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Cell_Biology_Alberts_810	Cell_Biology_Alberts	As might be expected, some correlation exists between the complexity of an organism and the number of genes in its genome (see Table 1–2, p. 29). For example, some simple bacteria have only 500 genes, compared to about 30,000 for humans. Bacteria, archaea, and some single-celled eukaryotes, such as yeast, have concise genomes, consisting of little more than strings of closely packed genes. However, the genomes of multicellular plants and animals, as well as many other eukaryotes, contain, in addition to genes, a large quantity of interspersed DNA whose function is poorly understood (Figure 4–13). Some of this additional DNA is crucial for the proper control of gene expression, and this may in part explain why there is so much of it in multicellular organisms, whose genes have to be switched on and off according to complicated rules during development (discussed in Chapters 7 and 21).	Cell_Biology_Alberts. As might be expected, some correlation exists between the complexity of an organism and the number of genes in its genome (see Table 1–2, p. 29). For example, some simple bacteria have only 500 genes, compared to about 30,000 for humans. Bacteria, archaea, and some single-celled eukaryotes, such as yeast, have concise genomes, consisting of little more than strings of closely packed genes. However, the genomes of multicellular plants and animals, as well as many other eukaryotes, contain, in addition to genes, a large quantity of interspersed DNA whose function is poorly understood (Figure 4–13). Some of this additional DNA is crucial for the proper control of gene expression, and this may in part explain why there is so much of it in multicellular organisms, whose genes have to be switched on and off according to complicated rules during development (discussed in Chapters 7 and 21).
Cell_Biology_Alberts_811	Cell_Biology_Alberts	Differences in the amount of DNA interspersed between genes, far more than differences in numbers of genes, account for the astonishing variations in genome size that we see when we compare one species with another (see Figure 1–32). For example, the human genome is 200 times larger than that of the yeast Saccharomyces cerevisiae, but 30 times smaller than that of some plants and amphibians and 200 times smaller than that of a species of amoeba. Moreover, because of differences in the amount of noncoding DNA, the genomes of closely related organisms (bony fish, for example) can vary several hundredfold in their DNA content, even though they contain roughly the same number of genes. Whatever the excess	Cell_Biology_Alberts. Differences in the amount of DNA interspersed between genes, far more than differences in numbers of genes, account for the astonishing variations in genome size that we see when we compare one species with another (see Figure 1–32). For example, the human genome is 200 times larger than that of the yeast Saccharomyces cerevisiae, but 30 times smaller than that of some plants and amphibians and 200 times smaller than that of a species of amoeba. Moreover, because of differences in the amount of noncoding DNA, the genomes of closely related organisms (bony fish, for example) can vary several hundredfold in their DNA content, even though they contain roughly the same number of genes. Whatever the excess
Cell_Biology_Alberts_812	Cell_Biology_Alberts	Figure 4–13 The arrangement of genes in the genome of S. cerevisiae compared to humans. (A) S. cerevisiae is a budding yeast widely used for brewing and baking. The genome of this single-celled eukaryote is distributed over 16 chromosomes. A small region of one chromosome has been arbitrarily selected to show its high density of genes. (b) A region of the human genome of equal length to the yeast segment in (A). The human genes are much less densely packed and the amount of interspersed DNA sequence is far greater. Not shown in this sample of human DNA is the fact that most human genes are much longer than yeast genes (see Figure 4–15). DNA may do, it seems clear that it is not a great handicap for a eukaryotic cell to carry a large amount of it.	Cell_Biology_Alberts. Figure 4–13 The arrangement of genes in the genome of S. cerevisiae compared to humans. (A) S. cerevisiae is a budding yeast widely used for brewing and baking. The genome of this single-celled eukaryote is distributed over 16 chromosomes. A small region of one chromosome has been arbitrarily selected to show its high density of genes. (b) A region of the human genome of equal length to the yeast segment in (A). The human genes are much less densely packed and the amount of interspersed DNA sequence is far greater. Not shown in this sample of human DNA is the fact that most human genes are much longer than yeast genes (see Figure 4–15). DNA may do, it seems clear that it is not a great handicap for a eukaryotic cell to carry a large amount of it.
Cell_Biology_Alberts_813	Cell_Biology_Alberts	DNA may do, it seems clear that it is not a great handicap for a eukaryotic cell to carry a large amount of it. How the genome is divided into chromosomes also differs from one eukaryotic species to the next. For example, while the cells of humans have 46 chromosomes, those of some small deer have only 6, while those of the common carp contain over 100. Even closely related species with similar genome sizes can have very different numbers and sizes of chromosomes (Figure 4–14). Thus, there is no simple relationship between chromosome number, complexity of the organism, and total genome size. Rather, the genomes and chromosomes of modern-day species have each been shaped by a unique history of seemingly random genetic events, acted on by poorly understood selection pressures over long evolutionary times. The Nucleotide Sequence of the Human genome Shows How Our genes Are Arranged	Cell_Biology_Alberts. DNA may do, it seems clear that it is not a great handicap for a eukaryotic cell to carry a large amount of it. How the genome is divided into chromosomes also differs from one eukaryotic species to the next. For example, while the cells of humans have 46 chromosomes, those of some small deer have only 6, while those of the common carp contain over 100. Even closely related species with similar genome sizes can have very different numbers and sizes of chromosomes (Figure 4–14). Thus, there is no simple relationship between chromosome number, complexity of the organism, and total genome size. Rather, the genomes and chromosomes of modern-day species have each been shaped by a unique history of seemingly random genetic events, acted on by poorly understood selection pressures over long evolutionary times. The Nucleotide Sequence of the Human genome Shows How Our genes Are Arranged
Cell_Biology_Alberts_814	Cell_Biology_Alberts	The Nucleotide Sequence of the Human genome Shows How Our genes Are Arranged With the publication of the full DNA sequence of the human genome in 2004, it became possible to see in detail how the genes are arranged along each of our chromosomes (Figure 4–15). It will be many decades before the information contained in the human genome sequence is fully analyzed, but it has already stimulated new experiments that have had major effects on the content of every chapter in this book. (A) human chromosome 22 in its mitotic conformation, composed of two double-stranded DNA molecules, each 48 ×106 nucleotide pairs long 10% of chromosome arm ~40 genes (B) ×10 1% of chromosome arm containing 4 genes (C) one gene of 3.4 ×104 nucleotide pairs (D) exon intron	Cell_Biology_Alberts. The Nucleotide Sequence of the Human genome Shows How Our genes Are Arranged With the publication of the full DNA sequence of the human genome in 2004, it became possible to see in detail how the genes are arranged along each of our chromosomes (Figure 4–15). It will be many decades before the information contained in the human genome sequence is fully analyzed, but it has already stimulated new experiments that have had major effects on the content of every chapter in this book. (A) human chromosome 22 in its mitotic conformation, composed of two double-stranded DNA molecules, each 48 ×106 nucleotide pairs long 10% of chromosome arm ~40 genes (B) ×10 1% of chromosome arm containing 4 genes (C) one gene of 3.4 ×104 nucleotide pairs (D) exon intron
Cell_Biology_Alberts_815	Cell_Biology_Alberts	Figure 4–14 Two closely related species of deer with very different chromosome numbers. In the evolution of the Indian muntjac, initially separate chromosomes fused, without having a major effect on the animal. These two species contain a similar number of genes. (Chinese muntjac photo courtesy of Deborah Carreno, Natural wonders Photography.)	Cell_Biology_Alberts. Figure 4–14 Two closely related species of deer with very different chromosome numbers. In the evolution of the Indian muntjac, initially separate chromosomes fused, without having a major effect on the animal. These two species contain a similar number of genes. (Chinese muntjac photo courtesy of Deborah Carreno, Natural wonders Photography.)
