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Cell_Biology_Alberts_1010	Cell_Biology_Alberts	Figure 4–66 A phylogenetic tree showing the evolutionary relationships of some present-day mammals. The length of each line is proportional to the number of “neutral substitutions”—that is, nucleotide changes at sites where there is assumed to be no purifying selection. (Adapted from g.m. Cooper et al., Genome Res. 15:901–913, 2005. with permission from Cold Spring Harbor laboratory Press.) Good evidence for the loss of DNA sequences in small blocks during evolution can be obtained from a detailed comparison of regions of synteny in the human and mouse genomes. The comparative shrinkage of the mouse genome can be clearly seen from such comparisons, with the net loss of sequences scattered throughout the long stretches of DNA that are otherwise homologous (Figure 4–68).	Cell_Biology_Alberts. Figure 4–66 A phylogenetic tree showing the evolutionary relationships of some present-day mammals. The length of each line is proportional to the number of “neutral substitutions”—that is, nucleotide changes at sites where there is assumed to be no purifying selection. (Adapted from g.m. Cooper et al., Genome Res. 15:901–913, 2005. with permission from Cold Spring Harbor laboratory Press.) Good evidence for the loss of DNA sequences in small blocks during evolution can be obtained from a detailed comparison of regions of synteny in the human and mouse genomes. The comparative shrinkage of the mouse genome can be clearly seen from such comparisons, with the net loss of sequences scattered throughout the long stretches of DNA that are otherwise homologous (Figure 4–68).
Cell_Biology_Alberts_1011	Cell_Biology_Alberts	DNA is added to genomes both by the spontaneous duplication of chromosomal segments that are typically tens of thousands of nucleotide pairs long (as will be discussed shortly) and by insertion of new copies of active transposons. Most transposition events are duplicative, because the original copy of the transposon stays where it was when a copy inserts at the new site; see, for example, Figure 5–63. Comparison of the DNA sequences derived from transposons in the human and the mouse readily reveals some of the sequence additions (Figure 4–69). It remains a mystery why all mammals have maintained genome sizes of roughly 3 billion nucleotide pairs that contain nearly identical sets of genes, even though only approximately 150 million nucleotide pairs appear to be under sequence-specific functional constraints. The Size of a vertebrate genome Reflects the Relative Rates of DNA Addition and DNA loss in a lineage	Cell_Biology_Alberts. DNA is added to genomes both by the spontaneous duplication of chromosomal segments that are typically tens of thousands of nucleotide pairs long (as will be discussed shortly) and by insertion of new copies of active transposons. Most transposition events are duplicative, because the original copy of the transposon stays where it was when a copy inserts at the new site; see, for example, Figure 5–63. Comparison of the DNA sequences derived from transposons in the human and the mouse readily reveals some of the sequence additions (Figure 4–69). It remains a mystery why all mammals have maintained genome sizes of roughly 3 billion nucleotide pairs that contain nearly identical sets of genes, even though only approximately 150 million nucleotide pairs appear to be under sequence-specific functional constraints. The Size of a vertebrate genome Reflects the Relative Rates of DNA Addition and DNA loss in a lineage
Cell_Biology_Alberts_1012	Cell_Biology_Alberts	The Size of a vertebrate genome Reflects the Relative Rates of DNA Addition and DNA loss in a lineage In more distantly related vertebrates, genome size can vary considerably, apparently without a drastic effect on the organism or its number of genes. Thus, the chicken genome, at one billion nucleotide pairs, is only about one-third the size 200,000 bases Figure 4–67 Synteny between human and mouse chromosomes. In this diagram, the human chromosome set is shown above, with each part of each chromosome colored according to the mouse chromosome with which it is syntenic. The color coding used for each mouse chromosome is shown below. Heterochromatic highly repetitive regions (such as centromeres) that are difficult to sequence cannot be mapped in this way; these are colored black. (Adapted from E.E. Eichler and D. Sankoff, Science 301:793–797, 2003. with permission from AAAS.) Figure 4–68 Comparison of a syntenic portion of mouse and human genomes.	Cell_Biology_Alberts. The Size of a vertebrate genome Reflects the Relative Rates of DNA Addition and DNA loss in a lineage In more distantly related vertebrates, genome size can vary considerably, apparently without a drastic effect on the organism or its number of genes. Thus, the chicken genome, at one billion nucleotide pairs, is only about one-third the size 200,000 bases Figure 4–67 Synteny between human and mouse chromosomes. In this diagram, the human chromosome set is shown above, with each part of each chromosome colored according to the mouse chromosome with which it is syntenic. The color coding used for each mouse chromosome is shown below. Heterochromatic highly repetitive regions (such as centromeres) that are difficult to sequence cannot be mapped in this way; these are colored black. (Adapted from E.E. Eichler and D. Sankoff, Science 301:793–797, 2003. with permission from AAAS.) Figure 4–68 Comparison of a syntenic portion of mouse and human genomes.
