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Structure of Chromosomes

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Syed Muhammad Khan
Syed Muhammad Khan

This is a comprehensive account of the structure of eukaryotic chromosomes. It deals with the morphology, formation, and types of chromosomes present in eukaryotic cells. The main point of interest is the folding and packaging of DNA and proteins to make chromatin.

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Syed Muhammad Khan (BS Zoology) Page | 1 STRUCTURE OF CHROMOSOMES All of the cell's information is stored in the form of a polymeric molecule known as DNA (Deoxyribonucleic Acid). DNA is composed of a specific sequence of monomers (nucleotides); this sequence acts as a code language that can be deciphered by the cell to make proteins. DNA molecules (in case of eukaryotes) can be as long as 3 meters but they reside in a cell that is 10 to 100µm long. This seemingly impossible goal is achieved by the intensive packaging of DNA molecules. This folding is accomplished by the binding of DNA with proteins to form a DNA protein complex known as chromatin (uncoiled form of the chromosome) which undergoes further coiling to become a compact structure known as a chromosome. MORPHOLOGY OF CHROMOSOMES At metaphase, chromosomes possess two arms joined together by a centromere. One of the arms is called p arm (petit arm) while the other is known as q arm (long arm). Figure: Eukaryotic metaphase chromosome. (1) Chromatid, (2) Centromere, (3) Short or p arm (p), and (4) Long or q arm. [Source: Wikimedia, CC-BY-SA]
Syed Muhammad Khan (BS Zoology) Page | 2 Based on the position of the centromere, a chromosome may either be acrocentric (one very short arm and one very long one), metacentric (centromere in the middle, equal length of arms), sub-metacentric (almost equal length of arms), or telocentric (centromere lies on the tip, only one arm). Figure: The position of centromere affects the morphology of chromosomes. (I) Telocentric, (II) Acrocentric, (III) Sub-metacentric, and (IV) Metacentric. [Source: Wikimedia, CC-BY-SA] SINGLE STRANDED & MULTI STRANDED HYPOTHESES The fibrils of chromosomes are 2 to 4nm in thickness, since DNA is 2nm wide, it can be assumed that a single DNA molecule is present in a single chromosome fibril. The DNA content of chromosome fibrils varies in different species, it is due to two causes: (1) lateral multiplication and (2) tandem duplication. In lateral multiplication, the DNA divides laterally (left/right side) and hence causes multi strandedness in the fibril. Whereas in the tandem duplication, the DNA divides lengthwise and hence retains the single-stranded feature of chromosomes. Generally, the chromosomes are single-stranded (made up of a single linear DNA molecule), this was confirmed by the pulsed gel electrophoresis of the chromatin of Saccharomyces cerevisiae (yeast).
Syed Muhammad Khan (BS Zoology) Page | 3 MODELS OF DNA COILING & FOLDING IN CHROMATIN Many models of DNA coiling in chromatin were proposed by scientists, but the two most important ones are: (1) Folded Fiber Model and (2) Nucleosome Model. They are discussed as follows: 1. Folded Fiber Model: This model of DNA folding was proposed by E.J. Dupraw in 1965. This model suggests that the chromatin is tightly folded fiber that consists of a supercoiled DNA histone helix. The DNA was proposed to be the main axis of the structure and the histones were proposed to be bound on the exterior of the DNA coils, i.e. forming a histone shell around the DNA. The only flaw in this model is the fact that it proposes that the DNA is covered, but this cannot be true if the DNA is to express itself which can only be possible if the DNA is exposed. 