Часть 1 (1120999), страница 84
Текст из файла (страница 84)
A similarcluster of a-globin genes is located on a separate human chromosome.Because the cr- and B-globin gene clusters are on separate chromosomes inbirds and mammals but are together in the frog Xenopus, it is believed that achromosome translocation event separated the two gene clusters about 300million years ago (see Figure 4-87).There are several duplicated globin DNA sequencesin the cx-and B-globingene clusters that are not functional genesbut pseudogenes.These have a closesequencesimilarity to the functional genesbut have been disabled by mutationsthat prevent their expression.The existenceof such pseudogenesmakes it clearthat, as expected, not every DNA duplication leads to a new functional gene.Wealso know that nonfunctional DNA sequencesare not rapidly discarded, as indicated by the large excess of noncoding DNA that is found in mammaliangenomes.GenesEncodingNewProteinsCanBeCreatedby theRecombinationof ExonsThe role of DNA duplication in evolution is not confined to the expansion ofgene families.
It can also act on a smaller scale to create single genes by stringing together short duplicated segments of DNA. The proteins encoded by genesgenerated in this way can be recognized by the presence of repeating similarprotein domains, which are covalently linked to one another in series. Theimmunoglobulins (Figure 4-88) and albumins, for example, as well as mostfibrous proteins (such as collagens) are encoded by genes that have evolved byrepeated duplications of a primordial DNA sequence.In genesthat have evolved in this way, as well as in many other genes,eachseparateexon often encodes an individual protein folding unit, or domain. It isbelieved that the organization of DNA coding sequences as a series of suchexons separatedby long introns has greatly facilitated the evolution of new proteins. The duplications necessaryto form a single gene coding for a protein withrepeating domains, for example, can often occur by breaking and rejoining theDNA anl"where in the long introns on either side of an exon; without intronsthere would be only a few sites in the original gene at which a recombinationalexchangebetween DNA molecules could duplicate the domain.
By enabling theduplication to occur by recombination at many potential sites rather than just afew, introns increase the probability of a favorable duplication event.More generally,we know from genome sequencesthat the various parts ofgenes-both their individual exons and their regulatory elements-have servedas modular elements that have been duplicated and moved about the genometo createthe great diversity of living things. Thus, for example, many present-dayproteins are formed as a patchwork of domains from different origins, reflectingtheir long evolutionary history (seeFigure 3-19).NeutralMutationsOftenSpreadto BecomeFixedin a Population,Sizewith a Probabilitythat Dependson PopulationIn comparisons between two species that have diverged from one another bymillions of years, it makes little difference which individuals from each speciesare compared.
For example, typical human and chimpanzee DNA sequencesdiffer from one another by about 1%. In contrast, when the same region of thegenome is sampled from two different humans, the differences are typically lessthan 0.1%. For more distantly related organisms, the inter-species differencesovershadow intra-species variation even more dramatically. However, each"fixed difference" between the human and the chimpanzee (in other words, eachdifference that is now characteristic of all or nearly all individuals of eachspecies) started out as a new mutation in a single individual.
If the size of theh e a v yc h a i nHzNHzNNHz- NHzlightchainHOOC COOHFigure4-88 Schematicview of anantibody(immunoglobulin)molecule.Thismoleculeis a complexof twoidenticalheavychainsand two identicallightchains.Eachheavychaincontainsfour similar,covalentlylinkeddomains,whileeachlight chaincontainstwo suchdomains.Eachdomainis encodedby aseparateexon,and all of the exonsarethoughtto haveevolvedby the serialexon.duplicationof a singleancestral258Chapter4: DNA,Chromosomes,and Genomesinterbreeding population in which the mutation occurred is 14 the initial allelefrequency of a new mutation would be I I (2Il) for a diploid organism.