Cell_Biology_Alberts_1013	Cell_Biology_Alberts	About 90% of the two genomes can be aligned in this way. Note that while there is an identical order of the matched index sequences (red marks), there has been a net loss of DNA in the mouse lineage that is interspersed throughout the entire region. This type of net loss is typical for all such regions, and it accounts for the fact that the mouse genome contains 14% less DNA than does the human genome. (Adapted from mouse genome Sequencing Consortium, Nature 420:520–562, 2002. with permission from macmillan Publishers ltd.) 10,000 nucleotide pairs of the mammalian genome. An extreme example is the puffer fish, Fugu rubripes (Figure 4–70), which has a tiny genome for a vertebrate (0.4 billion nucleotide pairs compared to 1 billion or more for many other fish). The small size of the Fugu genome is largely due to the small size of its introns. Specifically, Fugu introns, as well as other noncoding segments of the Fugu genome, lack the repetitive DNA that makes up a large portion of the	Cell_Biology_Alberts. About 90% of the two genomes can be aligned in this way. Note that while there is an identical order of the matched index sequences (red marks), there has been a net loss of DNA in the mouse lineage that is interspersed throughout the entire region. This type of net loss is typical for all such regions, and it accounts for the fact that the mouse genome contains 14% less DNA than does the human genome. (Adapted from mouse genome Sequencing Consortium, Nature 420:520–562, 2002. with permission from macmillan Publishers ltd.) 10,000 nucleotide pairs of the mammalian genome. An extreme example is the puffer fish, Fugu rubripes (Figure 4–70), which has a tiny genome for a vertebrate (0.4 billion nucleotide pairs compared to 1 billion or more for many other fish). The small size of the Fugu genome is largely due to the small size of its introns. Specifically, Fugu introns, as well as other noncoding segments of the Fugu genome, lack the repetitive DNA that makes up a large portion of the
Cell_Biology_Alberts_1014	Cell_Biology_Alberts	is largely due to the small size of its introns. Specifically, Fugu introns, as well as other noncoding segments of the Fugu genome, lack the repetitive DNA that makes up a large portion of the genomes of most well-studied vertebrates. Nevertheless, the positions of the Fugu introns between the exons of each gene are almost the same as in mammalian genomes (Figure 4–71).	Cell_Biology_Alberts. is largely due to the small size of its introns. Specifically, Fugu introns, as well as other noncoding segments of the Fugu genome, lack the repetitive DNA that makes up a large portion of the genomes of most well-studied vertebrates. Nevertheless, the positions of the Fugu introns between the exons of each gene are almost the same as in mammalian genomes (Figure 4–71).
Cell_Biology_Alberts_1015	Cell_Biology_Alberts	While initially a mystery, we now have a simple explanation for such large differences in genome size between similar organisms: because all vertebrates experience a continuous process of DNA loss and DNA addition, the size of a genome merely depends on the balance between these opposing processes acting over millions of years. Suppose, for example, that in the lineage leading to Fugu, the rate of DNA addition happened to slow greatly. Over long periods of time, this would result in a major “cleansing” from this fish genome of those DNA sequences whose loss could be tolerated. The result is an unusually compact genome, relatively free of junk and clutter, but retaining through purifying selection the vertebrate DNA sequences that are functionally important. This makes Fugu, with its 400 million nucleotide pairs of DNA, a valuable resource for genome research aimed at understanding humans. we Can Infer the Sequence of Some Ancient genomes	Cell_Biology_Alberts. While initially a mystery, we now have a simple explanation for such large differences in genome size between similar organisms: because all vertebrates experience a continuous process of DNA loss and DNA addition, the size of a genome merely depends on the balance between these opposing processes acting over millions of years. Suppose, for example, that in the lineage leading to Fugu, the rate of DNA addition happened to slow greatly. Over long periods of time, this would result in a major “cleansing” from this fish genome of those DNA sequences whose loss could be tolerated. The result is an unusually compact genome, relatively free of junk and clutter, but retaining through purifying selection the vertebrate DNA sequences that are functionally important. This makes Fugu, with its 400 million nucleotide pairs of DNA, a valuable resource for genome research aimed at understanding humans. we Can Infer the Sequence of Some Ancient genomes
Cell_Biology_Alberts_1016	Cell_Biology_Alberts	The genomes of ancestral organisms can be inferred, but most can never be directly observed. DNA is very stable compared with most organic molecules, but it is not perfectly stable, and its progressive degradation, even under the best circumstances, means that it is virtually impossible to extract sequence information from fossils that are more than a million years old. Although a modern organism such as the horseshoe crab looks remarkably similar to fossil ancestors that lived 200 million years ago, there is every reason to believe that the horse-shoe-crab genome has been changing during all that time in much the same way as in other evolutionary lineages, and at a similar rate. Selection must have maintained key functional properties of the horseshoe-crab genome to account for the morphological stability of the lineage. However, comparisons between different present-day organisms show that the fraction of the genome subject to purifying selection is small; hence, it is fair to	Cell_Biology_Alberts. The genomes of ancestral organisms can be inferred, but most can never be directly observed. DNA is very stable compared with most organic molecules, but it is not perfectly stable, and its progressive degradation, even under the best circumstances, means that it is virtually impossible to extract sequence information from fossils that are more than a million years old. Although a modern organism such as the horseshoe crab looks remarkably similar to fossil ancestors that lived 200 million years ago, there is every reason to believe that the horse-shoe-crab genome has been changing during all that time in much the same way as in other evolutionary lineages, and at a similar rate. Selection must have maintained key functional properties of the horseshoe-crab genome to account for the morphological stability of the lineage. However, comparisons between different present-day organisms show that the fraction of the genome subject to purifying selection is small; hence, it is fair to
Cell_Biology_Alberts_1017	Cell_Biology_Alberts	morphological stability of the lineage. However, comparisons between different present-day organisms show that the fraction of the genome subject to purifying selection is small; hence, it is fair to assume that the genome of the modern horseshoe crab, while preserving features critical for function, must differ greatly from that of its extinct ancestors, known to us only through the fossil record.	Cell_Biology_Alberts. morphological stability of the lineage. However, comparisons between different present-day organisms show that the fraction of the genome subject to purifying selection is small; hence, it is fair to assume that the genome of the modern horseshoe crab, while preserving features critical for function, must differ greatly from that of its extinct ancestors, known to us only through the fossil record.
