B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 89
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As will bedescribed in the overview of genetics in Chapter 8, SNPs in the human genomeMBoC6 m4.90/4.77can be extremely useful for genetic mapping analyses, in which one attempts toassociate specific traits (phenotypes) with specific DNA sequences for medical orscientific purposes (see p. 493). But while useful as genetic markers, there is goodevidence that most of these SNPs have little or no effect on human fitness. Thisis as expected, since deleterious variants will have been selected against duringhuman evolution and, unlike SNPs, should therefore be rare.Against the background of ordinary SNPs inherited from our prehistoricancestors, certain sequences with exceptionally high mutation rates stand out.
Adramatic example is provided by CA repeats, which are ubiquitous in the humangenome and in the genomes of other eukaryotes. Sequences with the motif (CA)nare replicated with relatively low fidelity because of a slippage that occurs betweenthe template and the newly synthesized strands during DNA replication; hence,the precise value of n can vary over a considerable range from one genome to thenext. These repeats make ideal DNA-based genetic markers, since most humansare heterozygous, having inherited one repeat length (n) from their mother and adifferent repeat length from their father. While the value of n changes sufficientlyrarely that most parent–child transmissions propagate CA repeats faithfully, thechanges are sufficiently frequent to maintain high levels of heterozygosity in thehuman population. These and some other simple repeats that display exceptionally high variability therefore provide the basis for identifying individuals by DNAanalysis in crime investigations, paternity suits, and other forensic applications(see Figure 8–39).While most of the SNPs and CNVs in the human genome sequence are thoughtto have little or no effect on phenotype, a subset of the genome sequence variations must be responsible for the heritable aspects of human individuality.
Weknow that even a single nucleotide change that alters one amino acid in a proteincan cause a serious disease, as for example in sickle-cell anemia, which is causedby such a mutation in hemoglobin (Movie 4.3). We also know that gene dosage—adoubling or halving of the copy number of some genes—can have a profoundeffect on development by altering the level of gene product, as can changes inregulatory DNA sequences. There is therefore every reason to suppose that someof the many differences between any two human beings will have substantialFigure 4–80 Detection of copy numbervariations on human chromosome 17.When 100 individuals were tested by aDNA microarray analysis that detectsthe copy number of DNA sequencesthroughout the entire length of thischromosome, the indicated distributionsof DNA additions (green bars) and DNAlosses (red bars) were observed comparedwith an arbitrary human referencesequence.
The shortest red and green barsrepresent a single occurrence among the200 chromosomes examined, whereas thelonger bars indicate that the addition orloss was correspondingly more frequent.The results show preferred regions wherethe variations occur, and these tend tobe in or near regions that already containblocks of segmental duplications.
Manyof the changes include known genes.(Adapted from J.L. Freeman et al., GenomeRes. 16:949–961, 2006. With permissionfrom Cold Spring Harbor Laboratory Press.)234Chapter 4: DNA, Chromosomes, and Genomeseffects on human health, physiology, behavior, and physique. A major challengein human genetics is to recognize those relatively few variations that are functionally important against a large background of variation that is neutral and of noconsequence.SummaryComparisons of the nucleotide sequences of present-day genomes have revolutionized our understanding of gene and genome evolution. Because of the extremelyhigh fidelity of DNA replication and DNA repair processes, random errors in maintaining the nucleotide sequences in genomes occur so rarely that only about onenucleotide in a thousand is altered in every million years in any particular eukaryotic line of descent.
Not surprisingly, therefore, a comparison of human and chimpanzee chromosomes—which are separated by about 6 million years of evolution—reveals very few changes. Not only are our genes essentially the same, but their orderon each chromosome is almost identical. Although a substantial number of segmental duplications and segmental deletions have occurred in the past 6 millionyears, even the positions of the transposable elements that make up a major portionof our noncoding DNA are mostly unchanged.When one compares the genomes of two more distantly related organisms—suchas a human and a mouse, separated by about 80 million years—one finds manymore changes.
