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These are simply points in thegenome sequence where one large fraction of the human population has onenucleotide, while another substantial fraction has another. TWo humangenomes sampled from the modern world population at random will differ atapproximately 2.5 x 106 such sites (l per 1300 nucleotide pairs). As will bedescribed in the overview of genetics in Chapter B, mapped sites in the humangenome that are polymorphic-meaningthat there is a reasonable probability(generally more than I%) that the genomes of two individuals will differ at thatsite-are extremely useful for genetic analyses,in which one attempts to associate specific traits (phenotypes) with specific DNA sequencesfor medical or scientific purposes (seep. 560).Against the background of ordinary SNPs inherited from our prehistoricancestors,certain sequenceswith exceptionally high mutation rates stand out.A dramatic example is provided by CA repeats, which are ubiquitous in thehuman genome and in the genomes of other eucaryotes.
Sequenceswith themotif (CA), are replicated with relatively Iow fidelity because of a slippage thatoccurs between the template and the newly synthesized strands during DNAreplication; hence, the precise value of n can vary over a considerable rangefrom one genome to the next. These repeats make ideal DNA-based geneticmarkers, since most humans are heterozygous-carrying two values of n at anyparticular CA repeat, having inherited one repeat length (n) from their motherand a different repeat length from their father.
rvVhilethe value of zl changes sufficiently rarely that most parent-child transmissions propagate CA repeatsfaithfully, the changes are sufficiently frequent to maintain high levels of heterozygosity in the human population. These and some other simple repeats that display exceptionally high variability therefore provide the basis for identifyingindividuals by DNA analysis in crime investigations, paternity suits, and otherforensic applications (seeFigure 8-47).lVhile most of the SNPs and copy number variations in the human genomesequence are thought to have no effect on phenotype, a subset ofthem must be10,000,000n u c l e o t i d ep a i r sh u m a nc h r o m o s o m e1 7DNA additionsin individualhumans12copiesprobe for 5' endof amylasegenep r o b ef o r 3 ' e n do f a m y l a s eg e n e9 copies5 copies+DNA lossFigure4-90 Detectionof copy numbervariantson human chromosome17.weretestedby aWhen 100individualsanalysisthat detectstheDNAmicroarraycopynumberof DNAsequencesthroughoutthe entirelengthof thisthe indicateddistributionschromosome,of DNAadditions(greenbars)and DNAlosses(redbars)were observedcomparedwith an arbitraryhuman referenceThe shortestred and greenbarssequence.amongthea singleoccurrencerepresentwhereasexamined,200chromosomesthe longerbarsindicatethat the additionmoreor losswascorrespondinglyfrequent.The resultsshow preferredoccur,andregionswherethe variationsthesetend to be in or nearregionsthatalreadycontainblocksof segmentalManyof the changesduplications.includeknown genes.(AdaptedfromJ.L.Freemanet al.,GenomeRes.16:949-961,2006.With permissionfromCold SpringHarborLaboratoryPress.)260Chapter4: DNA,Chromosomes,and Genomesresponsible for nearly all the heritable aspectsof human individuality.
we knowthat even a single nucleotide change that alters one amino acid in a protein cancause a serious disease,as for example in sickle cell anemia, which is caused bysuch a mutation in hemoglobin. <TTTT> We also know that gene dosage-adoubling or halving of the copy number of some genes-can have a profoundeffect on human development by altering the level of gene product. There istherefore every reason to suppose that some of the many differences betweenany two human beings will have substantial effects on human health, physiology, and behavior, whether they be SNPsor copy number variations. The majorchallenge in human genetics is to learn to recognize those relatively few variations that are functionally important against a large background of neutral variation in the genomes of different humans.Su m m a r yComparisonsof the nucleotidesequencesof present-daygenomeshaue reuolutionizedour understanding of gene and genome euolution.
Becauseof the extremely highrandom errors in maintainingftdelity of DNA replication and DNA repair processes,the nucleotidesequencesin genomesoccurso rarelythat only about one nucleotidein1000 is altered euerymillion years in any particular line of descent.Not surprisingly,therefore,a comparisonof human and chimpanzeechromosomes-which are separatedby about 6 million yearsof euolution-reuealsueryfew changes.Notonly are ourgenesessentiallythe same, but their order on each chromosome is almost identical.Although a substantial number of segmentalduplications and segmentaldeletionshaue occurred in the past 6 million years,euen the positions of the transposableelements that make up a major portion of our noncoding DNA are mostly unchanged.when one comparesthe genomesof two more distantly related organisms-suchas a human and a mouse,separatedby about B0 million years-one finds mqny morechanges.Now the effectsof natural selection can be clearly seen:through purifyingselection,essential nucleotide sequences-both in regulatory regions and in codingsequences(exon sequences)-haue been highly conserued.In contrast, nonessentialsequences(for example, much of the DNA in introns) haue been altered to such anextent thcttan accuratealignment according to ancestryisfrequently not Ttossible.Becauseof purifuingselection,the comparisonof the genomesequencesof multiplerelated speciesis an especiallypowerful way to ftnd DNA sequenceswith importantfunctions.