Cell_Biology_Alberts_1018	Cell_Biology_Alberts	It is possible to get direct sequence information by examining DNA samples from ancient materials if these are not too old. In recent years, technical advances have allowed DNA sequencing from exceptionally well-preserved bone fragments that date from more than 100,000 years ago. Although any DNA this old will be imperfectly preserved, a sequence of the Neanderthal genome has been reconstructed from many millions of short DNA sequences, revealing—among other things—that our human ancestors interbred with Neanderthals in Europe and	Cell_Biology_Alberts. It is possible to get direct sequence information by examining DNA samples from ancient materials if these are not too old. In recent years, technical advances have allowed DNA sequencing from exceptionally well-preserved bone fragments that date from more than 100,000 years ago. Although any DNA this old will be imperfectly preserved, a sequence of the Neanderthal genome has been reconstructed from many millions of short DNA sequences, revealing—among other things—that our human ancestors interbred with Neanderthals in Europe and
Cell_Biology_Alberts_1019	Cell_Biology_Alberts	Figure 4–69 A comparison of the β-globin gene cluster in the human and mouse genomes, showing the locations of transposable elements. This stretch of the human genome contains five functional β-globin-like genes (orange); the comparable region from the mouse genome has only four. The positions of the human Alu sequences are indicated by green circles, and the human L1 sequences by red circles. The mouse genome contains different but related transposable elements: the positions of b1 elements (which are related to the human Alu sequences) are indicated by blue triangles, and the positions of the mouse L1 elements (which are related to the human L1 sequences) are indicated by orange triangles. The absence of transposable elements from the globin structural genes can be attributed to purifying selection, which would have eliminated any insertion that compromised gene function. (Courtesy of Ross Hardison and webb miller.)	Cell_Biology_Alberts. Figure 4–69 A comparison of the β-globin gene cluster in the human and mouse genomes, showing the locations of transposable elements. This stretch of the human genome contains five functional β-globin-like genes (orange); the comparable region from the mouse genome has only four. The positions of the human Alu sequences are indicated by green circles, and the human L1 sequences by red circles. The mouse genome contains different but related transposable elements: the positions of b1 elements (which are related to the human Alu sequences) are indicated by blue triangles, and the positions of the mouse L1 elements (which are related to the human L1 sequences) are indicated by orange triangles. The absence of transposable elements from the globin structural genes can be attributed to purifying selection, which would have eliminated any insertion that compromised gene function. (Courtesy of Ross Hardison and webb miller.)
Cell_Biology_Alberts_1020	Cell_Biology_Alberts	Figure 4–70 The puffer fish, Fugu rubripes. (Courtesy of byrappa venkatesh.) 0.0 100.0 180.0 thousands of nucleotide pairs that modern humans have inherited specific genes from them (Figure 4–72). The average difference in DNA sequence between humans and Neanderthals shows that our two lineages diverged somewhere between 270,000 and 440,000 years ago, well before the time that humans are believed to have migrated out of Africa.	Cell_Biology_Alberts. Figure 4–70 The puffer fish, Fugu rubripes. (Courtesy of byrappa venkatesh.) 0.0 100.0 180.0 thousands of nucleotide pairs that modern humans have inherited specific genes from them (Figure 4–72). The average difference in DNA sequence between humans and Neanderthals shows that our two lineages diverged somewhere between 270,000 and 440,000 years ago, well before the time that humans are believed to have migrated out of Africa.
Cell_Biology_Alberts_1021	Cell_Biology_Alberts	But what about deciphering the genomes of much older ancestors, those for which no useful DNA samples can be isolated? For organisms that are as closely related as human and chimpanzee, we saw that this may not be difficult: reference to the gorilla sequence can be used to sort out which of the few sequence differences between human and chimpanzee are inherited from our common ancestor some 6 million years ago (see Figure 4–64). And for an ancestor that has produced a large number of different organisms alive today, the DNA sequences of many species can be compared simultaneously to unscramble much of the ancestral sequence, allowing scientists to derive DNA sequences much farther back in time. For example, from the genome sequences currently being obtained for dozens of modern placental mammals, it should be possible to infer much of the genome sequence of their 100 million-year-old common ancestor—the precursor of species as diverse as dog, mouse, rabbit, armadillo, and human (see	Cell_Biology_Alberts. But what about deciphering the genomes of much older ancestors, those for which no useful DNA samples can be isolated? For organisms that are as closely related as human and chimpanzee, we saw that this may not be difficult: reference to the gorilla sequence can be used to sort out which of the few sequence differences between human and chimpanzee are inherited from our common ancestor some 6 million years ago (see Figure 4–64). And for an ancestor that has produced a large number of different organisms alive today, the DNA sequences of many species can be compared simultaneously to unscramble much of the ancestral sequence, allowing scientists to derive DNA sequences much farther back in time. For example, from the genome sequences currently being obtained for dozens of modern placental mammals, it should be possible to infer much of the genome sequence of their 100 million-year-old common ancestor—the precursor of species as diverse as dog, mouse, rabbit, armadillo, and human (see
Cell_Biology_Alberts_1022	Cell_Biology_Alberts	mammals, it should be possible to infer much of the genome sequence of their 100 million-year-old common ancestor—the precursor of species as diverse as dog, mouse, rabbit, armadillo, and human (see Figure 4–66).	Cell_Biology_Alberts. mammals, it should be possible to infer much of the genome sequence of their 100 million-year-old common ancestor—the precursor of species as diverse as dog, mouse, rabbit, armadillo, and human (see Figure 4–66).
