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The CpG dinucleotide is present at -20% of its expected frequency in vertebrate genomes, a deficiency thought due to a high mutation rate from the methylated form of CpG to TpG and CpA. We examine the hypothesis that the 20% frequency represents an equilibrium between rate of creation of new CpGs and accelerated rate of CpG loss from methylation. Using this model, we calculate the expected reduction in the equilibrium frequency of the CpG dinucleotide and find that the observed CpG deficiency can be explained by mutation from methylated CpG to TpG/CpA at -12 times the normal transition rate, the exact rate depending on the ratio of transitions to transversions. The observed rate of CpG dinucleotide loss in a human a-globin nonprocessed pseudogene, Weal, and the apparent replenishment of the CpG pool in this sequence by new mutations, agree with the above parameters. These calculations indicate that it would take 25 million years or less, a small fraction of the time for vertebrate evolution, for CpG frequency to be reduced from undepleted levels to the current depleted levels.It is generally accepted that methylcytosine mutates at a high rate to thymine (1,2). Because methylcytosine in vertebrate DNA exists primarily in the dinucleotide CpG, the net result is an increase of the dinucleotide TpG and its complementary pair CpA (3). It is this mechanism that is held responsible for the observed deficiency ofthe CpG dinucleotide in vertebrate genomes (4,5). This supposition is sustained by the observation that the extent of CpG deficiency and of the corresponding TpG/CpA excess is proportional to the level of DNA methylation in a variety of animals (3). The correlation can also be seen within the mammalian genome, where the small fraction of DNA that escapes methylation (the so-called "CpG island" fraction) fails to show any CpG deficiency (6-8). When a CpG island becomes methylated, however, as has happened at a pseudogene in the human a-globin region, CpGs are lost to TpG/CpA at a comparatively high rate (9). The instability of methylated CpG is directly evident from the preferential detection of restriction fragment length polymorphisms with enzymes that recognize CpG (10) and from the frequency with which CpG -+ TpG/CpA transitions are responsible for human genetic disorders (11).Continued unidirectional mutation, in the absence of selection against genetic changes, might be expected to lead eventually to the complete depletion ofthe CpG dinucleotide. From this viewpoint the level of CpG in the genome has steadily declined since ancestral genomes first became heavily methylated, and a still lower CpG frequency is ultimately to be expected (12). An alternative view, which we examine here, is that the present CpG deficiency represents an equilibrium state. This model takes into account the fact that mutation continually leads to the production of the CpG dinucleotide and should, therefore, generate a balance between rapid rate of CpG loss and rate of CpG creation. Equilibrium would also occur were loss of ...

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A syndrome of associated aberrant traits is described in Drosophila melanogaster. Six of these traits, mutation, sterility, male recombination, transmission ratio distortion, chromosomal aberrations and local increases in female recombination, have previously been reported. A seventh trait, nondisjunction, is described for the first time. All of the traits we have examined are found nonreciprocally in F1 hybrids. We present evidence that at least four of the traits are not found in nonhybrids. Therefore we have proposed the name hybrid dysgenesis to describe this syndrome.—A partition of tested strains into two types, designated P and M, was made according to the paternal or maternal contribution required to produce hybrid dysgenesis. This classification seems to hold for crosses of strains from within the United States and Australia, as well as for crosses between strains from the two countries. Strains collected recently from natural populations are typically of the P type and those having a long laboratory history are generally of the M type. However, a group of six strains collected from the wild in the 1960's are unambiguously divided equally between the P and M types. The dichotomy of this latter group raises interesting questions concerning possible implications for speciation.—Temperature often has a critical effect on the manifestation of hybrid dysgenesis. High F1 developmental temperatures tend to increase the expression of sterility, sometimes to extreme levels. Conversely, low developmental temperatures tend to inhibit the expression of some dysgenic traits.—There are potentially important practical implications of hybrid dysgenesis for laboratory experimentation. The results suggest that care should be exercised in planning experiments involving strain crosses.