how much of the conserved DNA can be accountedfor in these ways, and the bulk of it is still a deep mystery.
The solution to thismystery is bound to have profound consequences for medicine, and it revealshow much more we need to learn about the biology of vertebrate organisms.How can cell biologists tackle this problem? The first step is to distinguishbetween the conserved regions that code for protein and those that do not, andthen, among the latter, to focus on those that do not already have some otheridentified function, in coding for structural RNA molecules, for example. Thenext task is to discover what proteins or RNA molecules bind to these mysterious DNA sequences,how they are packaged into chromatin, and whether theyever serve as templates for RNA synthesis. Most of this task still lies before us,but a start has been made, and some remarkable insights have been obtained.One of the most intriguing concerns the evolutionary changes that have madeus humans different from other animals-changes, that is, in sequences thathave been conserved among our close relatives but have undergone suddenrapid change in the human sublineage.AcceleratedChangesin PreviouslyCanConservedSequencesHelpDecipherCriticalStepsin HumanEvolutionAs soon as both the human and the chimpanzee genome sequences becameavailable, scientists began searching for DNA sequence changes that mightaccount for the striking differences between us and them.
With 3 billionnucleotide pairs to compare in the two species,this might seem an impossibletask. But the job was made much easierby confining the search to 35,000clearlydefined multispecies conserved sequences(a total of about 5 million nucleotidepairs), representing parts of the genome that are most likely to be functionallyimportant. Though these sequences are conserved strongly, they are not conserved perfectly, and when the version in one species is compared with that inanother they are generally found to have drifted apart by a small amount corresponding simply to the time elapsed since the last common ancestor.In a smallproportion of cases,however, one seessigns of a sudden evolutionary spurt. Forexample, some DNA sequencesthat have been highly conserved in other mammalian speciesare found to have changed exceptionally fast during the six milIion years of human evolution since we diverged from the chimpanzees.
Suchhuman accelerated regions IFIARs) are thought to reflect functions that havebeen especially important in making us different in some useful way.About 50 such sites were identified in one study, one-fourth of which werelocated near genes associatedwith neural development. The sequence exhibiting the most rapid change (18 changesbetween human and chimp, compared toonly two changesbetween chimp and chicken) was examined further and foundto encode a 1l8-nucleotide noncoding RNA molecule that is produced in thehuman cerebral cortex at a critical time during brain development (Figure4-84). Although the function of this FIARIF RNA is not yet known, this excitingfinding is stimulating further studies that will hopefully shed light on crucial features of the human brain.Gene DuplicationProvidesan lmportant Sourceof GeneticNoveltyDuring EvolutionEvolution depends on the creation of new genes,as well as on the modificationof those that already exist.
How does this occur?lVhen we compare organismsthat seem very different-a primate with a rodent, for example, or a mouse with253254Chapter4: DNA,Chromosomes,and GenomesC R E S YVLI O L E TS T A I Noutersurfaceof cortexInnersurfaceof cortex4mm/ N S / T UH Y B R I D I Z A T I O NIrISF.;?.If$..'{{"I?*ItJ(A)(B):s'1mma fish-we rarely encounter genes in the one species that have no homolog inthe other. Genes without homologous counterparts are relatively scarce evenwhen we compare such divergent organisms as a mammal and a worm. On theother hand, we frequently find gene families that have different numbers ofmembers in different species.To create such families, genes have been repeatedly duplicated, and the copies have then diverged to take on new functions thatoften vary from one speciesto another.The genes encoding nuclear hormone receptors in humans, a nematodeworm, and a fruit fly illustrate this point (Figure 4-85).
Many of the subtypes ofthese nuclear receptors (also called intracellular receptors) have close homologsin all three organisms that are more similar to each other than they are to otherfamily subtypes present in the same species.Therefore, much of the functionaldivergence of this large gene family must have preceded the divergence of thesethree evolutionary lineages.Subsequently,one major branch of the gene familyunderwent an enormous expansion in the worm lineage only. Similar, butsmaller, lineage-specific expansions of particular subtypes are evident throughout the gene family tree.Gene duplication occurs at high rates in all evolutionary lineages, contributing to the vigorous process of DNA addition discussed previously.
In adetailed study of spontaneous duplications in yeast, duplications of 50,000 to250,000 nucleotide pairs were commonly observed, most of which weretandemly repeated. These appeared to result from DNA replication errors thatIed to the inexact repair of double-strand chromosome breaks.A comparison ofthe human and chimpanzee genomes revealsthat, since the time that these twoorganisms diverged, segmental duplications have added about 5 millionnucleotide pairs to each genome every million years, with an average duplication size being about 50,000 nucleotide pairs (however, there are duplicationsfive times larger, as in yeast). In fact, if one counts nucleotides, duplicationevents have created more differences between our two speciesthan have singlenucleotide substitutions.DuplicatedGenesDivergeA major question in genome evolution concerns the fate of newly duplicatedgenes.In most cases,there is presumed to be little or no selection-at least initially-to maintain the duplicated state since either copy can provide an equiv-Figure4-84 Initial characterizationof anew gene detected as a previouslyconservedDNA sequencethat evolvedrapidlyin humans.(A)Drawingby Ramony Cajalof the outersurfaceof the humanneocortex,highlightingthe Cajal-Retziusneurons.(B)Tissueslicesfrom anembryonichumanbrainshowingpart ofthe cortex,with the regioncontainingtheCajal-Retziusneuronshighlightedinyellow.Upper photograph:cresylvioletstain.Lowerphotograph:ln sifuhybridization.The redarrowsindicatethecellsthat oroduceHARlF RNAasdetectedby in situhybridization(b/ue).HARlF is anovelnoncodingRNAthat hasevolvedrapidlyin the humanlineageleadingfromthe greatapes.TheCajal-Retziusneuronsmakethis RNAat the time when theneocortexis developing.The resultsareintriguing,becausea largeneocortexisspecialto humans;for the behaviorof cellsin formingthis cortex,seeFigure22-99.(Adaptedfrom K.S,Pollardet al.,Nature443:167-172, 2006.With permissionfromMacmillanPublishersLtd.)255HOW GENOMESEVOLVEalent function.
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