Cell_Biology_Alberts_1023	Cell_Biology_Alberts	multispecies Sequence Comparisons Identify Conserved DNA Sequences of Unknown Function The mass of DNA sequence now in databases (hundreds of billions of nucleotide pairs) provides a rich resource that scientists can mine for many purposes. This information can be used not only to unscramble the evolutionary pathways that have led to modern organisms, but also to provide insights into how cells and organisms function. Perhaps the most remarkable discovery in this realm comes from the observation that a striking amount of DNA sequence that does not code for protein has been conserved during mammalian evolution (see Table 4–1, p. 184). This is most clearly revealed when we align and compare DNA synteny	Cell_Biology_Alberts. multispecies Sequence Comparisons Identify Conserved DNA Sequences of Unknown Function The mass of DNA sequence now in databases (hundreds of billions of nucleotide pairs) provides a rich resource that scientists can mine for many purposes. This information can be used not only to unscramble the evolutionary pathways that have led to modern organisms, but also to provide insights into how cells and organisms function. Perhaps the most remarkable discovery in this realm comes from the observation that a striking amount of DNA sequence that does not code for protein has been conserved during mammalian evolution (see Table 4–1, p. 184). This is most clearly revealed when we align and compare DNA synteny
Cell_Biology_Alberts_1024	Cell_Biology_Alberts	Figure 4–71 Comparison of the genomic sequences of the human and Fugu genes encoding the protein huntingtin. both genes (indicated in red) contain 67 short exons that align in 1:1 correspondence to one another; these exons are connected by curved lines. The human gene is 7.5 times larger than the Fugu gene (180,000 versus 24,000 nucleotide pairs). The size difference is entirely due to larger introns in the human gene. The larger size of the human introns is due in part to the presence of retrotransposons (discussed in Chapter 5), whose positions are represented by green vertical lines; the Fugu introns lack retrotransposons. In humans, mutation of the huntingtin gene causes Huntington’s disease, an inherited neurodegenerative disorder. (Adapted from S. baxendale et al., Nat. Genet. 10:67–76, 1995. with permission from macmillan Publishers ltd.)	Cell_Biology_Alberts. Figure 4–71 Comparison of the genomic sequences of the human and Fugu genes encoding the protein huntingtin. both genes (indicated in red) contain 67 short exons that align in 1:1 correspondence to one another; these exons are connected by curved lines. The human gene is 7.5 times larger than the Fugu gene (180,000 versus 24,000 nucleotide pairs). The size difference is entirely due to larger introns in the human gene. The larger size of the human introns is due in part to the presence of retrotransposons (discussed in Chapter 5), whose positions are represented by green vertical lines; the Fugu introns lack retrotransposons. In humans, mutation of the huntingtin gene causes Huntington’s disease, an inherited neurodegenerative disorder. (Adapted from S. baxendale et al., Nat. Genet. 10:67–76, 1995. with permission from macmillan Publishers ltd.)
Cell_Biology_Alberts_1025	Cell_Biology_Alberts	Figure 4–72 The Neanderthals. (A) map of Europe showing the location of the cave in Croatia where most of the bones used to isolate the DNA used to derive the Neanderthal genome sequence were discovered. (b) Photograph of the vindija cave. (C) Photograph of the 38,000-yearold bones from vindija. more recent studies have succeeded in extracting DNA sequence information from hominid remains that are considerably older (see movie 8.3). (b, courtesy of Johannes krause; C, from R.E. green et al., Science 328: 710–722, 2010. Reprinted with permission from AAAS.) cave in Vindija, Croatia blocks from many different species, thereby identifying large numbers of so-called multispecies conserved sequences: some of these code for protein, but most of them do not (Figure 4–73).	Cell_Biology_Alberts. Figure 4–72 The Neanderthals. (A) map of Europe showing the location of the cave in Croatia where most of the bones used to isolate the DNA used to derive the Neanderthal genome sequence were discovered. (b) Photograph of the vindija cave. (C) Photograph of the 38,000-yearold bones from vindija. more recent studies have succeeded in extracting DNA sequence information from hominid remains that are considerably older (see movie 8.3). (b, courtesy of Johannes krause; C, from R.E. green et al., Science 328: 710–722, 2010. Reprinted with permission from AAAS.) cave in Vindija, Croatia blocks from many different species, thereby identifying large numbers of so-called multispecies conserved sequences: some of these code for protein, but most of them do not (Figure 4–73).
Cell_Biology_Alberts_1026	Cell_Biology_Alberts	Most of the noncoding conserved sequences discovered in this way turn out to be relatively short, containing between 50 and 200 nucleotide pairs. Among the most mysterious are the so-called “ultraconserved” noncoding sequences, exemplified by more than 5000 DNA segments over 100 nucleotides long that are exactly the same in human, mouse, and rat. Most have undergone little or no change since mammalian and bird ancestors diverged about 300 million years ago. The strict 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.	Cell_Biology_Alberts. Most of the noncoding conserved sequences discovered in this way turn out to be relatively short, containing between 50 and 200 nucleotide pairs. Among the most mysterious are the so-called “ultraconserved” noncoding sequences, exemplified by more than 5000 DNA segments over 100 nucleotides long that are exactly the same in human, mouse, and rat. Most have undergone little or no change since mammalian and bird ancestors diverged about 300 million years ago. The strict 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.
Cell_Biology_Alberts_1027	Cell_Biology_Alberts	Many of the conserved sequences that do not code for protein are now known to produce untranslated RNA molecules, such as the thousands of long noncoding RNAs (lncRNAs) that are thought to have important functions in regulating gene transcription. As we shall also see in Chapter 7, others are short regions of DNA scattered throughout the genome that directly bind proteins involved in gene regulation. But it is uncertain how much of the conserved noncoding DNA can be accounted for in these ways, and the function of most of it remains a mystery. This enigma highlights how much more we need to learn about the fundamental biological mechanisms that operate in animals and other complex organisms, and its solution is certain to have profound consequences for medicine.	Cell_Biology_Alberts. Many of the conserved sequences that do not code for protein are now known to produce untranslated RNA molecules, such as the thousands of long noncoding RNAs (lncRNAs) that are thought to have important functions in regulating gene transcription. As we shall also see in Chapter 7, others are short regions of DNA scattered throughout the genome that directly bind proteins involved in gene regulation. But it is uncertain how much of the conserved noncoding DNA can be accounted for in these ways, and the function of most of it remains a mystery. This enigma highlights how much more we need to learn about the fundamental biological mechanisms that operate in animals and other complex organisms, and its solution is certain to have profound consequences for medicine.
Cell_Biology_Alberts_1028	Cell_Biology_Alberts	How can cell biologists tackle the mystery of noncoding conserved DNA? Traditionally, attempts to determine the function of a puzzling DNA sequence begin by looking at the consequences of its experimental disruption. But many DNA sequences that are crucial for an organism in the wild can be expected to have no noticeable effect on its phenotype under laboratory conditions: what is required for a mouse to survive in a laboratory cage is very much less than what is required 190,000 nucleotide pairs 100 nucleotide pairs 10,000 nucleotide pairs Figure 4–73 The detection of multispecies conserved sequences.	Cell_Biology_Alberts. How can cell biologists tackle the mystery of noncoding conserved DNA? Traditionally, attempts to determine the function of a puzzling DNA sequence begin by looking at the consequences of its experimental disruption. But many DNA sequences that are crucial for an organism in the wild can be expected to have no noticeable effect on its phenotype under laboratory conditions: what is required for a mouse to survive in a laboratory cage is very much less than what is required 190,000 nucleotide pairs 100 nucleotide pairs 10,000 nucleotide pairs Figure 4–73 The detection of multispecies conserved sequences.