2. Nucleosome Model: Another model of DNA folding was proposed by R.D. Kornberg in 1974, this model proposed that the DNA wraps around almost an equal mass of histone proteins to form a structure called a nucleosome. Contrary to the folded fiber model, the nucleosome model suggests that the DNA is exposed and available for genetic expression (not covered by histones). This model was confirmed in 1975 by P. Oudet and his colleagues. There are two major components of the nucleosome: (1) histone proteins and (2) DNA. There are four nucleosome histones: H2A, H2B, H3, and H4 (core histones); 2 copies of each of these proteins are present in one nucleosome, in the form of an octamer. The DNA molecule then wraps around this octamer 1.65 times. The DNA then extends as a single fiber to another octamer to form another nucleosome. The DNA in between two nucleosomes (linker DNA) is sealed by another histone protein – H1 (linker histone). Thus each nucleosome has a diameter of 11-nm and a height of 5.7-nm and the chromatin appears as a "beads on a string" like structure. Histones are basic; they have many positively charged amino acids in them, i.e. Lysine, Arginine, etc. At normal pH of the cell, these amino acids have a positive charge, hence rendering a positive charge on the histones, which facilitates their binding with the negatively charged (acidic – phosphate) DNA molecule. The non-
Syed Muhammad Khan (BS Zoology) Page | 4 histones are negatively charged proteins; they bind with the positively charged histones of the nucleosome. Figure: Structural configuration of a nucleosome. [Source: Wikimedia, CC-BY-SA] STAGES OF CHROMOSOME PACKAGING The nucleosome (11-nm) is the first stage of chromatin packaging; it has to undergo much coiling and folding to ultimately become a highly compact 1400-nm thick chromosome, able to fit within the nucleus. The stages of chromatin packaging are as follows: 1. Nucleosome [10-nm fiber]: This is the basic level of chromatin packaging. When nucleosomes are in close apposition, they form 10-nm fibers. These fibers are 5 to 7 times more compact than free DNA. But still, this fiber cannot fit inside the nucleus. It must undergo further coiling. 2. Solenoid [30-nm fiber]: The nucleosomes undergo folding in a helical manner and become closely packed in a 30-nm fiber called a solenoid. A solenoid has 6 nucleosomes per turn and is 40
Syed Muhammad Khan (BS Zoology) Page | 5 times more compact than a free DNA molecule. The solenoid fiber is found in interphase chromatin and metaphase chromosomes. The H1 histone aids in the packing of nucleosomes in the 30nm fiber. The chromatin at this stage is 0.1cm long. 3. Looped Domain / Radial Loops [300-nm fiber]: The solenoid fiber (30-nm) forms radial loops that extend at an angle from the main chromosome axis. The DNA binding proteins clamp two regions of the solenoid together by recognizing a specific DNA sequence that will form the neck of each loop. The loops are based on a scaffold (non-histone protein base). The chromatin at this level is 300-nm in diameter. 4. Condensed Loop / Chromatid [700-nm fiber]: The scaffold with a loop of solenoid on it, itself start folding in the form of loops and forms a 700-nm fiber. This fiber is the chromatid, two of which are present in the metaphase chromosome. 5. Metaphase Chromosome [1400- nm fiber]: Two chromatids of 700-nm each join at a centromere, to form a metaphase chromosome that is 1400-nm thick. The chromatin, in this form, is said to be transcriptionally inert (cannot be transcribed) due to a high level of packing. Figure: Formation of 30-nm fiber. [Source: Wikimedia, CC-BY-SA)
Syed Muhammad Khan (BS Zoology) Page | 6 Figure: The process of chromosome folding. [Source: Wikimedia, CC-BY-SA]
Syed Muhammad Khan (BS Zoology) Page | 7 EUCHROMATIN & HETEROCHROMATIN Depending on the extent of packaging, chromatin can be classified as either (1) euchromatin or (2) heterochromatin. Euchromatin (true chromatin) is relatively less tightly bound, its DNA is available for genetic expression, i.e. it can be easily uncoiled for transcription. It stains lightly as compared to heterochromatin. Figure: Locations of euchromatin and heterochromatin inside a eukaryotic nucleus. [Source: Wikimedia, CC-BY-SA] Heterochromatin is tightly packed and hence it is not easy to open it up for transcription. It also has a lot of repeated DNA sequences (satellite DNA) and very few structural genes (that code for proteins). It is genetically inactive. It stains darker as compared to euchromatin. Heterochromatin may be: around or near nucleolus (nucleolar heterochromatin), in contact with the inner side of the inner membrane of the nuclear envelope (condensed peripheral chromatin), or it may lie between peripheral and nucleolar heterochromatin (dispersed heterochromatin).