Cell_Biology_Alberts_816	Cell_Biology_Alberts	Figure 4–15 The organization of genes on a human chromosome. (A) Chromosome 22, one of the smallest human chromosomes, contains 48 × 106 nucleotide pairs and makes up approximately 1.5% of the human genome. most of the left arm of chromosome 22 consists of short repeated sequences of DNA that are packaged in a particularly compact form of chromatin (heterochromatin) discussed later in this chapter. (b) A tenfold expansion of a portion of chromosome 22, with about 40 genes indicated. Those in dark brown are known genes and those in red are predicted genes. (C) An expanded portion of (b) showing four genes. (D) The intron–exon arrangement of a typical gene is shown after a further tenfold expansion. Each exon (red) codes for a portion of the protein, while the DNA sequence of the introns (gray) is relatively unimportant, as discussed in detail in Chapter 6.	Cell_Biology_Alberts. Figure 4–15 The organization of genes on a human chromosome. (A) Chromosome 22, one of the smallest human chromosomes, contains 48 × 106 nucleotide pairs and makes up approximately 1.5% of the human genome. most of the left arm of chromosome 22 consists of short repeated sequences of DNA that are packaged in a particularly compact form of chromatin (heterochromatin) discussed later in this chapter. (b) A tenfold expansion of a portion of chromosome 22, with about 40 genes indicated. Those in dark brown are known genes and those in red are predicted genes. (C) An expanded portion of (b) showing four genes. (D) The intron–exon arrangement of a typical gene is shown after a further tenfold expansion. Each exon (red) codes for a portion of the protein, while the DNA sequence of the introns (gray) is relatively unimportant, as discussed in detail in Chapter 6.
Cell_Biology_Alberts_817	Cell_Biology_Alberts	The human genome (3.2 × 109 nucleotide pairs) is the totality of genetic information belonging to our species. Almost all of this genome is distributed over the 22 different autosomes and 2 sex chromosomes (see Figures 4–10 and 4–11) found within the nucleus. A minute fraction of the human genome (16,569 nucleotide pairs—in multiple copies per cell) is found in the mitochondria (introduced in Chapter 1, and discussed in detail in Chapter 14). The term human genome sequence refers to the complete nucleotide sequence of DNA in the 24 nuclear chromosomes and the mitochondria. being diploid, a human somatic cell nucleus contains roughly twice the haploid amount of DNA, or 6.4 × 109 nucleotide pairs, when not duplicating its chromosomes in preparation for division. (Adapted from International Human genome Sequencing Consortium, Nature 409:860–921, 2001. with permission from macmillan Publishers ltd.)	Cell_Biology_Alberts. The human genome (3.2 × 109 nucleotide pairs) is the totality of genetic information belonging to our species. Almost all of this genome is distributed over the 22 different autosomes and 2 sex chromosomes (see Figures 4–10 and 4–11) found within the nucleus. A minute fraction of the human genome (16,569 nucleotide pairs—in multiple copies per cell) is found in the mitochondria (introduced in Chapter 1, and discussed in detail in Chapter 14). The term human genome sequence refers to the complete nucleotide sequence of DNA in the 24 nuclear chromosomes and the mitochondria. being diploid, a human somatic cell nucleus contains roughly twice the haploid amount of DNA, or 6.4 × 109 nucleotide pairs, when not duplicating its chromosomes in preparation for division. (Adapted from International Human genome Sequencing Consortium, Nature 409:860–921, 2001. with permission from macmillan Publishers ltd.)
Cell_Biology_Alberts_818	Cell_Biology_Alberts	The first striking feature of the human genome is how little of it (only a few percent) codes for proteins (Table 4–1 and Figure 4–16). It is also notable that nearly half of the chromosomal DNA is made up of mobile pieces of DNA that have gradually inserted themselves in the chromosomes over evolutionary time, multiplying like parasites in the genome (see Figure 4–62). We discuss these transposable elements in detail in later chapters.	Cell_Biology_Alberts. The first striking feature of the human genome is how little of it (only a few percent) codes for proteins (Table 4–1 and Figure 4–16). It is also notable that nearly half of the chromosomal DNA is made up of mobile pieces of DNA that have gradually inserted themselves in the chromosomes over evolutionary time, multiplying like parasites in the genome (see Figure 4–62). We discuss these transposable elements in detail in later chapters.
