Biomedical subjects
Publications and source records attributed to G T McVean.
The conflict theory is the only hypothesis to have attracted any critical attention for the evolution of genomic imprinting. Although the earliest data appeared supportive, recent systematic analyses have not confirmed the model's predictions. The status of theory remains undecided, however, as post-hoc explanations can be provided as to why these predictions are not borne out.
Genomically imprinted genes are those for which expression is dependent on the sex of the parent from which they are derived. Numerous theories have been proposed for the evolution of genomic imprinting: one theory is that it is an intra-individual manifestation of classical parent -offspring conflict. This theory is unique in predicting that an arms race may develop between maternally and paternally derived genes for the control of foetal growth demands. Such antagonistic coevolution may be mediated through changes in the structure of the proteins concerned. Comparable coevolution is the most likely explanation for the rapid changes seen in antigenic components of parasites and antigen recognition components of immune systems. We have examined the evolution of insulin-like growth factor Igf2, and its antagonistic receptor Igf2r) and find that in contrast to immune genes, at the sites of mutual binding they are highly conserved. In addition, we have analysed the rate of molecular evolution of seven imprinted genes including Igf2 and Igf2r), sequenced in both mouse and rat, and had that this is the same as that of nonimprinted receptors and significantly lower than that of immune genes controlling for differences in mutation rates. Contrary to the expectations of the conflict hypothesis, we hence find no evidence for antagonistic coevolution of imprinted genes mediated by changes in sequence.
The equilibrium per-genome mutation rate in sexual species is thought to result from a trade-off between the benefits of reducing the deleterious mutation rate and the costs of increasing fidelity. We propose that selection will often favour a lower mutation rate on the X chromosome than on autosomes, owing to the exposure of deleterious recessive mutations on hemizygous chromosomes. We tested this hypothesis by examining 33 X-linked genes that have been sequenced in both mouse and rat, and compared their rate of evolution against 238 autosomal genes. The X-linked genes were found to have a significantly lower rate of synonymous substitution than the autosomal genes. Neither the supposed higher mutation rate in males nor stronger purifying selection against slightly deleterious mutations on the X chromosome can account for the low value. The most parsimonious explanation is that rodents have a lower mutation rate on the X chromosome than on autosomes. It is therefore likely that previous indirect estimates of the excess male mutation rate are inaccurate. Indeed, after correction we find no evidence for a male-biased mutation rate in rodents. Furthermore, the rate of synonymous substitution in Y-linked genes is not significantly different from that in autosomal ones. The extent to which enhanced male mutation rates are problematic for the mutational deterministic model of the evolution of sex must, in turn, be questioned.
While numerous theories have been proposed for the evolution of genomic imprinting, few have been tested. The conflict theory proposes that imprinting is an intra-individual manifestation of classical parent-offspring conflict. This theory is unique in predicting that imprinted genes expressed from the paternally derived genome should be enhancers of pre- and post-natal growth, while those expressed from the maternally derived genome should be growth suppressors. We examine this prediction by reviewing the literature on growth of human and mouse progeny that have inherited both copies (or part thereof) of a particular chromosome from only one parent. Perhaps surprisingly, we find that much of the data do not support the hypothesis.
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Close analysis of intron phase - the position of introns within codons - is claimed to provide novel evidence supporting the view that introns predate the divergence of bacteria and eukaryotes and, via 'exon shuffling', played a crucial role in protein evolution. But just how compelling is this evidence?
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Supernumerary B chromosomes are dispensable elements of the genome which can be retained in populations at high frequencies, despite being deleterious, through the ability to undergo non-Mendelian inheritance. Their mode of origin is, however, obscure. Recent work on gynogenetic fish has demonstrated the incorporation of small, unstable, centromere-containing microchromosomes, probably of interspecific derivation, into an asexual lineage (1). That these resemble B chromosomes both in structure and behaviour is consistent with the proposal that hybridisation between closely related species may be a significant mode of origin for such selfish genetic elements. Additional work on the B chromosome of a parasitoid wasp and observations on patterns of chromosome breakage from somatic cell hybrids also support this hypothesis.