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In addition, as indicated in Figure 4-77, rodent lineages (representedbythe rat and the mouse) have unusually fast molecular clocks. Hence, these lineages have diverged from the human lineage more rapidly than otherwiseexpected.As indicated by the DNA sequencecomparison in Figure 4-78, mutation hasled to extensive sequence divergencebetween humans and mice at all sites thatare not under selection-such as most nucleotide sequencesin introns.
In con-of a portionofFigure4-78 Comparisonthe mouseand humanleptingenes.differby awherethe sequencesPositionsareboxedsubstitutionsinglenucleotideporiio"r ut"itr"trast,in human-chimpanzeenearlyalliequencecomparisons,[3'f,'* Slij!|,:f]ffi3jT,:'.?:ll'same simply because not enough time has elapsed since the last commonancestor for large numbers of changes to have occurred.In contrast to the situation for humans and chimpanzees, local gene orderand overall chromosome organization have diverged greatly between humansro*"Jinyellor.Notethatthecodingof the exonismuchmoresequenceintronthanisthe adjacentconservedsequence.exon .<_-r--> intron:::i:ffi:txi:s;trt$::ii*::mn::ff:il:i:i::ffi::il:il:ffi:i:ffiH:i::ffi:il:ffi:i:i#:i:ffiff#il::i:tff:il:mouseTATTTCTGGTCATGGCTCTTGTCACTGCTGCCTGCTGAAATACAGGGCTGAACCAGAGTCTGAGAAACATGTCATGCACCTCCTAGAAGCTGAGAGTTTAT.AAGCCTCGAGTGTACAT.GAAGGATTTGAAAGCACAGCCAG- - CCC-AGCACTGGCTCCTAGTGGCACTGGACCCAGATAGTCCAAGAAACATTTATTGAACGCCTCCTGAATGCCAGGCACCTACTGGAAGCTGAhuman250Chapter4: DNA,Chromosomes,and Genomesh u m a nc h r o m o s o m e1 4m o u s ec h r o m o s o m1e22 0 0 , 0 0 0b a s e sand mice.
According to rough estimates, a total of about 180 break-and-rejoinevents have occurred in the human and mouse lineages since these two speciesIast shared a common ancestor. In the process, although the number of chromosomes is similar in the two species(23 per haploid genome in the human versus 20 in the mouse), their overall structures differ greatly.
Nonetheless, evenafter the extensive genomic shuffling, there are many large blocks of DNA inwhich the gene order is the same in the human and the mouse. These stretchesof conserved gene order in chromosomes are referred to as regions of synteny.An unexpected conclusion from a detailed comparison of the completemouse and human genome sequences, confirmed from subsequent comparisons between the genomes of other vertebrates, is that small blocks ofsequencesare being deleted from and added to genomes at a surprisingly rapidrate. Thus, if we assumethat our common ancestor had a genome of human size(about 3 billion nucleotide pairs),mice would have lost a total of about 45 percent of that genome from accumulated deletions during the past B0 millionyears, while humans would have lost about 25 percent.
However, substantialsequence gains from many small chromosome duplications and from the multiplication of transposons have compensated for these deletions. As a result, ourgenome size is unchanged from that of the last common ancestor for humansand mice, while the mouse genome is smaller by only 0.3 billion nucleotides.Good evidence for the loss of DNA sequencesin small blocks during evolution can be obtained from a detailed comparison of most regions of synteny inthe human and mouse genomes.
The comparative shrinkage of the mousegenome can be clearly seen from such comparisons, with the net loss ofsequences scattered throughout the long stretches of DNA that are otherwisehomologous (Figure 4-79).DNA is added to genomes both by the spontaneous duplication of chromosomal segments that contain tens of thousands of nucleotide pairs (as will bediscussed shortly), and by active transposition (most transposition events areduplicative, becausethe original copy of the transposon stayswhere it was whena copy inserts at the new site; for example, see Figure 5-74).