Cell_Biology_Alberts_819	Cell_Biology_Alberts	A second notable feature of the human genome is the large average gene size—about 27,000 nucleotide pairs. As discussed above, a typical gene carries in its linear sequence of nucleotides the information for the linear sequence of the amino acids of a protein. Only about 1300 nucleotide pairs are required to encode a protein of average size (about 430 amino acids in humans). Most of the remaining sequence in a gene consists of long stretches of noncoding DNA that interrupt the relatively short segments of DNA that code for protein. As will be discussed in detail in Chapter 6, the coding sequences are called exons; the intervening (noncoding) sequences in genes are called introns (see Figure 4–15 and Table 4–1). The majority of human genes thus consist of a long string of alternating exons and introns, with most of the gene consisting of introns. In contrast, the majority of genes from organisms with concise genomes lack introns. This accounts for the much smaller size of their genes	Cell_Biology_Alberts. A second notable feature of the human genome is the large average gene size—about 27,000 nucleotide pairs. As discussed above, a typical gene carries in its linear sequence of nucleotides the information for the linear sequence of the amino acids of a protein. Only about 1300 nucleotide pairs are required to encode a protein of average size (about 430 amino acids in humans). Most of the remaining sequence in a gene consists of long stretches of noncoding DNA that interrupt the relatively short segments of DNA that code for protein. As will be discussed in detail in Chapter 6, the coding sequences are called exons; the intervening (noncoding) sequences in genes are called introns (see Figure 4–15 and Table 4–1). The majority of human genes thus consist of a long string of alternating exons and introns, with most of the gene consisting of introns. In contrast, the majority of genes from organisms with concise genomes lack introns. This accounts for the much smaller size of their genes
Cell_Biology_Alberts_820	Cell_Biology_Alberts	and introns, with most of the gene consisting of introns. In contrast, the majority of genes from organisms with concise genomes lack introns. This accounts for the much smaller size of their genes (about one-twentieth that of human genes), as well as for the much higher fraction of coding DNA in their chromosomes.	Cell_Biology_Alberts. and introns, with most of the gene consisting of introns. In contrast, the majority of genes from organisms with concise genomes lack introns. This accounts for the much smaller size of their genes (about one-twentieth that of human genes), as well as for the much higher fraction of coding DNA in their chromosomes.
Cell_Biology_Alberts_821	Cell_Biology_Alberts	Figure 4–16 Scale of the human genome. If drawn with a 1 mm space between each nucleotide pair, as in (A), the human genome would extend 3200 km (approximately 2000 miles), far enough to stretch across the center of Africa, the site of our human origins (red line in b). At this scale, there would be, on average, a protein-coding gene every 150 m. An average gene would extend for 30 m, but the coding sequences in this gene would add up to only just over a meter.	Cell_Biology_Alberts. Figure 4–16 Scale of the human genome. If drawn with a 1 mm space between each nucleotide pair, as in (A), the human genome would extend 3200 km (approximately 2000 miles), far enough to stretch across the center of Africa, the site of our human origins (red line in b). At this scale, there would be, on average, a protein-coding gene every 150 m. An average gene would extend for 30 m, but the coding sequences in this gene would add up to only just over a meter.
Cell_Biology_Alberts_822	Cell_Biology_Alberts	In addition to introns and exons, each gene is associated with regulatory DNA sequences, which are responsible for ensuring that the gene is turned on or off at the proper time, expressed at the appropriate level, and only in the proper type of cell. In humans, the regulatory sequences for a typical gene are spread out over tens of thousands of nucleotide pairs. As would be expected, these regulatory sequences are much more compressed in organisms with concise genomes. We discuss how regulatory DNA sequences work in Chapter 7.	Cell_Biology_Alberts. In addition to introns and exons, each gene is associated with regulatory DNA sequences, which are responsible for ensuring that the gene is turned on or off at the proper time, expressed at the appropriate level, and only in the proper type of cell. In humans, the regulatory sequences for a typical gene are spread out over tens of thousands of nucleotide pairs. As would be expected, these regulatory sequences are much more compressed in organisms with concise genomes. We discuss how regulatory DNA sequences work in Chapter 7.
Cell_Biology_Alberts_823	Cell_Biology_Alberts	Research in the last decade has surprised biologists with the discovery that, in addition to 21,000 protein-coding genes, the human genome contains many thousands of genes that encode RNA molecules that do not produce proteins, but instead have a variety of other important functions. What is thus far known about these molecules will be presented in Chapters 6 and 7. Last, but not least, the nucleotide sequence of the human genome has revealed that the archive of information needed to produce a human seems to be in an alarming state of chaos. As one commentator described our genome, “In some ways it may resemble your garage/bedroom/refrigerator/life: highly individualistic, but unkempt; little evidence of organization; much accumulated clutter (referred to by the uninitiated as ‘junk’); virtually nothing ever discarded; and the few patently valuable items indiscriminately, apparently carelessly, scattered throughout.” We shall discuss how this is thought to have come about in the final	Cell_Biology_Alberts. Research in the last decade has surprised biologists with the discovery that, in addition to 21,000 protein-coding genes, the human genome contains many thousands of genes that encode RNA molecules that do not produce proteins, but instead have a variety of other important functions. What is thus far known about these molecules will be presented in Chapters 6 and 7. Last, but not least, the nucleotide sequence of the human genome has revealed that the archive of information needed to produce a human seems to be in an alarming state of chaos. As one commentator described our genome, “In some ways it may resemble your garage/bedroom/refrigerator/life: highly individualistic, but unkempt; little evidence of organization; much accumulated clutter (referred to by the uninitiated as ‘junk’); virtually nothing ever discarded; and the few patently valuable items indiscriminately, apparently carelessly, scattered throughout.” We shall discuss how this is thought to have come about in the final
Cell_Biology_Alberts_824	Cell_Biology_Alberts	nothing ever discarded; and the few patently valuable items indiscriminately, apparently carelessly, scattered throughout.” We shall discuss how this is thought to have come about in the final sections of this chapter entitled “How Genomes Evolve.”	Cell_Biology_Alberts. nothing ever discarded; and the few patently valuable items indiscriminately, apparently carelessly, scattered throughout.” We shall discuss how this is thought to have come about in the final sections of this chapter entitled “How Genomes Evolve.”