How doessuch a rare mutation become fixed in the population, and hence become a characteristic of the speciesrather than of a particular individual genome?The answer to this question depends on the functional consequencesof themutation. If the mutation has a significantly deleterious effect, it will simply beeliminated by purifying selection and will not become fixed. (In the mostextreme case, the individual carrying the mutation will die without producingprogeny.) Conversely, the rare mutations that confer a major reproductiveadvantage on individuals who inherit them can spread rapidly in the population.
Because humans reproduce sexually and genetic recombination occurseach time a gamete is formed (discussedin Chapter 5), the genome of each individual who has inherited the mutation will be a unique recombinational mosaicof segments inherited from a large number of ancestors.The selected mutationalong with a modest amount of neighboring sequence-ultimately inheritedfrom the individual in which the mutation occurred-will simply be one piece ofthis huge mosaic.The great majority of mutations that are not harmful are not beneficialeither. These selectivelyneutral mutations can also spread and become fixed ina population, and they make a large contribution to the evolutionary change ingenomes.Their spread is not as rapid as the spread of the rare strongly advantageous mutations. The process by which such neutral genetic variation is passeddown through an idealized interbreeding population can be described mathematically by equations that are surprisingly simple.
The idealized model that hasproven most useful for analyzing human genetic variation assumes a constantpopulation size and random mating, as well as selectiveneutrality for the mutations. \.A/hileneither of the first two assumptions is a good description of humanpopulation history they nonetheless provide a useful starting point for analyzing intra-speciesvariation.\Arhena new neutral mutation occurs in a constant population of size N thatis undergoing random mating, the probability that it will ultimately becomefixed is approximately l/(21v). For those mutations that do become fixed, theaveragetime to fixation is approximately 41y'generations.A detailed analysis ofdata on human genetic variation suggests an ancestral population size ofapproximately 10,000 during the period when the current pattern of geneticvariation was largely established.with a population that has reached this size,the probability that a new selectively neutral mutation would become fixed issmall (5 x I0-5), while the average time to fixation would be on the order of800,000years (assuming a 2O-yeargeneration time).
Thus, while we know thatthe human population has gror,rmenormously since the development of agriculture approximately 15,000years ago, most of the present-day set of commonhuman genetic variants reflects the mixture of variants that was already presentlong before this time, when the human population was still small enough toallow their widespread dissemination.A GreatDealCanBeLearnedfrom Analysesof the VariationAm o n gH u m an sEven though most of the variation among modern humans originates from variation present in a comparatively tiny group of ancestors,the number of variations encountered is very large.
one important source of variation, which wasmissed for many years, is the presence of many duplications and deletions oflarge blocks of DNA. According to one estimate, when any individual human iscompared with the standard reference genome in the database, one shouldexpect to find roughly I00 differences involving long sequence blocks. some ofthese "copy number variations" will be very common (Figure 4-gg), while others will be present in only a minority of humans (Figure 4-90). From an initialsampling, nearly half will contain knor,rmgenes. In retrospect this Rpe of variation is not surprising, given the extensivehistory of DNA addition and DNA lossin vertebrate genomes (for example, see Figure 4-79).259HOWGENOMESEVOLVEAboutFigure4-89Visualizationamonghumans.of a frequenttypeof variationgene(/eft),whichproduceshalfof thehumanstestedhadninecopiesof theamylasean importantenzymethatdigestsstarch.Inotherhumans,therehasbeeneitherfromtheresultingDNAlossor DNAadditionchromosome,to produceanaltered(loss)(addition)obtainthesedeletionortheduplicationof a partof thisregion.Tocoloredwith differentlyimages,stretchedchromatinfibershavebeenhybridizedprobesgene,asindicated.Theb/uelinesmarktheto thetwoendsof theamylasegeneralpathsofthechromatin.Theystainandby a secondhavebeendetermineddisplacedto onesidefor clarity.(AdaptedfromA.J.lafrateet al.,Nat.Genet.Ltd.)fromMacmillanPublishers36:949-951,2004.WithpermissionThe intra-species variations that have been most extensively characterizedare single-nucleotide polymorphisms (SNPs).
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
