Genome organization

Few disciplines are more burdened with jargon than molecular genetics. This is partly due to a proliferation of molecular techniques, but it is also partly intrinsic to the subject; the only unifying principle is evolution, which often operates in a very ad hoc fashion. Biological solutions to the problems posed by selection result in the adaptation of existing structures to new uses, rather than to the invention of purpose-built systems. Nowhere is this more true than at the level of the genome which, rather than being an efficiently organized plan of the organism consisting of precise drawings, resembles a working copy written over countless rough drafts and discarded versions, among which there are literally thousands of jottings and scribbles, mostly irrelevant to the final structure.

DNA within cells is packaged into chromosomes in the cell nucleus, with a tiny amount (16 569 bases containing 37 genes) in the mitochondria. Since mitochondria in the fertilized egg are maternally derived, mitochondrial inheritance is through the female lineage. Although small, mitochondrial disorders contribute substantially to degenerative disorders including ageing.(7) More important is nuclear DNA. The total size of the nuclear genome is approximately 3000 million bp (megabases) and codes for between 65 000 and 100 000 genes. Only 3 per cent of the genome codes for protein. Perhaps 90 per cent of nuclear DNA has no function, consisting primarily of repetitive sequences.

Nuclear DNA is contained in the 22 pairs of chromosomes (the autosomes), one inherited from the mother and one from the father, and the two sex chromosomes, X and Y. Each chromosome pair exchanges stretches of DNA during sexual division (meiosis) in a process called recombination (without which genetic mapping, the basic method of finding disease genes, would be impossible).

Chromosomes have three functional elements: origins of replication, centromeres, and telomeres. Replication origins are required to initiate DNA replication and maintain chromosome copy number. Their molecular structure is unknown. Centromeres are responsible for the segregation of chromosomes during cell division. Their molecular nature is also not understood, but they are visible in light microscopy as a constriction where the duplicated chromosomes (called chromatids) are held together. Chromosomes are said to have two arms, separated by the centromere which, despite its name, is not always at the centre. Short arms are termed p (petit) and long arms q (queue). Telomeres are the ends of chromosomes and their molecular nature is well understood. They consist of long stretches of the sequence TTAGGG without which the chromosome is unstable, tending to break apart and fuse with itself or to other chromosomes.

No one has found any general principles that organize genetic material within chromosomes. While there are examples of gene families clustered in the same chromosomal location (for instance genes involved in immune regulation are clustered on chromosome 6p), more commonly the position of genes on chromosomes does not reflect functional similarity. For example, the most complete structural and functional analysis to date of a large region of human genomic sequence (the terminal region of chromosome 16p) shows that genes expressed only in erythroid tissue are immediately adjacent to widely expressed housekeeping genes. (8)

Figure.3 shows the organization of genes at the end of chromosome 16p and summarizes many of the points made here. It highlights our poor understanding of the relationship between genome structure and function, for, despite extensive characterization of the region, we know the function of only a few of the genes shown. Potential binding sites for regulatory proteins are scattered across the region, with no apparent logic. The major regulatory element for the a-globin genes (which encode one half of the oxygen-transporting protein haemoglobin) lies within an intron of another gene (of unknown function). Similar pictures of genome organization are emerging from analysis of other regions of the genome.

Trisomy 16p

Fig. 3 The relationship between chromosome structure and function at the end of chromosome 16p. The oval on the left of the figure indicates the telomere (the end of the chromosome). Boxes above the line indicate genes transcribed towards the centromere and boxes under the line indicate genes transcribed towards the telomere. Black boxes are tissue-specific genes: the four a-globin-like genes (one z, two a, and one q gene) and a liver-specific gene (an inhibitor of the dissociation of guanine diphosphate from rho). Grey boxes are ubiquitously expressed genes. The distinction between introns and exons is not shown. The function of only some genes is known, as indicated on the figure. Apart from the globins, we are confident of the function of only four genes (the DNA repair enzyme, protein disulphide isomerase, the inhibitor of guanine diphosphate dissociation, and axin). The function of a few others is inferred from sequence analysis, but for the remainder we have no clue at all. Two sorts of putative control regions are indicated. Above the line, arrows indicate regions devoid of nucleosomes where regulatory proteins may bind. They fall into two classes, those present in every tissue (constitutive) and those present only in erythroid tissues (erythroid specific). Note that the latter extend well beyond the region containing the a-globin genes. Underneath the line are shown the position of CpG islands (as defined in Fig 1).

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