Structure of Human Chromosomes
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P8-10
2025-10-26
73
The composition of genes in the human genome, as well as the determinants of their expression, is specified in the DNA of the 46 human chromosomes in the nucleus plus the mitochondrial chromosome. Each human chromo some consists of a single, continuous DNA double helix; that is, each chromosome is one long, double-stranded DNA molecule, and the nuclear genome consists there fore of 46 linear DNA molecules, totaling more than 6 billion nucleotide pairs (see Fig. 1).
Fig1. The human genome, encoded on both nuclear and mitochondrial chromosomes. (Based on Brown TA: Genomes, ed 2, New York, 2002, Wiley-Liss. Inset from Paulson JR, Laemmli UK: The structure of histone-depleted metaphase chromosomes, Cell 12:817–828, 1977. Reprinted with permission of the authors and Cell Press.)
Chromosomes are not naked DNA double helices, however. Within each cell, the genome is packaged as chromatin, in which genomic DNA is complexed with several classes of specialized proteins. Except during cell division, chromatin is distributed throughout the nucleus and is relatively homogeneous in appearance under the microscope. When a cell divides, however, its genome condenses to appear as microscopically visible chromosomes. Chromosomes are thus visible as discrete structures only in dividing cells, although they retain their integrity between cell divisions.
The DNA molecule of a chromosome exists in chromatin as a complex with a family of basic chromosomal proteins called histones. This fundamental unit interacts with a heterogeneous group of nonhistone proteins, which are involved in establishing a proper spatial and functional environment to ensure normal chromosome behavior and appropriate gene expression.
Five major types of histones play a critical role in the proper packaging of chromatin. Two copies each of the four core histones H2A, H2B, H3, and H4 constitute an octamer, around which a segment of DNA double helix winds, like thread around a spool (Fig. 2). Approximately 140 base pairs (bp) of DNA are associated with each histone core, making just under two turns around the octamer. After a short (20- to 60-bp) “spacer” segment of DNA, the next core DNA complex forms, and so on, giving chromatin the appearance of beads on a string. Each complex of DNA with core histones is called a nucleosome (see Fig. 2), which is the basic structural unit of chromatin, and each of the 46 human chromosomes contains several hundred thousand to well over 1 million nucleosomes. A fifth histone, H1, appears to bind to DNA at the edge of each nucleosome, in the internucleosomal spacer region. The amount of DNA associated with a core nucleosome, together with the spacer region, is approximately 200 bp.
Fig2. Hierarchical levels of chromatin packaging in a human chromosome.
In addition to the major histone types, a number of specialized histones can substitute for H3 or H2A and confer specific characteristics on the genomic DNA at that location. Histones can also be modified by chemical changes, and these modifications can change the properties of nucleosomes that contain them. As discussed further in Chapter 3, the pattern of major and specialized histone types and their modifications can vary from cell type to cell type and is thought to specify how DNA is packaged and how accessible it is to regulatory molecules that deter mine gene expression or other genome functions.
During the cell cycle, as we will see later in this chapter, chromosomes pass through orderly stages of condensation and decondensation. However, even when chromosomes are in their most decondensed state, in a stage of the cell cycle called interphase, DNA pack aged in chromatin is substantially more condensed than it would be as a native, protein-free, double helix. Further, the long strings of nucleosomes are themselves compacted into a secondary helical structure, a cylindrical solenoid fiber (from the Greek solenoeides, “pipe shaped”) that appears to be the fundamental unit of chromatin organization (see Fig. 2.5). The solenoids are themselves packed into loops or domains attached at intervals of approximately 100,000 bp (equivalent to 100 kilobase pairs [kb] because 1 kb = 1000 bp) to a protein scaffold within the nucleus. It has been speculated that these loops are the functional units of the genome and that the attachment points of each loop are specified along the chromosomal DNA. As we shall see, one level of control of gene expression depends on how DNA and genes are packaged into chromosomes and on their association with chromatin proteins in the packaging process.
The enormous amount of genomic DNA packaged into a chromosome can be appreciated when chromosomes are treated to release the DNA from the underlying protein scaffold (see Fig. 1). When DNA is released in this manner, long loops of DNA can be visualized, and the residual scaffolding can be seen to reproduce the outline of a typical chromosome.
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