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Structure of Chromosomes

  • 1. Syed Muhammad Khan (BS Zoology) Page | 1 STRUCTURE OF CHROMOSOMES All of the cell's information is stored in the form of a polymeric molecule known as DNA (Deoxyribonucleic Acid). DNA is composed of a specific sequence of monomers (nucleotides); this sequence acts as a code language that can be deciphered by the cell to make proteins. DNA molecules (in case of eukaryotes) can be as long as 3 meters but they reside in a cell that is 10 to 100µm long. This seemingly impossible goal is achieved by the intensive packaging of DNA molecules. This folding is accomplished by the binding of DNA with proteins to form a DNA protein complex known as chromatin (uncoiled form of the chromosome) which undergoes further coiling to become a compact structure known as a chromosome. MORPHOLOGY OF CHROMOSOMES At metaphase, chromosomes possess two arms joined together by a centromere. One of the arms is called p arm (petit arm) while the other is known as q arm (long arm). Figure: Eukaryotic metaphase chromosome. (1) Chromatid, (2) Centromere, (3) Short or p arm (p), and (4) Long or q arm. [Source: Wikimedia, CC-BY-SA]
  • 2. Syed Muhammad Khan (BS Zoology) Page | 2 Based on the position of the centromere, a chromosome may either be acrocentric (one very short arm and one very long one), metacentric (centromere in the middle, equal length of arms), sub-metacentric (almost equal length of arms), or telocentric (centromere lies on the tip, only one arm). Figure: The position of centromere affects the morphology of chromosomes. (I) Telocentric, (II) Acrocentric, (III) Sub-metacentric, and (IV) Metacentric. [Source: Wikimedia, CC-BY-SA] SINGLE STRANDED & MULTI STRANDED HYPOTHESES The fibrils of chromosomes are 2 to 4nm in thickness, since DNA is 2nm wide, it can be assumed that a single DNA molecule is present in a single chromosome fibril. The DNA content of chromosome fibrils varies in different species, it is due to two causes: (1) lateral multiplication and (2) tandem duplication. In lateral multiplication, the DNA divides laterally (left/right side) and hence causes multi strandedness in the fibril. Whereas in the tandem duplication, the DNA divides lengthwise and hence retains the single-stranded feature of chromosomes. Generally, the chromosomes are single-stranded (made up of a single linear DNA molecule), this was confirmed by the pulsed gel electrophoresis of the chromatin of Saccharomyces cerevisiae (yeast).
  • 3. Syed Muhammad Khan (BS Zoology) Page | 3 MODELS OF DNA COILING & FOLDING IN CHROMATIN Many models of DNA coiling in chromatin were proposed by scientists, but the two most important ones are: (1) Folded Fiber Model and (2) Nucleosome Model. They are discussed as follows: 1. Folded Fiber Model: This model of DNA folding was proposed by E.J. Dupraw in 1965. This model suggests that the chromatin is tightly folded fiber that consists of a supercoiled DNA histone helix. The DNA was proposed to be the main axis of the structure and the histones were proposed to be bound on the exterior of the DNA coils, i.e. forming a histone shell around the DNA. The only flaw in this model is the fact that it proposes that the DNA is covered, but this cannot be true if the DNA is to express itself which can only be possible if the DNA is exposed. 2. Nucleosome Model: Another model of DNA folding was proposed by R.D. Kornberg in 1974, this model proposed that the DNA wraps around almost an equal mass of histone proteins to form a structure called a nucleosome. Contrary to the folded fiber model, the nucleosome model suggests that the DNA is exposed and available for genetic expression (not covered by histones). This model was confirmed in 1975 by P. Oudet and his colleagues. There are two major components of the nucleosome: (1) histone proteins and (2) DNA. There are four nucleosome histones: H2A, H2B, H3, and H4 (core histones); 2 copies of each of these proteins are present in one nucleosome, in the form of an octamer. The DNA molecule then wraps around this octamer 1.65 times. The