Comparison of theDNA sequencesderived from transposons in the human and the mouse therefore readily reveals some of the sequence additions (Figure 4-80).For unknown reasons, all mammals have genome sizes of about 3 billionnucleotide pairs that contain nearly identical sets of genes,even though only onthe order of 150 million nucleotide pairs appear to be under sequence-specificfunctional constraints.h u m a n p - g l o b i ng e n e c l u s t e rC'l IY-rttttlltltlaal' "l ll'lm o u s eB - g l o b i ng e n e c l u s t e r'.ti',:: ::'.::::'''l" ll 1/\ I ll10,000n u c l e o t i d ep a i r sBmaJorInBm rnorFigure 4-79 Comparisonof a syntenicportion of mouseand human genomes.About90 percentofthe two genomescanbe alignedin thisway.Notethat whilethereis an identicalorderof the matched(redmarks),therehasindexsequencesbeena net lossof DNAin the mouselineagethat is interspersedthroughouttheentireregion.Thistype of net lossistypicalfor all suchregions,and it accountsfor thefact that the mousegenomecontains14percentlessDNAthan doesthe humangenome.(Adaptedfrom MouseSequencingConsortium, Noture420:520-573, 2002.With permissionfromMacmillanPublishersLtd.)Figure4-80 A comparisonof thep-globingene clusterin the human andmousegenomes,showingthe locationof transposableelements.ThisstretchofhumangenomecontainsfivefunctionalB-globin-likegenes(orange);thecomparableregionfrom the mousegenomehasonlyfour.The positionsofthe humanAlu sequenceareindicatedbygreencircles,and the humanLlsequencesby redcircles.The mousegenomecontainsdifferentbut relatedtransposableelements:the positionsofB1elements(whichare relatedto thehumanAlu sequences)areindicatedbybluetriangles,and the positionsof themouseL1elements(whichare relatedtothe humanL1 sequences)are indicatedby orangetriangles.The absenceoftransposableelementsfrom the globinstructuralgenescan be attributedtopurifyingselection,whichwould haveeliminatedany insertionthatgenefunction.(Courtesycompromisedof RossHardisonandWebbMiller.)HOWGENOMESEVOLVE.:251TheSizeof a VertebrateGenomeReflectsthe RelativeRatesofDNAAdditionand DNALossin a LineageNow that we know the complete sequence of a number of vertebrate genomes,we see that genome size can vary considerably, apparently without a drasticeffect on the organism or its number of genes.Thus, while the mouse and doggenomes are both in the typical mammalian size range, the chicken has agenome that is only about one-third human size (one billion nucleotide pairs).A particularly notable example of an organism with a genome of anomalous sizeis the puffer fis}:',Fugu rubripes (Figure 4-81), which has a tiny genome for a vertebrate (0.4 billion nucleotide pairs compared to I billion or more for manyother fish).
The small size of the Fugu genome is largely due to the small size ofits introns. Specifically,Fugu introns, as well as other noncoding segmentsof theFugu genome, lack the repetitive DNA that makes up a large portion of thegenomes of most well-studied vertebrates. Nevertheless,the positions of Fuguintrons are nearly perfectly conserved relative to their positions in mammaliangenomes (Figure 4-82).\Mhile initially a mystery we now have a simple explanation for such largedifferences in genome size between similar organisms: because all vertebratesexperience a continuous process of DNA loss and DNA addition, the size of agenome merely depends on the balance between these opposing processesacting over millions of years.
Suppose,for example, that in the lineage leading toFugu, the rate of DNA addition happened to slow greatly. Over long periods oftime, this would result in a major "cleansing" from this fish genome of thoseDNA sequenceswhose loss could be tolerated. In retrospect,the processof purifying selection in the Fugu lineage has partitioned those vertebrate DNAsequencesmost likely to be functional into only 400 million nucleotide pairs ofDNA, providing a major resource for scientists.Figure4-81 The pufferfish, Fugurubripes.(Courtesyof ByrappaVenkatesh.)WeCanReconstructthe Sequenceof SomeAncientGenomesThe genomes of ancestral organisms can be inferred, but never directlyobserved: there are no ancient organisms alive today.
Although a modern organism such as the horseshoe crab looks remarkably similar to fossil ancestors thatlived 200 million years ago, there is every reason to believe that the horseshoecrab genome has been changing during all that time at a rate similar to thatoccurring in other evolutionary lineages.Selection constraints must have maintained key functional properties of the horseshoe-crab genome to account forthe morphological stability of the lineage. However, genome sequencesrevealthat the fraction of the genome subject to purifying selection is small; hence thegenome of the modern horseshoe crab must differ greatly from that of its extinctancestors, known to us only through the fossil record.Is there any way around this problem? Can we ever hope to decipher largesections of the genome sequence of the extinct ancestors of organisms that areh u m a ng e n e100.0pairsthousandsof nucleotideFigure 4-82 Comparisonof the genomicsequencesof the human and Fugugenesencodingthe protein huntingtin.
Bothgenes(indicatedin red)contain67 shortexonsthat alignin 1:1to one another;thesecorrespondenceexonsare connectedby curvedlines.Thehumangeneis 7.5timeslargerthan theFugugene(180,000versus27,000nucleotidepairs).The sizedifferenceisentirelydue to largerintronsin the humangene.Thelargersizeof the humanintronsis due in part to the presenceofwhose positionsareretrotransposons,representedby greenverticallines;theInFuguintronslackretrotransposons.humans,mutationof the huntingtingenecausesHuntington'sdisease,an inheriteddisorder.(Adaptedneurodegenerativefrom S.Baxendaleet al.,Nat.Genet.'l0:67-7 6, 1995.With permissionfromLtd.)MacmillanPublishers252alive today?For organismsthat are as closelyrelated as human and chimp, wesawthat this may not be difficult.
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