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The evolution of isochores

Abstract

One of the most striking features of mammalian chromosomes is the variation in G+C content that occurs over scales of hundreds of kilobases to megabases, the so-called 'isochore' structure of the human genome. This variation in base composition affects both coding and non-coding sequences and seems to reflect a fundamental level of genome organization. However, although we have known about isochores for over 25 years, we still have a poor understanding of why they exist. In this article, we review the current evidence for the three main hypotheses.

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Figure 1: Large-scale variation in G+C content.
Figure 2: Correlation between G+C content of a gene and that of its surrounding region.
Figure 3: The density of Alu and L1 elements in the human genome.

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Acknowledgements

Many thanks to M. Lercher, N. Smith, E. and A. Urrutia. Both A.E.-W. and L.D.H. are supported by the Royal Society, to whom they are grateful.

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Glossary

ALU ELEMENT

A dispersed, intermediately repetitive, 300-bp DNA sequence, 1,000,000 copies of which exist in the human genome.

BIASED GENE CONVERSION

(BGC). Gene conversion is a non-reciprocal recombination process that causes one sequence to be converted into the other. BGC is when the two possible directions occur with unequal probabilities.

BOUNDARY (ISOCHORE)

A genomic region in which base composition changes markedly between regions of homogeneous composition.

CODON USAGE BIAS

Unequal frequencies, in a protein-coding sequence of DNA, of the alternative codons that specify the same amino acid.

CYTOSINE DEAMINATION

The reaction of a water molecule with the amino-group on position 4 of the pyrimidine ring of cytosine, which results in the conversion of cytosine to uracil. The deamination of methyl-cytosine converts cytosine to thymine.

DIRECTIONAL SELECTION

Natural selection that acts to promote the establishment of a particular mutation.

EFFECTIVE POPULATION SIZE

(Ne). The size of a population as determined by the number of individuals who contribute to the next generation. Ne is related to, but never exceeds, the actual population size (N).

FIXATION (ALLELE)

When an allele replaces all other alleles in a population, so that its frequency is equal to one (100%).

GENETIC DRIFT

The random fluctuation that occurs in allele frequencies as genes are transmitted from one generation to the next. This is because allele frequencies in any sample of gametes perpetuating the population might not represent those of the adults in the previous generation.

HETERODUPLEX DNA

A double-stranded DNA molecule (or DNA–RNA hybrid), in which each strand is of a different origin.

HOMEOTHERM

An organism that uses cellular metabolism to stabilize its own body temperature.

HOMOLOGOUS RECOMBINATION

The process by which segments of DNA are exchanged between two DNA duplexes that share high sequence similarity.

LINE ELEMENT

Long, interspersed sequences, such as L1, generated by retrotransposition.

NEUTRAL MUTATION

A mutation that is selectively equivalent to the allele from which it arose.

PARALOGUE

A locus that is homologous to another in the same genome.

PSEUDOGENE

A DNA sequence originally derived from a functional protein-coding gene that has lost its function owing to the presence of one or more inactivating mutations.

SILENT CODON POSITION

One at which a nucleotide change is not accompanied by an amino-acid change in the translation product.

SINE ELEMENT

Short, interspersed, repetitive sequences, such as Alu elements, generated by retrotransposition.

SUBSTITUTION

A mutation that has become fixed and, therefore, shows a sequence difference between orthologous sites in different species.

SYNONYMOUS CODON

One at which a nucleotide change does not alter the amino acid encoded.

SYNONYMOUS SUBSTITUTION RATE

The number of synonymous changes per synonymous site.

TRANSITION

A point mutation in which a purine base (A or G) is substituted for a different purine base, and a pyrimidine base (C or T) is substituted for a different pyrimidine base; for example, an AT→GC transition.

TRANSVERSION

A point mutation in which a purine base is substituted for a pyrimidine base and vice versa; for example, an AT→CG transversion.

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Eyre-Walker, A., Hurst, L. The evolution of isochores. Nat Rev Genet 2, 549–555 (2001). https://doi.org/10.1038/35080577

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