Cell_Biology_Alberts_1029	Cell_Biology_Alberts	In this example, genome sequences for each of the organisms shown have been compared with the indicated region of the human CFTR (cystic fibrosis transmembrane conductance regulator) gene; this region contains one exon plus a large amount of intronic DNA. For each organism, the percent identity with human for each 25-nucleotide block is plotted in green. In addition, a computational algorithm has been used to detect the sequences within this region that are most highly conserved when the sequences from all of the organisms are taken into account. besides the exon (dark blue on the line at the top of the figure), the positions of three other blocks of multispecies conserved sequences are indicated (pale blue). The function of most such sequences in the human genome is not known. (Courtesy of Eric D. green.) for it to succeed in nature. Moreover, calculations based on population genetics reveal that just a tiny selective advantage—less than a 0.1% difference in survival—can be enough to	Cell_Biology_Alberts. In this example, genome sequences for each of the organisms shown have been compared with the indicated region of the human CFTR (cystic fibrosis transmembrane conductance regulator) gene; this region contains one exon plus a large amount of intronic DNA. For each organism, the percent identity with human for each 25-nucleotide block is plotted in green. In addition, a computational algorithm has been used to detect the sequences within this region that are most highly conserved when the sequences from all of the organisms are taken into account. besides the exon (dark blue on the line at the top of the figure), the positions of three other blocks of multispecies conserved sequences are indicated (pale blue). The function of most such sequences in the human genome is not known. (Courtesy of Eric D. green.) for it to succeed in nature. Moreover, calculations based on population genetics reveal that just a tiny selective advantage—less than a 0.1% difference in survival—can be enough to
Cell_Biology_Alberts_1030	Cell_Biology_Alberts	Eric D. green.) for it to succeed in nature. Moreover, calculations based on population genetics reveal 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 over evolutionary time spans. One should therefore not be surprised to find that many DNA sequences that are ultraconserved can be deleted from the mouse genome without any noticeable effect on that mouse in a laboratory.	Cell_Biology_Alberts. Eric D. green.) for it to succeed in nature. Moreover, calculations based on population genetics reveal 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 over evolutionary time spans. One should therefore not be surprised to find that many DNA sequences that are ultraconserved can be deleted from the mouse genome without any noticeable effect on that mouse in a laboratory.
Cell_Biology_Alberts_1031	Cell_Biology_Alberts	A second important approach for discovering the function of a mysterious noncoding DNA sequence uses biochemical techniques to identify proteins or RNA 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).	Cell_Biology_Alberts. A second important approach for discovering the function of a mysterious noncoding DNA sequence uses biochemical techniques to identify proteins or RNA 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).
Cell_Biology_Alberts_1032	Cell_Biology_Alberts	Given 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 its relatives? For example, as soon as both the human and the chimpanzee genome sequences became available, scientists began searching for DNA sequence changes that might account for the striking differences between us and chimpanzees. With 3.2 billion nucleotide pairs to compare in the two species, this might seem an impossible task. But the job was made much easier by confining the search to 35,000 clearly defined multispecies conserved sequences (a total of about 5 million nucleotide pairs), representing parts of the genome that are most likely to be functionally important. Though these sequences are conserved strongly, they are not conserved perfectly, and when the version in one species is compared with that in another they are generally found to have	Cell_Biology_Alberts. Given 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 its relatives? For example, as soon as both the human and the chimpanzee genome sequences became available, scientists began searching for DNA sequence changes that might account for the striking differences between us and chimpanzees. With 3.2 billion nucleotide pairs to compare in the two species, this might seem an impossible task. But the job was made much easier by confining the search to 35,000 clearly defined multispecies conserved sequences (a total of about 5 million nucleotide pairs), representing parts of the genome that are most likely to be functionally important. Though these sequences are conserved strongly, they are not conserved perfectly, and when the version in one species is compared with that in another they are generally found to have
Cell_Biology_Alberts_1033	Cell_Biology_Alberts	important. Though these sequences are conserved strongly, they are not conserved perfectly, and when the version in one species is compared with that in another they are generally found to have drifted apart by a small amount corresponding simply to the time elapsed since the last common ancestor. 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 nucleotide changes exceptionally rapidly during the 6 million years of human evolution since we diverged from the chimpanzees. These human accelerated regions (HARs) are thought to reflect functions that have been especially important in making us different in some useful way.	Cell_Biology_Alberts. important. Though these sequences are conserved strongly, they are not conserved perfectly, and when the version in one species is compared with that in another they are generally found to have drifted apart by a small amount corresponding simply to the time elapsed since the last common ancestor. 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 nucleotide changes exceptionally rapidly during the 6 million years of human evolution since we diverged from the chimpanzees. These human accelerated regions (HARs) are thought to reflect functions that have been especially important in making us different in some useful way.
Cell_Biology_Alberts_1034	Cell_Biology_Alberts	About 50 such sites were identified in one study, one-fourth of which were located near genes associated with neural development. The sequence exhibiting the most rapid change (18 changes between human and chimpanzee, compared to only two changes between chimpanzee and chicken) was examined further and found to encode a 118-nucleotide noncoding RNA molecule, HAR1F (human accelerated region 1F), that is produced in the human cerebral cortex at a critical time 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 on crucial features of the human brain.	Cell_Biology_Alberts. About 50 such sites were identified in one study, one-fourth of which were located near genes associated with neural development. The sequence exhibiting the most rapid change (18 changes between human and chimpanzee, compared to only two changes between chimpanzee and chicken) was examined further and found to encode a 118-nucleotide noncoding RNA molecule, HAR1F (human accelerated region 1F), that is produced in the human cerebral cortex at a critical time 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 on crucial features of the human brain.
