Eukaryotic chromosomes

If all the DNA in the nucleus of a human cell were laid out in a linear fashion, it would stretch more than 1 metre in length. Yet all this DNA has to be packaged into a nucleus that is less than 1 μm in diameter. To deal with this packaging problem, the genomic DNA becomes so condensed that it can be stored in one subcellular compartment, the nucleus. How does this condensation occur?

Chromosomes are not made of naked DNA but instead consist of chromatin, a complex of DNA and scaffolding proteins known as histones (Fig 22-1). These proteins form the structure on which the DNA can be wound, then coiled, and finally super-coiled. Initially the DNA in its double helical form is wound around core histones to form nucleosomes (diameter 10 nm). These structures look like a string of beads with some DNA tightly wound around a collection of histones then separated by a stretch of naked DNA before it winds around the next group of histones. Another specific protein, histone H1, is then added, which results in the nucleosomes associating closely to form a chromatin fibre (diameter 30 nm). More scaffolding proteins are then added and the fibre becomes super-coiled. Chromosomes vary in size and shape but each has several distinctive features (Fig 22-2). DNA replication produces pairs of identical sister chromatids, each of which generally carry the same genetic information. In metaphase, the chromatids interact at a point along their structure to form an X-shaped chromosome. This joining-point is referred to as the centromere. The position of the centromere can vary so the arms that are formed from a chromatid are not generally of equal length, though their position is always at the same point on each type of chromatid. Each of the arms of the chromosome carries a cap called a telomere, which protects the DNA strand from damage. These telomeres use a unique replication machinery that differs from the rest of the chromosome.

FIGURE 22-1 How DNA is condensed to make chromosomes. Initially DNA is wound around core histones, proteins that are highly positively charged to interact with the negatively charged phosphate groups in the backbone of the DNA. Addition of histone H1 helps to stabilise the nucleosomes formed around the core histones such that the DNA can be coiled more tightly. Super-coiling occurs following the addition of other scaffolding proteins to produce a recognisable chromosome.

[Based on Baynes & Dominiczak, 2009, Medical Biochemistry, 3rd edition, Mosby]

FIGURE 22-2 Critical features of eukaryotic chromosomes. Eukaryotic chromosomes are made from two sister chromatids joined at a centromere. The ends of the ‘arms’ carry a protective cap referred to as a telomere.

Different organisms have different numbers of chromosomes in their genetic composition (Table 22-1). The number can vary greatly and does not necessarily reflect the complexity of the organism. Thus, for example, a kingfisher has more than twice as many chromosomes as a human. The entire chromosome complement of an individual is referred to as a karyotype, which can be observed during mitotic metaphase, and is useful in the clinical setting. In most cases this is done by taking some cells from the individual (e.g. blood containing nucleated white cells), stimulating them with a drug to induce cell division, then processing the cells to see their chromosomes. A digital photograph of the chromosomes is then analysed by computer and the chromosomes sorted according to size and shape (Fig 22-3). The chromosomes can be stained to allow their finer details to be analysed. In humans, 44 of the 46 chromosomes in each cell can be sorted into 22 pairs of homologous chromosomes. Each of these pairs consist of chromosomes that are the same size, stain identically, have their centromeres in the same position, and carry information (i.e. the same genes) for the same inherited characters. However, the other two chromosomes cannot be placed in a matched pair because they are the ones which determine gender, the sex-determining chromosomes, of which there are two types, X and Y. A female has two X chromosomes whereas a male has one X and one Y chromosome. The other 22 pairs do not determine gender and are referred to as autosomes. These pairs of chromosomes are derived from the way in which we inherit genetic information from our parents (see below), with one of each pair of chromosomes originating from each parent.

TABLE 22-1 The number of chromosomes for different animals

Animal	Number of chromosomes
Common fruit fly	8
Chinese hamster	22
Common earthworm	36
Laboratory mouse	40
Rabbit	44
Humans	46
Sheep	54
Dog	78
Cow	60
Horse	64
Goldfish	100–104
Kingfisher	132

Note: The number of chromosomes required by each type of animal can vary greatly and does not seem to be related to its complexity.

FIGURE 22-3 Human karyotypes. The karyotypes of males and females are essentially similar except for the presence of two X chromosomes in the female, and a single X plus a Y chromosome in the male. All the other chromosomes are essentially the same since they do not determine gender.

[Based on Kronenberg, 2008, Williams Textbook of Endocrinology, 11th edition, Saunders]

The cell cycle

The vast majority of cells in the human body, which are referred to as somatic cells, are in the diploid state (2n). This means that they contain two complete genomes, in humans 46 chromosomes. Dividing cells exist in a series of defined states which together constitute the cell cycle (Fig 22-4A). For about 90% of the time most cells are in the stage referred to as interphase, during which the cell enlarges and copies its DNA in preparation for cell division. Interphase itself can be divided into three sub-stages: the G₁ phase (1st gap), the S phase (synthesis), and the G₂ phase (2nd gap). During all three of these sub-stages the production of new proteins and organelles proceeds but it is only in S phase that DNA synthesis, or replication, occurs. After completion of the interphase stage the cell undergoes mitosis, with the whole process from start to finish taking roughly 24 hours for rapidly dividing human cells (e.g. those of the skin, oral cavity, alimentary tract and vagina) (Fig 22-4B). However, a number of cells divide very slowly (e.g. those of the liver, pancreas and kidney) or not at all (e.g. cardiac and skeletal muscle or nervous tissue) over the course of a lifetime. These cells spend most of their lives in what is referred to as the G₀, or resting phase.