Now the effects of natural selection can be clearly seen: through purifying selection, essential nucleotide sequences—both in regulatory regions and incoding sequences (exons)—have been highly conserved. In contrast, nonessentialsequences (for example, much of the DNA in introns) have been altered to such anextent that one can no longer see any family resemblance.Because of purifying selection, the comparison of the genome sequences ofmultiple related species is an especially powerful way to find DNA sequences withimportant functions. Although about 5% of the human genome has been conservedas a result of purifying selection, the function of the majority of this DNA (tens ofthousands of multispecies conserved sequences) remains mysterious. Future experiments characterizing its functions should teach us many new lessons about vertebrate biology.Other sequence comparisons show that a great deal of the genetic complexity ofpresent-day organisms is due to the expansion of ancient gene families.
DNA duplication followed by sequence divergence has clearly been a major source of geneticnovelty during evolution. On a more recent time scale, the genomes of any twohumans will differ from each other both because of nucleotide substitutions (single-nucleotide polymorphisms, or SNPs) and because of inherited DNA gains andDNA losses that cause copy number variations (CNVs). Understanding the effectsof these differences will improve both medicine and our understanding of humanbiology.WHAT WE DON’T KNOW• How many different types ofchromatin structure are important forcells? How is each of these structuresestablished and maintained, andwhich ones tend to be inheritedfollowing DNA replication?• Why are there so many differentchromatin remodeling complexes incells? What are their essential roles,and how do they get loaded ontochromatin at specific places and atspecific times?• How do chromosomal loops formduring interphase, and what happensto these loops in condensed mitoticchromosomes?• What genetic changes madeus uniquely human? What furtheraspects of our recent evolutionarydevelopment can be reconstructedby sequencing DNA from remains ofancient hominids?• How much of the enormouscomplexity that we find in cell biologyis unnecessary, having evolved byrandom drift?PROBLEMSWhich statements are true? Explain why or why not.4–1Human females have 23 different chromosomes,whereas human males have 24.served DNA sequences facilitates the search for functionally important regions.4–2The four core histones are relatively small proteinswith a very high proportion of positively charged aminoacids; the positive charge helps the histones bind tightly toDNA, regardless of its nucleotide sequence.4–5Gene duplication and divergence is thought tohave played a critical role in the evolution of increased biological complexity.4–3Nucleosomes bind DNA so tightly that they cannotmove from the positions where they are first assembled.4–4In a comparison between the DNAs of relatedorganisms such as humans and mice, identifying the con-Discuss the following problems.4–6DNA isolated from the bacterial virus M13 contains 25% A, 33% T, 22% C, and 20% G.
Do these resultsstrike you as peculiar? Why or why not? How might youexplain these values?CHAPTER 4 END-OF-CHAPTER PROBLEMSFigure Q4–1 Three nucleotides from the interiorof a single strand of DNA (Problem 4–7). Arrowsat the ends of the DNA strand indicate that thestructure continues in both directions.235OAtelomereCH2 OtelomereAde2 gene at normal location4–7A segment of DNA from theinterior of a single strand is shown inFigure Q4–1. What is the polarity of thisDNA from top to bottom?4–8Human DNA contains 20% Con a molar basis.
What are the molepercents of A, G, and T?4–9Chromosome 3 in orangutansdiffers from chromosome 3 in humansby two inversion events that occurredin the human lineage (Figure Q4–2).Draw the intermediate chromosomethat resulted from the first inversionand explicitly indicate the segmentsincluded in each inversion.–O POOCCH2 OAde2 gene moved near telomerered colony ofyeast cellswith white sectorsO–O POOTCH2 OOFigure Q4–3 Position effect on expression of the yeast Ade2 gene(Problem 4–13). The Ade2 gene codes for one of the enzymes ofadenosine biosynthesis, and the absence of the Ade2 gene productleads to the accumulation of a red pigment. Therefore a colony of cellsthat express Ade2 is white, and one composed of cells in which theAde2 gene is not expressed is red.Problems p4.18/4.13gene is still located near telomeres.
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