Mendel stayed home

J.S. Haldane said that he would give his life to save three drowning brothers or nine first cousins, but what about three half-brothers? Yes, if they are maternal, because of asymmetric survival advantages of maternally and paternally transmitted genes, said David Haig (Harvard University, USA) at this recent conference on genomic imprinting (reviewed in 1xGenomic imprinting in mammals. Bartolomei, M.S. and Tilghman, S.M. Annu. Rev. Genet. 1997; 31: 493–525Crossref | PubMed | Scopus (437)See all References, 2xCreation of genomic methylation patterns. Bestor, T.H. and Tycko, B. Nat. Genet. 1996; 12: 363–367Crossref | PubMedSee all References) organized by Randy Jirtle (Duke University, USA) and cosponsored by the US National Institute of Environmental Health Sciences (NIEHS). The conference was not meant to be comprehensive, for example, the SNRPN crowd was not there, but there was an excitement caused, I believe, by the perception that imprinting challenges the classical view of genetics, that is, the study of inheritance of traits, which was thought to be a dead issue until recently.The atmosphere among non-mendelian biologists resembles what I have read about non-newtonian physics in the early part of the century. I would like to use the topics of this meeting to draw some parallels between the two eras. First is an unconventional view of the fabric of the system, in this case the idea of gene regulation at a domain or chromosomal level rather than at the gene itself. For example, Mitsuo Oshimura (Tottori University, Japan) reported that an imprinted chromosome can be moved by microcell transfer to an EC cell, where allele-specific expression and methylation are lost, but they are re-established on differentiation. Similarly, I described loss of imprinting (LOI) of a genomic domain in cancer and Beckwith–Wiedemann syndrome3xLoss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Cui, H. et al. Nat. Med. 1998; 4: 1276–1280Crossref | PubMed | Scopus (245)See all References3. Oshimura drew a dramatic parallel between the cell background-induced plasticity of domain-wide imprinting he sees, and the domain-wide reversibility of LOI our laboratory finds using inhibitors of DNA methylation.Second, imprinting, like modern physics, appears to require a fusion of separate disciplines to be understood. These include mathematical genetics, embodied by Haig and Carmen Sapienza (Temple University, USA), the latter of whom mapped an X-linked locus that causes X-chromosome transmission ratio distortion among male offspring when improperly imprinted4xParental origin-dependent, male offspring-specific transmission ratio distortion at loci on the human X chromosome. Naumova, A.K. et al. Am. J. Hum. Genet. 1998; 62: 1493–1499Abstract | Full Text | Full Text PDF | PubMed | Scopus (51)See all References4. Imprinting biology is also converging with neuroscience. Paternally expressed genes were linked in novel ways to behavior, by mapping a locus for social skills in Turner syndrome and deletion patients (David Skuse, Institute of Child Health, UK; Ref. 5xEvidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Skuse, D.H. et al. Nature. 1997; 387: 705–708Crossref | PubMed | Scopus (477)See all ReferencesRef. 5), and by knocking out the mouse Peg1 gene (Barry Keverne, University of Cambridge, UK), which impairs maternal nurturing. Indeed, the epigenetic community shows an unusual lack of respect for species boundaries in designing experiments, exceeding the usual confluence of human and mouse systems6xAn imprinting element from the mouse H19 locus functions as a silencer in Drosophila. Lyko, F. et al. Nat. Genet. 1997; 16: 171–173Crossref | PubMed | Scopus (86)See all References6. For example, Max Costa (New York University) has found that nickel-induced carcinogenesis appears to be caused by silencing genes by inducing heterochromatin formation, and he has used yeast telomere silencing to model this effect. Hopefully, NIEHS was listening, since a goal of the meeting was to encourage them to fund additional imprinting research.Third, the observations of the imprinting community, like those of modern physics, continue to startle and demand new theories. For example, Wolf Reik (University of Cambridge, UK) has studied a ‘minute’ mouse from Bruce Cattanach's collection (MRC Harwell, UK), that displays intrauterine growth retardation. This mutation, generated by random radiation mutagenesis, shows single gene paternal transmission and is linked to Igf2 (Ref. 7xGenomic imprinting and the strange case of the insulin-like growth factor II receptor. Haig, D. and Graham, C. Cell. 1991; 64: 1045–1046Abstract | Full Text PDF | PubMedSee all ReferencesRef. 7) but is not within the known sequence of the gene. The maternal H19 allele is abnormally methylated, suggesting a novel mechanism of imprinting control. Shirley Tilghman (Princeton University, USA) examined imprinting of a monogamous strain of the Peromyscus mouse, and it was normal, an unexpected result given Haig's theory that imprinting arose from competition between the parental genomes in polygamous mammals. However, the offspring produced by crosses of the monogamous strain with a polygamous strain were unusually large or unusually small, depending on the direction of the cross, and imprinting in the offspring was disturbed, but not at the genes one would have expected.Fourth, much of imprinting research is directed towards finding these oddly behaving genes, just as much of modern physics was aimed at discovering new elements. Japanese scientists (Takashi Ito, Tokyo University) have contributed yet another method, allelic message display, to this effort, and have found at least one new gene on chromosome 18 (human and mouse).Fifth and finally, imprinting biologists, show a gratifying lack of inhibition at proposing and rejecting models. For example, most participants now accept Shirley Tilghman's model of enhancer competition between IGF2 and H19, but she now questions it. Ben Tycko (Columbia University, USA) suggested that epigenetic mutations can arise by methylation transfer between chromosomes. The point is that the models of imprinting, like those of early 20th century physics, are an essential component of the science, and the models, like the observations, are in flux. For this reason, more than any other, I believe, Randy Jirtle should not have been surprised that his meeting was threefold oversubscribed. Perhaps one lesson of imprinting conferences should be (with apologies to a movie about early 20th century baseball), ‘Bill it and they will come’ (but Mendel won't).