B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 85
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Thisinformation can be used not only to unscramble the evolutionary pathways thathave led to modern organisms, but also to provide insights into how cells andorganisms function. Perhaps the most remarkable discovery in this realm comesfrom the observation that a striking amount of DNA sequence that does not codefor protein has been conserved during mammalian evolution (see Table 4–1,p. 184). This is most clearly revealed when we align and compare DNA syntenyFigure 4–71 Comparison of thegenomic sequences of the humanand Fugu genes encoding the proteinhuntingtin.
Both genes (indicated in red)contain 67 short exons that align in 1:1correspondence to one another; theseexons are connected by curved lines.The human gene is 7.5 times larger thanthe Fugu gene (180,000 versus 24,000nucleotide pairs). The size difference isentirely due to larger introns in the humangene.
The larger size of the humanintrons is due in part to the presence ofretrotransposons (discussed in Chapter5), whose positions are represented bygreen vertical lines; the Fugu introns lackretrotransposons. In humans, mutation ofthe huntingtin gene causes Huntington’sdisease, an inherited neurodegenerativedisorder. (Adapted from S.
Baxendale etal., Nat. Genet. 10:67–76, 1995. Withpermission from Macmillan Publishers Ltd.)Figure 4–72 The Neanderthals. (A) Mapof Europe showing the location of thecave in Croatia where most of the bonesused to isolate the DNA used to derivethe Neanderthal genome sequence werediscovered. (B) Photograph of the Vindijacave. (C) Photograph of the 38,000-yearold bones from Vindija. More recentstudies have succeeded in extractingDNA sequence information from hominidremains that are considerably older (seeMovie 8.3).
(B, courtesy of JohannesKrause; C, from R.E. Green et al., Science328: 710–722, 2010. Reprinted withpermission from AAAS.)cave inVindija, Croatia(A)(B)(C)5 cmHOW GENOMES EVOLVE225blocks from many different species, thereby identifying large numbers of so-calledmultispecies conserved sequences: some of these code for protein, but most ofthem do not (Figure 4–73).Most of the noncoding conserved sequences discovered in this way turn outto be relatively short, containing between 50 and 200 nucleotide pairs. Among themost mysterious are the so-called “ultraconserved” noncoding sequences, exemplified by more than 5000 DNA segments over 100 nucleotides long that are exactlythe same in human, mouse, and rat. Most have undergone little or no changesince mammalian and bird ancestors diverged about 300 million years ago.
Thestrict conservation implies that even though the sequences do not encode proteins, each nevertheless has an important function maintained by purifying selection. The puzzle is to unravel what those functions are.Many of the conserved sequences that do not code for protein are now knownto produce untranslated RNA molecules, such as the thousands of long noncodingRNAs (lncRNAs) that are thought to have important functions in regulating genetranscription. As we shall also see in Chapter 7, others are short regions of DNAscattered throughout the genome that directly bind proteins involved in gene regulation. But it is uncertain how much of the conserved noncoding DNA can beaccounted for in these ways, and the function of most of it remains a mystery.
Thisenigma highlights how much more we need to learn about the fundamental biological mechanisms that operate in animals and other complex organisms, and itssolution is certain to have profound consequences for medicine.How can cell biologists tackle the mystery of noncoding conserved DNA? Traditionally, attempts to determine the function of a puzzling DNA sequence beginby looking at the consequences of its experimental disruption. But many DNAsequences that are crucial for an organism in the wild can be expected to have nonoticeable effect on its phenotype under laboratory conditions: what is requiredfor a mouse to survive in a laboratory cage is very much less than what is requiredhuman CFTR gene (cystic fibrosis transmembrane conductance regulator)190,000 nucleotide pairs5′3′intronexonmultispecies conserved sequences100%50%chimpanzeeorangutanbaboonmarmosetlemurrabbitpercentidentityhorsecatdogmouseopossumchicken100%50%Fugu100 nucleotide pairs10,000 nucleotide pairsFigure 4–73 The detection ofmultispecies conserved sequences.In this example, genome sequencesfor each of the organisms shown havebeen compared with the indicated regionof the human CFTR (cystic fibrosistransmembrane conductance regulator)gene; this region contains one exon plusa large amount of intronic DNA.
For eachorganism, the percent identity with humanfor each 25-nucleotide block is plottedin green. In addition, a computationalalgorithm has been used to detect thesequences within this region that are mosthighly conserved when the sequences fromall of the organisms are taken into account.Besides the exon (dark blue on the line atthe top of the figure), the positions of threeother blocks of multispecies conservedsequences are indicated (pale blue).
Thefunction of most such sequences in thehuman genome is not known. (Courtesy ofEric D. Green.)226Chapter 4: DNA, Chromosomes, and Genomesfor it to succeed in nature. Moreover, calculations based on population geneticsreveal that just a tiny selective advantage—less than a 0.1% difference in survival—can be enough to strongly favor retaining a particular DNA sequence overevolutionary time spans.
One should therefore not be surprised to find that manyDNA sequences that are ultraconserved can be deleted from the mouse genomewithout any noticeable effect on that mouse in a laboratory.A second important approach for discovering the function of a mysteriousnoncoding DNA sequence uses biochemical techniques to identify proteins orRNA molecules that bind to it—and/or to any RNA molecules that it produces.Most of this task still lies before us, but a start has been made (see p. 435).Changes in Previously Conserved Sequences Can Help DecipherCritical Steps in EvolutionGiven genome sequence information, we can tackle another intriguing question:What alterations in our DNA have made humans so different from other animals—or for that matter, what makes any individual species so different from itsrelatives? For example, as soon as both the human and the chimpanzee genomesequences became available, scientists began searching for DNA sequencechanges that might account for the striking differences between us and chimpanzees.
With 3.2 billion nucleotide pairs to compare in the two species, thismight seem an impossible task. But the job was made much easier by confiningthe search to 35,000 clearly defined multispecies conserved sequences (a totalof about 5 million nucleotide pairs), representing parts of the genome that aremost likely to be functionally important. Though these sequences are conservedstrongly, they are not conserved perfectly, and when the version in one species iscompared with that in another they are generally found to have drifted apart bya small amount corresponding simply to the time elapsed since the last commonancestor.
In a small proportion of cases, however, one sees signs of a sudden evolutionary spurt. For example, some DNA sequences that have been highly conserved in other mammalian species are found to have accumulated nucleotidechanges exceptionally rapidly during the 6 million years of human evolution sincewe diverged from the chimpanzees. These human accelerated regions (HARs) arethought to reflect functions that have been especially important in making us different in some useful way.About 50 such sites were identified in one study, one-fourth of which werelocated near genes associated with neural development. The sequence exhibitingthe most rapid change (18 changes between human and chimpanzee, comparedto only two changes between chimpanzee and chicken) was examined furtherand found to encode a 118-nucleotide noncoding RNA molecule, HAR1F (humanaccelerated region 1F), that is produced in the human cerebral cortex at a criticaltime during brain development.
The function of this HAR1F RNA is not yet known,but findings of this type are stimulating research studies that may shed light oncrucial features of the human brain.A related approach in the search for the important mutations that contributedto human evolution likewise begins with DNA sequences that have been conserved during mammalian evolution, but rather than screening for acceleratedchanges in individual nucleotides, it focuses instead on chromosome sites thathave experienced deletions in the 6 million years since our lineage diverged fromthat of chimpanzees. More than 500 such sequences—conserved among otherspecies but deleted in humans—have been discovered.
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