Cell_Biology_Alberts_825	Cell_Biology_Alberts	Each DNA molecule That Forms a linear Chromosome must Contain a Centromere, Two Telomeres, and Replication Origins	Cell_Biology_Alberts. Each DNA molecule That Forms a linear Chromosome must Contain a Centromere, Two Telomeres, and Replication Origins
Cell_Biology_Alberts_826	Cell_Biology_Alberts	To form a functional chromosome, a DNA molecule must be able to do more than simply carry genes: it must be able to replicate, and the replicated copies must be separated and reliably partitioned into daughter cells at each cell division. This process occurs through an ordered series of stages, collectively known as the cell cycle, which provides for a temporal separation between the duplication of chromosomes and their segregation into two daughter cells. The cell cycle is briefly summarized in Figure 4–17, and it is discussed in detail in Chapter 17. Briefly, during a long interphase, genes are expressed and chromosomes are replicated, with the two replicas remaining together as a pair of sister chromatids. Throughout this time, the chromosomes are extended and much of their chromatin exists as long threads in the nucleus so that individual chromosomes cannot be easily distinguished. It is only during a much briefer period of mitosis that each chromosome condenses so that its two	Cell_Biology_Alberts. To form a functional chromosome, a DNA molecule must be able to do more than simply carry genes: it must be able to replicate, and the replicated copies must be separated and reliably partitioned into daughter cells at each cell division. This process occurs through an ordered series of stages, collectively known as the cell cycle, which provides for a temporal separation between the duplication of chromosomes and their segregation into two daughter cells. The cell cycle is briefly summarized in Figure 4–17, and it is discussed in detail in Chapter 17. Briefly, during a long interphase, genes are expressed and chromosomes are replicated, with the two replicas remaining together as a pair of sister chromatids. Throughout this time, the chromosomes are extended and much of their chromatin exists as long threads in the nucleus so that individual chromosomes cannot be easily distinguished. It is only during a much briefer period of mitosis that each chromosome condenses so that its two
Cell_Biology_Alberts_827	Cell_Biology_Alberts	exists as long threads in the nucleus so that individual chromosomes cannot be easily distinguished. It is only during a much briefer period of mitosis that each chromosome condenses so that its two sister chromatids can be separated and distributed to the two daughter nuclei. The highly condensed chromosomes in a dividing cell are known as mitotic chromosomes (Figure 4–18). This is the form in which chromosomes are most easily visualized; in fact, the images of chromosomes shown so far in the chapter are of chromosomes in mitosis.	Cell_Biology_Alberts. exists as long threads in the nucleus so that individual chromosomes cannot be easily distinguished. It is only during a much briefer period of mitosis that each chromosome condenses so that its two sister chromatids can be separated and distributed to the two daughter nuclei. The highly condensed chromosomes in a dividing cell are known as mitotic chromosomes (Figure 4–18). This is the form in which chromosomes are most easily visualized; in fact, the images of chromosomes shown so far in the chapter are of chromosomes in mitosis.
Cell_Biology_Alberts_828	Cell_Biology_Alberts	Each chromosome operates as a distinct structural unit: for a copy to be passed on to each daughter cell at division, each chromosome must be able to replicate, and the newly replicated copies must subsequently be separated and partitioned	Cell_Biology_Alberts. Each chromosome operates as a distinct structural unit: for a copy to be passed on to each daughter cell at division, each chromosome must be able to replicate, and the newly replicated copies must subsequently be separated and partitioned
Cell_Biology_Alberts_829	Cell_Biology_Alberts	Figure 4–17 A simplified view of the eukaryotic cell cycle. During interphase, the cell is actively expressing its genes and is therefore synthesizing proteins. Also, during interphase and before cell division, the DNA is replicated and each chromosome is duplicated to produce two closely paired sister DNA molecules (called sister chromatids). A cell with only one type of chromosome, present in maternal and paternal copies, is illustrated here. Once DNA replication is complete, the cell can enter M phase, when mitosis occurs and the nucleus is divided into two daughter nuclei. During this stage, the chromosomes condense, the nuclear envelope breaks down, and the mitotic spindle forms from microtubules and other proteins. The condensed mitotic chromosomes are captured by the mitotic spindle, and one complete set of chromosomes is then pulled to each end of the cell by separating the members of each sister-chromatid pair. A nuclear envelope re-forms around each chromosome set, and in	Cell_Biology_Alberts. Figure 4–17 A simplified view of the eukaryotic cell cycle. During interphase, the cell is actively expressing its genes and is therefore synthesizing proteins. Also, during interphase and before cell division, the DNA is replicated and each chromosome is duplicated to produce two closely paired sister DNA molecules (called sister chromatids). A cell with only one type of chromosome, present in maternal and paternal copies, is illustrated here. Once DNA replication is complete, the cell can enter M phase, when mitosis occurs and the nucleus is divided into two daughter nuclei. During this stage, the chromosomes condense, the nuclear envelope breaks down, and the mitotic spindle forms from microtubules and other proteins. The condensed mitotic chromosomes are captured by the mitotic spindle, and one complete set of chromosomes is then pulled to each end of the cell by separating the members of each sister-chromatid pair. A nuclear envelope re-forms around each chromosome set, and in
Cell_Biology_Alberts_830	Cell_Biology_Alberts	and one complete set of chromosomes is then pulled to each end of the cell by separating the members of each sister-chromatid pair. A nuclear envelope re-forms around each chromosome set, and in the final step of m phase, the cell divides to produce two daughter cells. most of the time in the cell cycle is spent in interphase; m phase is brief in comparison, occupying only about an hour in many mammalian cells.	Cell_Biology_Alberts. and one complete set of chromosomes is then pulled to each end of the cell by separating the members of each sister-chromatid pair. A nuclear envelope re-forms around each chromosome set, and in the final step of m phase, the cell divides to produce two daughter cells. most of the time in the cell cycle is spent in interphase; m phase is brief in comparison, occupying only about an hour in many mammalian cells.