DNA then extends as a single fiber to another octamer to form another nucleosome. The DNA in between two nucleosomes (linker DNA) is sealed by another histone protein – H1 (linker histone). Thus each nucleosome has a diameter of 11-nm and a height of 5.7-nm and the chromatin appears as a "beads on a string" like structure. Histones are basic; they have many positively charged amino acids in them, i.e. Lysine, Arginine, etc. At normal pH of the cell, these amino acids have a positive charge, hence rendering a positive charge on the histones, which facilitates their binding with the negatively charged (acidic – phosphate) DNA molecule. The non-
  • 4. Syed Muhammad Khan (BS Zoology) Page | 4 histones are negatively charged proteins; they bind with the positively charged histones of the nucleosome. Figure: Structural configuration of a nucleosome. [Source: Wikimedia, CC-BY-SA] STAGES OF CHROMOSOME PACKAGING The nucleosome (11-nm) is the first stage of chromatin packaging; it has to undergo much coiling and folding to ultimately become a highly compact 1400-nm thick chromosome, able to fit within the nucleus. The stages of chromatin packaging are as follows: 1. Nucleosome [10-nm fiber]: This is the basic level of chromatin packaging. When nucleosomes are in close apposition, they form 10-nm fibers. These fibers are 5 to 7 times more compact than free DNA. But still, this fiber cannot fit inside the nucleus. It must undergo further coiling. 2. Solenoid [30-nm fiber]: The nucleosomes undergo folding in a helical manner and become closely packed in a 30-nm fiber called a solenoid. A solenoid has 6 nucleosomes per turn and is 40
  • 5. Syed Muhammad Khan (BS Zoology) Page | 5 times more compact than a free DNA molecule. The solenoid fiber is found in interphase chromatin and metaphase chromosomes. The H1 histone aids in the packing of nucleosomes in the 30nm fiber. The chromatin at this stage is 0.1cm long. 3. Looped Domain / Radial Loops [300-nm fiber]: The solenoid fiber (30-nm) forms radial loops that extend at an angle from the main chromosome axis. The DNA binding proteins clamp two regions of the solenoid together by recognizing a specific DNA sequence that will form the neck of each loop. The loops are based on a scaffold (non-histone protein base). The chromatin at this level is 300-nm in diameter. 4. Condensed Loop / Chromatid [700-nm fiber]: The scaffold with a loop of solenoid on it, itself start folding in the form of loops and forms a 700-nm fiber. This fiber is the chromatid, two of which are present in the metaphase chromosome. 5. Metaphase Chromosome [1400- nm fiber]: Two chromatids of 700-nm each join at a centromere, to form a metaphase chromosome that is 1400-nm thick. The chromatin, in this form, is said to be transcriptionally inert (cannot be transcribed) due to a high level of packing. Figure: Formation of 30-nm fiber. [Source: Wikimedia, CC-BY-SA)
  • 6. Syed Muhammad Khan (BS Zoology) Page | 6 Figure: The process of chromosome folding. [Source: Wikimedia, CC-BY-SA]
  • 7. Syed Muhammad Khan (BS Zoology) Page | 7 EUCHROMATIN & HETEROCHROMATIN Depending on the extent of packaging, chromatin can be classified as either (1) euchromatin or (2) heterochromatin. Euchromatin (true chromatin) is relatively less tightly bound, its DNA is available for genetic expression, i.e. it can be easily uncoiled for transcription. It stains lightly as compared to heterochromatin. Figure: Locations of euchromatin and heterochromatin inside a eukaryotic nucleus. [Source: Wikimedia, CC-BY-SA] Heterochromatin is tightly packed and hence it is not easy to open it up for transcription. It also has a lot of repeated DNA sequences (satellite DNA) and very few structural genes (that code for proteins). It is genetically inactive. It stains darker as compared to euchromatin. Heterochromatin may be: around or near nucleolus (nucleolar heterochromatin), in contact with the inner side of the inner membrane of the nuclear envelope (condensed peripheral chromatin), or it may lie between peripheral and nucleolar heterochromatin (dispersed heterochromatin).