Although about 5% of the human genomehas beenconseruedas a result ofpurfuing selection,thefunction of the majority of this DNA (tensof thousandsof multispeciesconseruedsequences)remains mysterious.Future experimentscharacterizingtheir functions should teach us a great deal about uertebratebiology.other sequencecomparisonsshow that a great deal of the genetic complexity ofpresent-dayorganismsis due to the expansionof ancient genefamilies. DNAduplication followed by sequencediuergencehas clearly beena major sourceof geneticnoueltyduring euolution. The genomesof any two humans wilt dffir from each other bothbecauseof nucleotide substitutions (single nucleotide polymorphisms, or sNps)andbecauseof inherited DNA gains and DNA lossesthat cause copy number uariants.Understandingthesedffirences will improue both medicineand.our understanding ofhuman biology.PROBLEMSWhichstatementsare true?Explainwhy or why not.4-1Human females have 23 different chromosomes,whereashuman maleshave 24.4-2In a comparisonbetweenthe DNAs of relatedorganisms such as humans and mice, identifying the conservedDNA sequences facilitates the search for functionallyimportant regions.4-3The four core histones are relatively small proteinswith a very high proportion of positively charged aminoacids;the positive chargehelps the histonesbind tightly toDNA, regardlessof its nucleotidesequence.4*4Nucleosomesbind DNA so tightly that they cannotmove from the positionswhere they are first assembled.4-5Gene duplication and divergenceis thought to haveplayed a critical role in the evolution of increasedbiologicalcomplexity.END-OF-CHAPTERPROBLEMSFigureQ4-3 Pull-downassaysFigureQ4-l ThreenucleotidesfromthetIinteriorof a singlestrandof DNA(Problem4-7\.Anowsat theendsoftheDNAstrandindicatethatthestructureincontinuesbothdirections,u n m o d to determinebindingunmodK9-Me S'10-PT, ' ' T u ' , T, ? T , ;Pax5Pc1Discussthe following problems.4-6 DNA isolated from the bacterialvirus M13 contains25ToA,33ToT,22VoC,and 20ToG.
Do these results strike you aspeculiar?\Mhy or why not? How might youexplain thesevalues?4-7 A segmentof DNA from the interiorof a single strand is sho'ornin Figure Q4-1.\Mhat is the polarity of this DNA from topto bottom?1Suv39h-OoH P lc rP:OHP 1 pHP 1 1o-O -P:OHuman DNA contains 20% C on a4-8molar basis.'Whatare the mole percentsofA, G, andT?4-9 Chromosome 3 in orangutansdiffers from chromosome 3 in humans bytwo inversion events (Figure Q4-2). Drawthe intermediate chromosome thatresulted from the first inversion andexplicitly indicate the segmentsincludedin each inversion.oJFigureQ4-2 Chromosome3 inand humans(Problemorangutans4-9). Differentlycoloredblocksindicatesegmentsof thechromosomesthat were derivedbypreviousfusions.orangutanhuman4-10 Assuming that the 30-nm chromatin fiber containsabout 20 nucleosomes(200bp/nucleosome) per 50 nm oflength, calculatethe degreeof compaction of DNA associated with this level of chromatin structure.
\A4ratfraction ofthe 10,000-foldcondensation that occurs at mitosis doesthis level of DNA packing represent?4-11 In contrast to histone acetylation, which always correlateswith gene activation, histone methylation can lead toeither transcriptional activation or repression.How do yousuppose that the same modification-methylation-canmediate different biologicaloutcomes?4-12 \.A/hyis a chromosome with two centromeres (adicentric chromosome) unstable?Would a back-up centromere not be a good thing for a chromosome,giving it twochancesto form a kinetochore and attach to microtubulesduring mitosis?Wouldthat not help to ensurethat the chromosome did not get left behind at mitosis?4-13 HP1 proteins, a family of proteins found in heterochromatin,areimplicatedin genesilencingand chromatinstructure.The three proteins in humans-HPlcr, HP1B,andHPly-share a highly conservedchromodomain, which isthought to direct chromatin localization.
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