Cell_Biology_Alberts_831	Cell_Biology_Alberts	nuclear envelope surrounding the nucleus INTERPHASE M PHASE INTERPHASE correctly into the two daughter cells. These basic functions are controlled by three types of specialized nucleotide sequences in the DNA, each of which binds specific proteins that guide the machinery that replicates and segregates chromosomes (Figure 4–19). Experiments in yeasts, whose chromosomes are relatively small and easy to manipulate, have identified the minimal DNA sequence elements responsible for each of these functions. One type of nucleotide sequence acts as a DNA replication origin, the location at which duplication of the DNA begins. Eukaryotic chromosomes contain many origins of replication to ensure that the entire chromosome can be replicated rapidly, as discussed in detail in Chapter 5.	Cell_Biology_Alberts. nuclear envelope surrounding the nucleus INTERPHASE M PHASE INTERPHASE correctly into the two daughter cells. These basic functions are controlled by three types of specialized nucleotide sequences in the DNA, each of which binds specific proteins that guide the machinery that replicates and segregates chromosomes (Figure 4–19). Experiments in yeasts, whose chromosomes are relatively small and easy to manipulate, have identified the minimal DNA sequence elements responsible for each of these functions. One type of nucleotide sequence acts as a DNA replication origin, the location at which duplication of the DNA begins. Eukaryotic chromosomes contain many origins of replication to ensure that the entire chromosome can be replicated rapidly, as discussed in detail in Chapter 5.
Cell_Biology_Alberts_832	Cell_Biology_Alberts	After DNA replication, the two sister chromatids that form each chromosome remain attached to one another and, as the cell cycle proceeds, are condensed further to produce mitotic chromosomes. The presence of a second specialized DNA sequence, called a centromere, allows one copy of each duplicated and condensed chromosome to be pulled into each daughter cell when a cell divides. A protein complex called a kinetochore forms at the centromere and attaches the duplicated chromosomes to the mitotic spindle, allowing them to be pulled apart (discussed in Chapter 17).	Cell_Biology_Alberts. After DNA replication, the two sister chromatids that form each chromosome remain attached to one another and, as the cell cycle proceeds, are condensed further to produce mitotic chromosomes. The presence of a second specialized DNA sequence, called a centromere, allows one copy of each duplicated and condensed chromosome to be pulled into each daughter cell when a cell divides. A protein complex called a kinetochore forms at the centromere and attaches the duplicated chromosomes to the mitotic spindle, allowing them to be pulled apart (discussed in Chapter 17).
Cell_Biology_Alberts_833	Cell_Biology_Alberts	The third specialized DNA sequence forms telomeres, the ends of a chromosome. Telomeres contain repeated nucleotide sequences that enable the ends of chromosomes to be efficiently replicated. Telomeres also perform another function: the repeated telomere DNA sequences, together with the regions adjoining them, form structures that protect the end of the chromosome from being mistaken by the cell for a broken DNA molecule in need of repair. We discuss both this type of repair and the structure and function of telomeres in Chapter 5.	Cell_Biology_Alberts. The third specialized DNA sequence forms telomeres, the ends of a chromosome. Telomeres contain repeated nucleotide sequences that enable the ends of chromosomes to be efficiently replicated. Telomeres also perform another function: the repeated telomere DNA sequences, together with the regions adjoining them, form structures that protect the end of the chromosome from being mistaken by the cell for a broken DNA molecule in need of repair. We discuss both this type of repair and the structure and function of telomeres in Chapter 5.
Cell_Biology_Alberts_834	Cell_Biology_Alberts	In yeast cells, the three types of sequences required to propagate a chromosome are relatively short (typically less than 1000 base pairs each) and therefore use only a tiny fraction of the information-carrying capacity of a chromosome. Although telomere sequences are fairly simple and short in all eukaryotes, the DNA sequences that form centromeres and replication origins in more complex organisms are much longer than their yeast counterparts. For example, experiments suggest that a human centromere can contain up to a million nucleotide pairs and that it may not require a stretch of DNA with a defined nucleotide sequence. Instead, as we shall discuss later in this chapter, a human centromere is thought to consist of a large, regularly repeating protein–nucleic acid structure that can be inherited when a chromosome replicates. Figure 4–18 A mitotic chromosome.	Cell_Biology_Alberts. In yeast cells, the three types of sequences required to propagate a chromosome are relatively short (typically less than 1000 base pairs each) and therefore use only a tiny fraction of the information-carrying capacity of a chromosome. Although telomere sequences are fairly simple and short in all eukaryotes, the DNA sequences that form centromeres and replication origins in more complex organisms are much longer than their yeast counterparts. For example, experiments suggest that a human centromere can contain up to a million nucleotide pairs and that it may not require a stretch of DNA with a defined nucleotide sequence. Instead, as we shall discuss later in this chapter, a human centromere is thought to consist of a large, regularly repeating protein–nucleic acid structure that can be inherited when a chromosome replicates. Figure 4–18 A mitotic chromosome.
Cell_Biology_Alberts_835	Cell_Biology_Alberts	Figure 4–18 A mitotic chromosome. A mitotic chromosome is a condensed duplicated chromosome in which the two new chromosomes, called sister chromatids, are still linked together (see Figure 4–17). The constricted region indicates the position of the centromere. (Courtesy of Terry D. Allen.) Figure 4–19 The three DNA sequences required to produce a eukaryotic chromosome that can be replicated and then segregated accurately at mitosis.	Cell_Biology_Alberts. Figure 4–18 A mitotic chromosome. A mitotic chromosome is a condensed duplicated chromosome in which the two new chromosomes, called sister chromatids, are still linked together (see Figure 4–17). The constricted region indicates the position of the centromere. (Courtesy of Terry D. Allen.) Figure 4–19 The three DNA sequences required to produce a eukaryotic chromosome that can be replicated and then segregated accurately at mitosis.
