Human Molecular Genetics, 2003, Vol. 12, No. 7 699
DOI: 10.1093/hmg/ddg095
© 2003 Oxford University Press
Editorial
The first issue of Human Molecular Genetics which came out in April 1992 included papers on genetic mapping of monogenic disease loci, disease mutation reports and somatic cell hybrid mapping, very much the hot topics of the day. Today the work of the molecular geneticist has moved into an age where the emphasis is much more on the functional studies of disease genes and the genetic mapping of complex disease. The biggest driver of this change has been the availability of genome sequence. First came the relatively simple genomes of bacteria and pathogens quickly to be followed by sequences of yeasts, a nematode worm, a fruit fly, plants, and, of course, human. This information has had an enormous impact on our understanding of many human disorders where the mutated genes have orthologues in these organisms. The review issues of Human Molecular Genetics over the last two years have reflected this change, describing progress in the understanding of disease processes taking advantage of the genetic tools and sequence information now available. However, the recent publication of the mouse genome sequence promises to have an even greater impact since so many useful models of human biology can be generated in the mouse. We finally have the tools to relate gene sequence to the function of the whole organism as highlighted by the special review article by Emes and colleagues in this issue.
The mouse genome sequence was eagerly awaited because of the advent of mouse genome mutagenesis programmes which generate phenotypes of interest to human geneticists. Moving from a genetically defined position on a chromosome to a candidate gene is now much less arduous, with time frames reduced from years to a matter of weeks or months. The comparison of the human and mouse genome sequence is a powerful method to identify candidate genes. Furthermore, evolutionary conserved positions can highlight the possible location of disease-causing mutations, as there is over-representation of amino acid changes causative in human disease at such conserved positions. This is a particularly important advantage, because of the high degree of polymorphism in the human genome that can confound efforts to convincingly distinguish potentially pathogenic changes from neutral ones. Eleven years on, papers in this journal now not only contain the identification of the causative gene, but also some important early indications of the function.
As pointed out by Emes and colleagues in this issue, the differences in genomes can provide valuable information about the physiology and behaviour of an organism. For example, the mouse, compared with man, has expanded several gene families that are involved in reproduction and the immune response. In addition, the conservation of sequences between man and mouse makes mouse an excellent model of human pathology. The new genomes provide not only substantive new information on single genetic loci (sparing the labour of geneticists in positional cloning of disease genes), but also the comprehensive gene set that allows holistic views to be taken. Genomes are more than the sum of their genes. Hence, medical research is increasingly reliant on evolutionary biology to assist the investigation of human disease gene function. New computational tools will need to be developed to compare the increasing volume of data from the many genome sequences available and to model the complexities of molecular evolution. The human (or mouse!) molecular geneticist will now need to work closely with the evolutionary biologist. As Theodosius Dobzhanksky said, ‘Nothing in biology makes sense except in the light of evolution’.
Human Molecular Genetics endeavours to keep pace with the ever changing world of human genetics and now genome biology. The next decade of publishing in this field, which now encompasses functional genetics and comparative computational genetics, promises to be even more exciting and challenging. Supported (and challenged) by technical advances in the new era of electronic publishing, we look forward to keeping pace with it!
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