Cell_Biology_Alberts_1035	Cell_Biology_Alberts	A related approach in the search for the important mutations that contributed to human evolution likewise begins with DNA sequences that have been conserved during mammalian evolution, but rather than screening for accelerated changes in individual nucleotides, it focuses instead on chromosome sites that have experienced deletions in the 6 million years since our lineage diverged from that of chimpanzees. More than 500 such sequences—conserved among other species but deleted in humans—have been discovered. Each deletion removes an average of 95 nucleotides of DNA sequence. Only one of these deletions affects a protein-coding region: the rest are thought to alter regions that affect how nearby genes are expressed, an expectation that has been experimentally confirmed in a few cases. A large proportion of the presumed regulatory regions identified in this way lie near genes that affect neural function and/or near genes involved in steroid signaling, suggesting that changes in the	Cell_Biology_Alberts. A related approach in the search for the important mutations that contributed to human evolution likewise begins with DNA sequences that have been conserved during mammalian evolution, but rather than screening for accelerated changes in individual nucleotides, it focuses instead on chromosome sites that have experienced deletions in the 6 million years since our lineage diverged from that of chimpanzees. More than 500 such sequences—conserved among other species but deleted in humans—have been discovered. Each deletion removes an average of 95 nucleotides of DNA sequence. Only one of these deletions affects a protein-coding region: the rest are thought to alter regions that affect how nearby genes are expressed, an expectation that has been experimentally confirmed in a few cases. A large proportion of the presumed regulatory regions identified in this way lie near genes that affect neural function and/or near genes involved in steroid signaling, suggesting that changes in the
Cell_Biology_Alberts_1036	Cell_Biology_Alberts	A large proportion of the presumed regulatory regions identified in this way lie near genes that affect neural function and/or near genes involved in steroid signaling, suggesting that changes in the nervous system and in immune or reproductive functions have played an especially important role in human evolution.	Cell_Biology_Alberts. A large proportion of the presumed regulatory regions identified in this way lie near genes that affect neural function and/or near genes involved in steroid signaling, suggesting that changes in the nervous system and in immune or reproductive functions have played an especially important role in human evolution.
Cell_Biology_Alberts_1037	Cell_Biology_Alberts	mutations in the DNA Sequences That Control gene Expression Have Driven many of the Evolutionary Changes in vertebrates	Cell_Biology_Alberts. mutations in the DNA Sequences That Control gene Expression Have Driven many of the Evolutionary Changes in vertebrates
Cell_Biology_Alberts_1038	Cell_Biology_Alberts	The vast hoard of genomic sequence data now being accumulated can be explored in many other ways to reveal events that happened even hundreds of millions of years ago. For example, one can attempt to trace the origins of the regulatory elements in DNA that have played critical parts in vertebrate evolution. One such study began with the identification of nearly 3 million noncoding sequences, averaging 28 base pairs in length, that have been conserved in recent vertebrate evolution while being absent in more ancient ancestors. Each of these special non-coding sequences is likely to represent a functional innovation peculiar to a particular branch of the vertebrate family tree, and most of them are thought to consist of regulatory DNA that governs the expression of a neighboring gene. Given full genome sequences, one can identify the genes that lie closest and thus appear most likely to have fallen under the sway of these novel regulatory elements. By comparing many different species,	Cell_Biology_Alberts. The vast hoard of genomic sequence data now being accumulated can be explored in many other ways to reveal events that happened even hundreds of millions of years ago. For example, one can attempt to trace the origins of the regulatory elements in DNA that have played critical parts in vertebrate evolution. One such study began with the identification of nearly 3 million noncoding sequences, averaging 28 base pairs in length, that have been conserved in recent vertebrate evolution while being absent in more ancient ancestors. Each of these special non-coding sequences is likely to represent a functional innovation peculiar to a particular branch of the vertebrate family tree, and most of them are thought to consist of regulatory DNA that governs the expression of a neighboring gene. Given full genome sequences, one can identify the genes that lie closest and thus appear most likely to have fallen under the sway of these novel regulatory elements. By comparing many different species,
Cell_Biology_Alberts_1039	Cell_Biology_Alberts	full genome sequences, one can identify the genes that lie closest and thus appear most likely to have fallen under the sway of these novel regulatory elements. By comparing many different species, with known divergence times, one can also estimate when each such regulatory element came into existence as a conserved feature. The findings suggest remarkable evolutionary differences between the various functional classes of genes (Figure 4–74). Conserved regulatory elements that originated early in vertebrate evolution—that is, more than about 300 million years ago, which is when the mammalian lineage split from the lineage leading to birds and reptiles—seem to be mostly associated with genes that code for transcription regulator proteins and for proteins with roles in organizing embryonic development. Then came an era when the regulatory DNA innovations arose next to genes coding for receptors for extracellular signals. Finally, over the course of the past 100 million years, the	Cell_Biology_Alberts. full genome sequences, one can identify the genes that lie closest and thus appear most likely to have fallen under the sway of these novel regulatory elements. By comparing many different species, with known divergence times, one can also estimate when each such regulatory element came into existence as a conserved feature. The findings suggest remarkable evolutionary differences between the various functional classes of genes (Figure 4–74). Conserved regulatory elements that originated early in vertebrate evolution—that is, more than about 300 million years ago, which is when the mammalian lineage split from the lineage leading to birds and reptiles—seem to be mostly associated with genes that code for transcription regulator proteins and for proteins with roles in organizing embryonic development. Then came an era when the regulatory DNA innovations arose next to genes coding for receptors for extracellular signals. Finally, over the course of the past 100 million years, the
Cell_Biology_Alberts_1040	Cell_Biology_Alberts	development. Then came an era when the regulatory DNA innovations arose next to genes coding for receptors for extracellular signals. Finally, over the course of the past 100 million years, the regulatory innovations seem to have been concentrated in the neighborhood of genes coding for proteins (such as protein kinases) that function to modify other proteins post-translationally.	Cell_Biology_Alberts. development. Then came an era when the regulatory DNA innovations arose next to genes coding for receptors for extracellular signals. Finally, over the course of the past 100 million years, the regulatory innovations seem to have been concentrated in the neighborhood of genes coding for proteins (such as protein kinases) that function to modify other proteins post-translationally.
