Molecular Evolution of an Imprinted Gene: Repeatability of Patterns of Evolution Within the Mammalian Insulin-Like Growth Factor Type II Receptor

Corresponding author: Nick G. C. Smith, Centre for Mathematical Biology, School of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK., n.smith{at}bath.ac.uk (E-mail).

Communicating editor: G. B. GOLDING

The repeatability of patterns of variation in K_a/K_s and K_s is expected if such patterns are the result of deterministic forces. We have contrasted the molecular evolution of the mammalian insulin-like growth factor type II receptor (Igf2r) in the mouse-rat comparison with that in the human-cow comparison. In so doing, we investigate explanations for both the evolution of genomic imprinting and for K_s variation (and hence putatively for mutation rate evolution). Previous analysis of Igf2r, in the mouse-rat comparison, found K_a/K_s patterns that were suggested to be contrary to those expected under the conflict theory of imprinting. We find that K_a/K_s variation is repeatable and hence confirm these patterns. However, we also find that the molecular evolution of Igf2r signal sequences suggests that positive selection, and hence conflict, may be affecting this region. The variation in K_s across Igf2r is also repeatable. To the best of our knowledge this is the first demonstration of such repeatability. We consider three explanations for the variation in K_s across the gene: (1) that it is the result of mutational biases, (2) that it is the result of selection on the mutation rate, and (3) that it is the product of selection on codon usage. Explanations 2 and 3 predict a K_a–K_s correlation, which is not found. Explanation 3 also predicts a negative correlation between codon bias and K_s, which is also not found. However, in support of explanation 1 we do find that in rodents the rate of silent C T mutations at CpG sites does covary with K_s, suggesting that methylation-induced mutational patterns can explain some of the variation in K_s. We find evidence to suggest that this CpG effect is due to both variation in CpG density, and to variation in the frequency with which CpGs mutate. Interestingly, however, a GC4 analysis shows no covariance with K_s, suggesting that to eliminate methyl-associated effects CpG rates themselves must be analyzed. These results suggest that, in contrast to previous studies of intragenic variation, K_s patterns are not simply caused by the same forces responsible for K_a/K_s correlations.

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