Cell_Biology_Alberts_836	Cell_Biology_Alberts	Figure 4–19 The three DNA sequences required to produce a eukaryotic chromosome that can be replicated and then segregated accurately at mitosis. Each chromosome has multiple origins of replication, one centromere, and two telomeres. Shown here is the sequence of events that a typical chromosome follows during the cell cycle. The DNA replicates in interphase, beginning at the origins of replication and proceeding bidirectionally from the origins across the chromosome. In m phase, the centromere attaches the duplicated chromosomes to the mitotic spindle so that a copy of the entire genome is distributed to each daughter cell during mitosis; the special structure that attaches the centromere to the spindle is a protein complex called the kinetochore (dark green). The centromere also helps to hold the duplicated chromosomes together until they are ready to be moved apart. The telomeres form special caps at each chromosome end.	Cell_Biology_Alberts. Figure 4–19 The three DNA sequences required to produce a eukaryotic chromosome that can be replicated and then segregated accurately at mitosis. Each chromosome has multiple origins of replication, one centromere, and two telomeres. Shown here is the sequence of events that a typical chromosome follows during the cell cycle. The DNA replicates in interphase, beginning at the origins of replication and proceeding bidirectionally from the origins across the chromosome. In m phase, the centromere attaches the duplicated chromosomes to the mitotic spindle so that a copy of the entire genome is distributed to each daughter cell during mitosis; the special structure that attaches the centromere to the spindle is a protein complex called the kinetochore (dark green). The centromere also helps to hold the duplicated chromosomes together until they are ready to be moved apart. The telomeres form special caps at each chromosome end.
Cell_Biology_Alberts_837	Cell_Biology_Alberts	All eukaryotic organisms have special ways of packaging DNA into chromosomes. For example, if the 48 million nucleotide pairs of DNA in human chromosome 22 could be laid out as one long perfect double helix, the molecule would extend for about 1.5 cm if stretched out end to end. But chromosome 22 measures only about 2 μm in length in mitosis (see Figures 4–10 and 4–11), representing an endto-end compaction ratio of over 7000-fold. This remarkable feat of compression is performed by proteins that successively coil and fold the DNA into higher and higher levels of organization. Although much less condensed than mitotic chromosomes, the DNA of human interphase chromosomes is still tightly packed.	Cell_Biology_Alberts. All eukaryotic organisms have special ways of packaging DNA into chromosomes. For example, if the 48 million nucleotide pairs of DNA in human chromosome 22 could be laid out as one long perfect double helix, the molecule would extend for about 1.5 cm if stretched out end to end. But chromosome 22 measures only about 2 μm in length in mitosis (see Figures 4–10 and 4–11), representing an endto-end compaction ratio of over 7000-fold. This remarkable feat of compression is performed by proteins that successively coil and fold the DNA into higher and higher levels of organization. Although much less condensed than mitotic chromosomes, the DNA of human interphase chromosomes is still tightly packed.
Cell_Biology_Alberts_838	Cell_Biology_Alberts	In reading these sections it is important to keep in mind that chromosome structure is dynamic. We have seen that each chromosome condenses to an extreme degree in the M phase of the cell cycle. Much less visible, but of enormous interest and importance, specific regions of interphase chromosomes decondense to allow access to specific DNA sequences for gene expression, DNA repair, and replication—and then recondense when these processes are completed. The packaging of chromosomes is therefore accomplished in a way that allows rapid localized, on-demand access to the DNA. In the next sections, we discuss the specialized proteins that make this type of packaging possible. Nucleosomes Are a basic Unit of Eukaryotic Chromosome Structure	Cell_Biology_Alberts. In reading these sections it is important to keep in mind that chromosome structure is dynamic. We have seen that each chromosome condenses to an extreme degree in the M phase of the cell cycle. Much less visible, but of enormous interest and importance, specific regions of interphase chromosomes decondense to allow access to specific DNA sequences for gene expression, DNA repair, and replication—and then recondense when these processes are completed. The packaging of chromosomes is therefore accomplished in a way that allows rapid localized, on-demand access to the DNA. In the next sections, we discuss the specialized proteins that make this type of packaging possible. Nucleosomes Are a basic Unit of Eukaryotic Chromosome Structure
Cell_Biology_Alberts_839	Cell_Biology_Alberts	Nucleosomes Are a basic Unit of Eukaryotic Chromosome Structure The proteins that bind to the DNA to form eukaryotic chromosomes are traditionally divided into two classes: the histones and the non-histone chromosomal proteins, each contributing about the same mass to a chromosome as the DNA. The complex of both classes of protein with the nuclear DNA of eukaryotic cells is known as chromatin (Figure 4–20).	Cell_Biology_Alberts. Nucleosomes Are a basic Unit of Eukaryotic Chromosome Structure The proteins that bind to the DNA to form eukaryotic chromosomes are traditionally divided into two classes: the histones and the non-histone chromosomal proteins, each contributing about the same mass to a chromosome as the DNA. The complex of both classes of protein with the nuclear DNA of eukaryotic cells is known as chromatin (Figure 4–20).
Cell_Biology_Alberts_840	Cell_Biology_Alberts	Histones are responsible for the first and most basic level of chromosome packing, the nucleosome, a protein–DNA complex discovered in 1974. When interphase nuclei are broken open very gently and their contents examined under the electron microscope, most of the chromatin appears to be in the form of a fiber with a diameter of about 30 nm (Figure 4–21A). If this chromatin is subjected to treatments that cause it to unfold partially, it can be seen under the electron microscope as a series of “beads on a string” (Figure 4–21B). The string is DNA, and each bead is a “nucleosome core particle” that consists of DNA wound around a histone core (Movie 4.2).	Cell_Biology_Alberts. Histones are responsible for the first and most basic level of chromosome packing, the nucleosome, a protein–DNA complex discovered in 1974. When interphase nuclei are broken open very gently and their contents examined under the electron microscope, most of the chromatin appears to be in the form of a fiber with a diameter of about 30 nm (Figure 4–21A). If this chromatin is subjected to treatments that cause it to unfold partially, it can be seen under the electron microscope as a series of “beads on a string” (Figure 4–21B). The string is DNA, and each bead is a “nucleosome core particle” that consists of DNA wound around a histone core (Movie 4.2).