Cell_Biology_Alberts_1041	Cell_Biology_Alberts	Many questions remain to be answered about these phenomena and what they mean. One possible interpretation is that the logic—the circuit diagram—of the gene regulatory network in vertebrates was established early, and that more recent evolutionary change has mainly occurred through the tuning of quantitative parameters. This could help to explain why, among the mammals, for example, the basic body plan—the topology of the tissues and organs—has been largely conserved. gene Duplication Also Provides an Important Source of genetic Novelty During Evolution Evolution depends on the creation of new genes, as well as on the modification of those that already exist. How does this occur? When we compare organisms that seem very different—a primate with a rodent, for example, or a mouse with a fish—we rarely encounter genes in the one species that have no homolog in the reception of extracellular signals HUMAN 500 400 300 200 100 0 millions of years before present	Cell_Biology_Alberts. Many questions remain to be answered about these phenomena and what they mean. One possible interpretation is that the logic—the circuit diagram—of the gene regulatory network in vertebrates was established early, and that more recent evolutionary change has mainly occurred through the tuning of quantitative parameters. This could help to explain why, among the mammals, for example, the basic body plan—the topology of the tissues and organs—has been largely conserved. gene Duplication Also Provides an Important Source of genetic Novelty During Evolution Evolution depends on the creation of new genes, as well as on the modification of those that already exist. How does this occur? When we compare organisms that seem very different—a primate with a rodent, for example, or a mouse with a fish—we rarely encounter genes in the one species that have no homolog in the reception of extracellular signals HUMAN 500 400 300 200 100 0 millions of years before present
Cell_Biology_Alberts_1042	Cell_Biology_Alberts	Figure 4–74 The types of changes in gene regulation inferred to have predominated during the evolution of our vertebrate ancestors. To produce the information summarized in this plot, wherever possible the type of gene regulated by each conserved noncoding sequence was inferred from the identity of its closest protein-coding gene. The fixation time for each conserved sequence was then used to derive the conclusions shown. (based on C.b. lowe et al., Science 333:1019–1024, 2011. with permission from AAAS.) other. Genes without homologous counterparts are relatively scarce even when we compare such divergent organisms as a mammal and a worm. On the other hand, we frequently find gene families that have different numbers of members in different species. To create such families, genes have been repeatedly duplicated, and the copies have then diverged to take on new functions that often vary from one species to another.	Cell_Biology_Alberts. Figure 4–74 The types of changes in gene regulation inferred to have predominated during the evolution of our vertebrate ancestors. To produce the information summarized in this plot, wherever possible the type of gene regulated by each conserved noncoding sequence was inferred from the identity of its closest protein-coding gene. The fixation time for each conserved sequence was then used to derive the conclusions shown. (based on C.b. lowe et al., Science 333:1019–1024, 2011. with permission from AAAS.) other. Genes without homologous counterparts are relatively scarce even when we compare such divergent organisms as a mammal and a worm. On the other hand, we frequently find gene families that have different numbers of members in different species. To create such families, genes have been repeatedly duplicated, and the copies have then diverged to take on new functions that often vary from one species to another.
Cell_Biology_Alberts_1043	Cell_Biology_Alberts	Gene duplication occurs at high rates in all evolutionary lineages, contributing to the vigorous process of DNA addition discussed previously. In a detailed study of spontaneous duplications in yeast, duplications of 50,000 to 250,000 nucleotide pairs were commonly observed, most of which were tandemly repeated. These appeared to result from DNA replication errors that led to the inexact repair of double-strand chromosome breaks. A comparison of the human and chimpanzee genomes reveals that, since the time that these two organisms diverged, such segmental duplications have added about 5 million nucleotide pairs to each genome every million years, with an average duplication size being about 50,000 nucleotide pairs (although there are some duplications five times larger). In fact, if one counts nucleotides, duplication events have created more differences between our two species than have single-nucleotide substitutions.	Cell_Biology_Alberts. Gene duplication occurs at high rates in all evolutionary lineages, contributing to the vigorous process of DNA addition discussed previously. In a detailed study of spontaneous duplications in yeast, duplications of 50,000 to 250,000 nucleotide pairs were commonly observed, most of which were tandemly repeated. These appeared to result from DNA replication errors that led to the inexact repair of double-strand chromosome breaks. A comparison of the human and chimpanzee genomes reveals that, since the time that these two organisms diverged, such segmental duplications have added about 5 million nucleotide pairs to each genome every million years, with an average duplication size being about 50,000 nucleotide pairs (although there are some duplications five times larger). In fact, if one counts nucleotides, duplication events have created more differences between our two species than have single-nucleotide substitutions.
Cell_Biology_Alberts_1044	Cell_Biology_Alberts	What is the fate of newly duplicated genes? In most cases, there is presumed to be little or no selection—at least initially—to maintain the duplicated state since either copy can provide an equivalent function. Hence, many duplication events are likely to be followed by loss-of-function mutations in one or the other gene. This cycle would functionally restore the one-gene state that preceded the duplication. Indeed, there are many examples in contemporary genomes where one copy of a duplicated gene can be seen to have become irreversibly inactivated by multiple mutations. Over time, the sequence similarity between such a pseudogene and the functional gene whose duplication produced it would be expected to be eroded by the accumulation of many mutations in the pseudogene—the homologous relationship eventually becoming undetectable.	Cell_Biology_Alberts. What is the fate of newly duplicated genes? In most cases, there is presumed to be little or no selection—at least initially—to maintain the duplicated state since either copy can provide an equivalent function. Hence, many duplication events are likely to be followed by loss-of-function mutations in one or the other gene. This cycle would functionally restore the one-gene state that preceded the duplication. Indeed, there are many examples in contemporary genomes where one copy of a duplicated gene can be seen to have become irreversibly inactivated by multiple mutations. Over time, the sequence similarity between such a pseudogene and the functional gene whose duplication produced it would be expected to be eroded by the accumulation of many mutations in the pseudogene—the homologous relationship eventually becoming undetectable.
