B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 88
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However, each “fixed difference”between the human and the chimpanzee (in other words, each difference that isnow characteristic of all or nearly all individuals of each species) started out as anew mutation in a single individual. If the size of the interbreeding population inwhich the mutation occurred is N, the initial allele frequency for a new mutationwould be 1/(2N) for a diploid organism. How does such a rare mutation becomefixed in the population, and hence become a characteristic of the species ratherthan of a few scattered individuals?The answer to this question depends on the functional consequences of themutation. If the mutation has a significantly deleterious effect, it will simply beeliminated by purifying selection and will not become fixed. (In the most extremecase, the individual carrying the mutation will die without producing progeny.)Conversely, the rare mutations that confer a major reproductive advantage onindividuals who inherit them can spread rapidly in the population.
Becausehumans reproduce sexually and genetic recombination occurs each time a gamete is formed (discussed in Chapter 5), the genome of each individual who hasinherited the mutation will be a unique recombinational mosaic of segmentsinherited from a large number of ancestors. The selected mutation along with amodest amount of neighboring sequence—ultimately inherited from the individual in which the mutation occurred—will simply be one piece of this huge mosaic.The great majority of mutations that are not harmful are not beneficial either.These selectively neutral mutations can also spread and become fixed in a population, and they make a large contribution to evolutionary change in genomes.For example, as we saw earlier, they account for most of the DNA sequence differences between apes and humans.
The spread of neutral mutations is not asrapid as the spread of the rare strongly advantageous mutations. It depends ona random variation in the number of mutation-bearing progeny produced byeach mutation-bearing individual, causing changes in the relative frequency ofthe mutant allele in the population. Through a sort of “random walk” process, themutant allele may eventually become extinct, or it may become commonplace.This can be modeled mathematically for an idealized interbreeding population,on the assumption of constant population size and random mating, as well asselective neutrality for the mutations.
While neither of the first two assumptionsis a good description of human population history, study of this idealized casereveals the general principles in a clear and simple way.When a new neutral mutation occurs in a population of constant size N thatis undergoing random mating, the probability that it will ultimately become fixedis approximately 1/(2N).
This is because there are 2N copies of the gene in thediploid population, and each of them has an equal chance of becoming the predominant version in the long run. For those mutations that do become fixed, themathematics shows that the average time to fixation is approximately 4N generations. Detailed analyses of data on human genetic variation have suggested anancestral population size of approximately 10,000 at the time when the currentpattern of genetic variation was largely established. With a population that hasreached this size, the probability that a new, selectively neutral mutation wouldbecome fixed is small (1/20,000), while the average time to fixation would be onthe order of 800,000 years (assuming a 20-year generation time).
Thus, while weknow that the human population has grown enormously since the developmentof agriculture approximately 15,000 years ago, most of the present-day set of common human genetic variants reflects the mixture of variants that was already present long before this time, when the human population was still small.Similar arguments explain another phenomenon with important practicalimplications for genetic counseling. In an isolated community descended froma small group of founders, such as the people of Iceland or the Jews of Eastern231232Chapter 4: DNA, Chromosomes, and Genomesdisease survivorsor migrantsindividual withrare alleleoriginal populationfounder groupnew populationFigure 4–78 How founder effectsdetermine the set of genetic variants ina population of individuals belonging tothe same species.
This example illustrateshow a rare allele (red) can becomeestablished in an isolated population,even though the mutation that producedit has no selective advantage—or is mildlydeleterious.Europe, genetic variants that are rare in the human population as a whole canoften be present at a high frequency, even if those variants are mildly deleterious(Figure 4–78).MBoC6 n4.448/4.76.5A Great Deal Can Be Learned from Analyses of the VariationAmong HumansEven though the common variant gene alleles among modern humans originatefrom variants present in a comparatively tiny group of ancestors, the total numberof variants now encountered, including those that are individually rare, is verylarge. New neutral mutations are constantly occurring and accumulating, eventhough no single one of them has had enough time to become fixed in the vastmodern human population.From detailed comparisons of the DNA sequences of a large number of modern humans located around the globe, scientists can estimate how many generations have elapsed since the origin of a particular neutral mutation.
From suchdata, it has been possible to map the routes of ancient human migrations. Forexample, by combining this type of genetic analysis with archaeological findings,scientists have been able to deduce the most probable routes that our ancestorstook when they left Africa 60,000 to 80,000 years ago (Figure 4–79).We have been focusing on mutations that affect a single gene, but these are notthe only source of variation. Another source, perhaps even more important butmissed for many years, lies in the many duplications and deletions of large blocksof human DNA.
When one compares any individual human with the standardreference genome in the database, one will generally find roughly 100 differencesinvolving gain or loss of long sequence blocks, totaling perhaps 3 million nucleotide pairs. Some of these copy number variations (CNVs) will be very common,presumably reflecting relatively ancient origins, while others will be present inonly a small minority of people (Figure 4–80). On average, nearly half of the CNVscontain known genes. CNVs have been implicated in many human traits, including color blindness, infertility, hypertension, and a wide variety of disease susceptibilities.
In retrospect, this type of variation is not surprising, given the prominentrole of DNA addition and DNA loss in vertebrate evolution.The intraspecies variations that have been most extensively characterized,however, are single-nucleotide polymorphisms (SNPs).
These are simply pointsin the genome sequence where one large fraction of the human population hasone nucleotide, while another substantial fraction has another. To qualify asECB4 e19.37/19.41Figure 4–79 Tracing the course ofhuman history by analyses of genomesequences.
The map shows theroutes of the earliest successful humanmigrations. Dotted lines indicate twoalternative routes that our ancestors arethought to have taken out of Africa. DNAsequence comparisons suggest thatmodern Europeans descended from asmall ancestral population that existedabout 30,000 to 50,000 years ago.In agreement, archaeological findingssuggest that the ancestors of modernnative Australians (solid red arrows)—andof modern European and Middle Easternpopulations—reached their destinationsabout 45,000 years ago.
Even more recentstudies, comparing the genome sequencesof living humans with those of Neanderthalsand another extinct population fromsouthern Siberia (the Denisovans), suggestthat our exit from Africa was a bit moreconvoluted, while also revealing that anumber of our ancestors interbred withthese hominid neighbors as they madetheir way across the globe. (Modified fromP. Forster and S.
Matsumura, Science308:965–966, 2005.)HOW GENOMES EVOLVEhuman chromosome 1723310,000,000nucleotide pairsdensity ofknown genesDNA additionsin individualhumansDNA lossesin individualhumansa polymorphism, the variants must be common enough to give a reasonablyhigh probability that the genomes of two randomly chosen individuals will differ at the given site; a probability of 1% is commonly chosen as the cutoff. Twohuman genomes sampled from the modern world population at random will differ at approximately 2.5 × 106 such sites (1 per 1300 nucleotide pairs).
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