Cell_Biology_Alberts_841	Cell_Biology_Alberts	The structural organization of nucleosomes was determined after first isolating them from unfolded chromatin by digestion with particular enzymes (called nucleases) that break down DNA by cutting between the nucleosomes. After digestion for a short period, the exposed DNA between the nucleosome core particles, the linker DNA, is degraded. Each individual nucleosome core particle consists of a complex of eight histone proteins—two molecules each of histones H2A, Figure 4–20 Chromatin. As illustrated, chromatin consists of DNA bound to both histone and non-histone proteins. The mass of histone protein present is about equal to the total mass of non-histone protein, but—as schematically indicated here—the latter class is composed of an enormous number of different species. In total, a chromosome is about one-third DNA and two-thirds protein by mass.	Cell_Biology_Alberts. The structural organization of nucleosomes was determined after first isolating them from unfolded chromatin by digestion with particular enzymes (called nucleases) that break down DNA by cutting between the nucleosomes. After digestion for a short period, the exposed DNA between the nucleosome core particles, the linker DNA, is degraded. Each individual nucleosome core particle consists of a complex of eight histone proteins—two molecules each of histones H2A, Figure 4–20 Chromatin. As illustrated, chromatin consists of DNA bound to both histone and non-histone proteins. The mass of histone protein present is about equal to the total mass of non-histone protein, but—as schematically indicated here—the latter class is composed of an enormous number of different species. In total, a chromosome is about one-third DNA and two-thirds protein by mass.
Cell_Biology_Alberts_842	Cell_Biology_Alberts	H2B, H3, and H4—and double-stranded DNA that is 147 nucleotide pairs long. The histone octamer forms a protein core around which the double-stranded DNA is wound (Figure 4–22). The region of linker DNA that separates each nucleosome core particle from the next can vary in length from a few nucleotide pairs up to about 80. (The term nucleosome technically refers to a nucleosome core particle plus one of its adjacent DNA linkers, but it is often used synonymously with nucleosome core particle.) On average, therefore, nucleosomes repeat at intervals of about 200 nucleotide pairs. For example, a diploid human cell with 6.4 × 109 nucleotide pairs contains approximately 30 million nucleosomes. The formation of nucleosomes converts a DNA molecule into a chromatin thread about one-third of its initial length. The Structure of the Nucleosome Core Particle Reveals How DNA Is Packaged	Cell_Biology_Alberts. H2B, H3, and H4—and double-stranded DNA that is 147 nucleotide pairs long. The histone octamer forms a protein core around which the double-stranded DNA is wound (Figure 4–22). The region of linker DNA that separates each nucleosome core particle from the next can vary in length from a few nucleotide pairs up to about 80. (The term nucleosome technically refers to a nucleosome core particle plus one of its adjacent DNA linkers, but it is often used synonymously with nucleosome core particle.) On average, therefore, nucleosomes repeat at intervals of about 200 nucleotide pairs. For example, a diploid human cell with 6.4 × 109 nucleotide pairs contains approximately 30 million nucleosomes. The formation of nucleosomes converts a DNA molecule into a chromatin thread about one-third of its initial length. The Structure of the Nucleosome Core Particle Reveals How DNA Is Packaged
Cell_Biology_Alberts_843	Cell_Biology_Alberts	The Structure of the Nucleosome Core Particle Reveals How DNA Is Packaged The high-resolution structure of a nucleosome core particle, solved in 1997, revealed a disc-shaped histone core around which the DNA was tightly wrapped in a left-handed coil of 1.7 turns (Figure 4–23). All four of the histones that make up the core of the nucleosome are relatively small proteins (102–135 amino acids), and they share a structural motif, known as the histone fold, formed from three α helices connected by two loops (Figure 4–24). In assembling a nucleosome, the histone folds first bind to each other to form H3–H4 and H2A–H2B dimers, and the H3–H4 dimers combine to form tetramers. An H3–H4 tetramer then further combines with two H2A–H2B dimers to form the compact octamer core, around which the DNA is wound.	Cell_Biology_Alberts. The Structure of the Nucleosome Core Particle Reveals How DNA Is Packaged The high-resolution structure of a nucleosome core particle, solved in 1997, revealed a disc-shaped histone core around which the DNA was tightly wrapped in a left-handed coil of 1.7 turns (Figure 4–23). All four of the histones that make up the core of the nucleosome are relatively small proteins (102–135 amino acids), and they share a structural motif, known as the histone fold, formed from three α helices connected by two loops (Figure 4–24). In assembling a nucleosome, the histone folds first bind to each other to form H3–H4 and H2A–H2B dimers, and the H3–H4 dimers combine to form tetramers. An H3–H4 tetramer then further combines with two H2A–H2B dimers to form the compact octamer core, around which the DNA is wound.
Cell_Biology_Alberts_844	Cell_Biology_Alberts	The interface between DNA and histone is extensive: 142 hydrogen bonds are formed between DNA and the histone core in each nucleosome. Nearly half of these bonds form between the amino acid backbone of the histones and the sugar-phosphate backbone of the DNA. Numerous hydrophobic interactions and salt linkages also hold DNA and protein together in the nucleosome. More than one-fifth of the amino acids in each of the core histones are either lysine or arginine (two amino acids with basic side chains), and their positive charges can effectively	Cell_Biology_Alberts. The interface between DNA and histone is extensive: 142 hydrogen bonds are formed between DNA and the histone core in each nucleosome. Nearly half of these bonds form between the amino acid backbone of the histones and the sugar-phosphate backbone of the DNA. Numerous hydrophobic interactions and salt linkages also hold DNA and protein together in the nucleosome. More than one-fifth of the amino acids in each of the core histones are either lysine or arginine (two amino acids with basic side chains), and their positive charges can effectively
Cell_Biology_Alberts_845	Cell_Biology_Alberts	Figure 4–22 Structural organization of the nucleosome. A nucleosome contains a protein core made of eight histone molecules. In biochemical experiments, the nucleosome core particle can be released from isolated chromatin by digestion of the linker DNA with a nuclease, an enzyme that breaks down DNA. (The nuclease can degrade the exposed linker DNA but cannot attack the DNA wound tightly around the nucleosome core.) After dissociation of the isolated nucleosome into its protein core and DNA, the length of the DNA that was wound around the core can be determined. This length of 147 nucleotide pairs is sufficient to wrap 1.7 times around the histone core.	Cell_Biology_Alberts. Figure 4–22 Structural organization of the nucleosome. A nucleosome contains a protein core made of eight histone molecules. In biochemical experiments, the nucleosome core particle can be released from isolated chromatin by digestion of the linker DNA with a nuclease, an enzyme that breaks down DNA. (The nuclease can degrade the exposed linker DNA but cannot attack the DNA wound tightly around the nucleosome core.) After dissociation of the isolated nucleosome into its protein core and DNA, the length of the DNA that was wound around the core can be determined. This length of 147 nucleotide pairs is sufficient to wrap 1.7 times around the histone core.