Cell_Biology_Alberts_1045	Cell_Biology_Alberts	An alternative fate for gene duplications is for both copies to remain functional, while diverging in their sequence and pattern of expression, thus taking on different roles. This process of “duplication and divergence” almost certainly explains the presence of large families of genes with related functions in biologically complex organisms, and it is thought to play a critical role in the evolution of increased biological complexity. An examination of many different eukaryotic genomes suggests that the probability that any particular gene will undergo a duplication event that spreads to most or all individuals in a species is approximately 1 percent every million years.	Cell_Biology_Alberts. An alternative fate for gene duplications is for both copies to remain functional, while diverging in their sequence and pattern of expression, thus taking on different roles. This process of “duplication and divergence” almost certainly explains the presence of large families of genes with related functions in biologically complex organisms, and it is thought to play a critical role in the evolution of increased biological complexity. An examination of many different eukaryotic genomes suggests that the probability that any particular gene will undergo a duplication event that spreads to most or all individuals in a species is approximately 1 percent every million years.
Cell_Biology_Alberts_1046	Cell_Biology_Alberts	Whole-genome duplications offer particularly dramatic examples of the duplication–divergence cycle. A whole-genome duplication can occur quite simply: all that is required is one round of genome replication in a germ-line cell lineage without a corresponding cell division. Initially, the chromosome number simply doubles. Such abrupt increases in the ploidy of an organism are common, particularly in fungi and plants. After a whole-genome duplication, all genes exist as duplicate copies. However, unless the duplication event occurred so recently that there has been little time for subsequent alterations in genome structure, the results of a series of segmental duplications—occurring at different times— are hard to distinguish from the end product of a whole-genome duplication. In mammals, for example, the role of whole-genome duplications versus a series of piecemeal duplications of DNA segments is quite uncertain. Nevertheless, it is clear that a great deal of gene duplication has	Cell_Biology_Alberts. Whole-genome duplications offer particularly dramatic examples of the duplication–divergence cycle. A whole-genome duplication can occur quite simply: all that is required is one round of genome replication in a germ-line cell lineage without a corresponding cell division. Initially, the chromosome number simply doubles. Such abrupt increases in the ploidy of an organism are common, particularly in fungi and plants. After a whole-genome duplication, all genes exist as duplicate copies. However, unless the duplication event occurred so recently that there has been little time for subsequent alterations in genome structure, the results of a series of segmental duplications—occurring at different times— are hard to distinguish from the end product of a whole-genome duplication. In mammals, for example, the role of whole-genome duplications versus a series of piecemeal duplications of DNA segments is quite uncertain. Nevertheless, it is clear that a great deal of gene duplication has
Cell_Biology_Alberts_1047	Cell_Biology_Alberts	for example, the role of whole-genome duplications versus a series of piecemeal duplications of DNA segments is quite uncertain. Nevertheless, it is clear that a great deal of gene duplication has occurred in the distant past.	Cell_Biology_Alberts. for example, the role of whole-genome duplications versus a series of piecemeal duplications of DNA segments is quite uncertain. Nevertheless, it is clear that a great deal of gene duplication has occurred in the distant past.
Cell_Biology_Alberts_1048	Cell_Biology_Alberts	Analysis of the genome of the zebrafish, in which at least one whole-genome duplication is thought to have occurred hundreds of millions of years ago, has cast some light on the process of gene duplication and divergence. Although many duplicates of zebrafish genes appear to have been lost by mutation, a significant fraction—perhaps as many as 30–50%—have diverged functionally while both Figure 4–75 A comparison of the structure of one-chain and four-chain globins. The four-chain globin shown is hemoglobin, which is a complex of two α-globin and two β-globin chains. The one-chain globin present in some primitive vertebrates represents an intermediate in the evolution of the four-chain globin. with oxygen bound it exists as a monomer; without oxygen it dimerizes.	Cell_Biology_Alberts. Analysis of the genome of the zebrafish, in which at least one whole-genome duplication is thought to have occurred hundreds of millions of years ago, has cast some light on the process of gene duplication and divergence. Although many duplicates of zebrafish genes appear to have been lost by mutation, a significant fraction—perhaps as many as 30–50%—have diverged functionally while both Figure 4–75 A comparison of the structure of one-chain and four-chain globins. The four-chain globin shown is hemoglobin, which is a complex of two α-globin and two β-globin chains. The one-chain globin present in some primitive vertebrates represents an intermediate in the evolution of the four-chain globin. with oxygen bound it exists as a monomer; without oxygen it dimerizes.
Cell_Biology_Alberts_1049	Cell_Biology_Alberts	copies have remained active. In many cases, the most obvious functional difference between the duplicated genes is that they are expressed in different tissues or at different stages of development. One attractive theory to explain such an end result imagines that different, mildly deleterious mutations occur quickly in both copies of a duplicated gene set. For example, one copy might lose expression in a particular tissue as a result of a regulatory mutation, while the other copy loses expression in a second tissue. Following such an occurrence, both gene copies would be required to provide the full range of functions that were once supplied by a single gene; hence, both copies would now be protected from loss through inactivating mutations. Over a longer period, each copy could then undergo further changes through which it could acquire new, specialized features. The Evolution of the globin gene Family Shows How DNA Duplications Contribute to the Evolution of Organisms	Cell_Biology_Alberts. copies have remained active. In many cases, the most obvious functional difference between the duplicated genes is that they are expressed in different tissues or at different stages of development. One attractive theory to explain such an end result imagines that different, mildly deleterious mutations occur quickly in both copies of a duplicated gene set. For example, one copy might lose expression in a particular tissue as a result of a regulatory mutation, while the other copy loses expression in a second tissue. Following such an occurrence, both gene copies would be required to provide the full range of functions that were once supplied by a single gene; hence, both copies would now be protected from loss through inactivating mutations. Over a longer period, each copy could then undergo further changes through which it could acquire new, specialized features. The Evolution of the globin gene Family Shows How DNA Duplications Contribute to the Evolution of Organisms