Cell_Biology_Alberts_846	Cell_Biology_Alberts	Figure 4–21 Nucleosomes as seen in the electron microscope. (A) Chromatin isolated directly from an interphase nucleus appears in the electron microscope as a thread about 30 nm thick. (b) This electron micrograph shows a length of chromatin that has been experimentally unpacked, or decondensed, after isolation to show the nucleosomes. (A, courtesy of barbara Hamkalo; b, courtesy of victoria Foe.) core histones linker DNA of nucleosome “beads-on-a-string” nucleosome includes form of chromatin ~200 nucleotide pairs of DNA	Cell_Biology_Alberts. Figure 4–21 Nucleosomes as seen in the electron microscope. (A) Chromatin isolated directly from an interphase nucleus appears in the electron microscope as a thread about 30 nm thick. (b) This electron micrograph shows a length of chromatin that has been experimentally unpacked, or decondensed, after isolation to show the nucleosomes. (A, courtesy of barbara Hamkalo; b, courtesy of victoria Foe.) core histones linker DNA of nucleosome “beads-on-a-string” nucleosome includes form of chromatin ~200 nucleotide pairs of DNA
Cell_Biology_Alberts_847	Cell_Biology_Alberts	Figure 4–23 The structure of a nucleosome core particle, as determined by x-ray diffraction analyses of crystals. Each histone is colored according to the scheme in Figure 4–22, with the DNA double helix in light gray. (Adapted from k. luger et al., Nature 389:251–260, 1997. with permission from macmillan Publishers ltd.) neutralize the negatively charged DNA backbone. These numerous interactions explain in part why DNA of virtually any sequence can be bound on a histone octamer core. The path of the DNA around the histone core is not smooth; rather, several kinks are seen in the DNA, as expected from the nonuniform surface of the	Cell_Biology_Alberts. Figure 4–23 The structure of a nucleosome core particle, as determined by x-ray diffraction analyses of crystals. Each histone is colored according to the scheme in Figure 4–22, with the DNA double helix in light gray. (Adapted from k. luger et al., Nature 389:251–260, 1997. with permission from macmillan Publishers ltd.) neutralize the negatively charged DNA backbone. These numerous interactions explain in part why DNA of virtually any sequence can be bound on a histone octamer core. The path of the DNA around the histone core is not smooth; rather, several kinks are seen in the DNA, as expected from the nonuniform surface of the
Cell_Biology_Alberts_848	Cell_Biology_Alberts	Figure 4–24 The overall structural organization of the core histones. (A) Each of the core histones contains an N-terminal tail, which is subject to several forms of covalent modification, and a histone fold region, as indicated. (b) The structure of the histone fold, which is formed by all four of the core histones. (C) Histones 2A and 2b form a dimer through an interaction known as the “handshake.” Histones H3 and H4 form a dimer through the same type of interaction. (D) The final histone octamer on DNA. Note that all eight N-terminal tails of the histones protrude from the disc-shaped core structure. Their conformations are highly flexible, and they serve as binding sites for sets of other proteins.	Cell_Biology_Alberts. Figure 4–24 The overall structural organization of the core histones. (A) Each of the core histones contains an N-terminal tail, which is subject to several forms of covalent modification, and a histone fold region, as indicated. (b) The structure of the histone fold, which is formed by all four of the core histones. (C) Histones 2A and 2b form a dimer through an interaction known as the “handshake.” Histones H3 and H4 form a dimer through the same type of interaction. (D) The final histone octamer on DNA. Note that all eight N-terminal tails of the histones protrude from the disc-shaped core structure. Their conformations are highly flexible, and they serve as binding sites for sets of other proteins.
Cell_Biology_Alberts_849	Cell_Biology_Alberts	core. The bending requires a substantial compression of the minor groove of the DNA helix. Certain dinucleotides in the minor groove are especially easy to compress, and some nucleotide sequences bind the nucleosome more tightly than others (Figure 4–25). This probably explains some striking, but unusual, cases of very precise positioning of nucleosomes along a stretch of DNA. However, the sequence preference of nucleosomes must be weak enough to allow other factors to dominate, inasmuch as nucleosomes can occupy any one of a number of positions relative to the DNA sequence in most chromosomal regions. In addition to its histone fold, each of the core histones has an N-terminal amino acid “tail,” which extends out from the DNA–histone core (see Figure 4–24D). These histone tails are subject to several different types of covalent modifications that in turn control critical aspects of chromatin structure and function, as we shall discuss shortly.	Cell_Biology_Alberts. core. The bending requires a substantial compression of the minor groove of the DNA helix. Certain dinucleotides in the minor groove are especially easy to compress, and some nucleotide sequences bind the nucleosome more tightly than others (Figure 4–25). This probably explains some striking, but unusual, cases of very precise positioning of nucleosomes along a stretch of DNA. However, the sequence preference of nucleosomes must be weak enough to allow other factors to dominate, inasmuch as nucleosomes can occupy any one of a number of positions relative to the DNA sequence in most chromosomal regions. In addition to its histone fold, each of the core histones has an N-terminal amino acid “tail,” which extends out from the DNA–histone core (see Figure 4–24D). These histone tails are subject to several different types of covalent modifications that in turn control critical aspects of chromatin structure and function, as we shall discuss shortly.