Medical implications of HGP's sequence of chromosome 22

Abstract

The Human Genome Project (HGP) has now reported its first DNA sequence, that of human chromosome 22.1Dunham I Shimizu N Roe BA et al.The DNA sequence of human chromosome 22.Nature. 1999; 402: 489-495Crossref PubMed Scopus (906) Google Scholar This sequence contains at least 525 genes, perhaps 1000, many of which may be of intense medical interest. One important facet of the HGP is the identification, from the novel sequence data, of new genes. Understanding the molecular basis of a disease is seen as the route to fresh diagnostic and therapeutic strategies. But can we be fully confident that genes predisposing to disease will always be detected by the HGP? First, we must look carefully at the methods used. Every diploid human cell contains two copies of chromosome 22. The DNA sequence of these two chromosomes is not identical and represents the genes inherited from each parent. Let us suppose that a gene on one chromosome has become deleted somewhere back down the family tree and that this part of chromosome 22 has been sequenced by the HGP team. This gene may have important medical ramifications, yet to be discovered. Is it possible that this important piece of molecular medicine would have escaped detection by HGP? CYP2D6 is a highly polymorphic human gene with many medical consequences and which was first reported over two decades ago.2Mahgoub A Idle JR Dring LG Lancaster R Smith RL Polymorphic hydroxylation of debrisoquine in man.Lancet. 1977; ii: 584-586Summary Scopus (1003) Google Scholar CYP2D6 plays an important role in many adverse drug reactions3Hadidi H Guzey C Idle JR Pharmacogenetics and toxicological consequences of human drug oxidation and reduction.in: Ballantyne B Marrs T Syversen T General and applied toxicology. second edn. Macmillan Reference, Basingstoke1999: 215-250Google Scholar and has been implicated in increased susceptibility to various cancers and to Parkinson's disease.3Hadidi H Guzey C Idle JR Pharmacogenetics and toxicological consequences of human drug oxidation and reduction.in: Ballantyne B Marrs T Syversen T General and applied toxicology. second edn. Macmillan Reference, Basingstoke1999: 215-250Google Scholar The genomic sequence has been established, CYP2D6 occurring downstream on chromosome 22 from two related but inactive genes CYP2D7 and CYP2D8P.4Kimura S Umeno M Skoda RC Meyer UA Gonzalez FJ The human debrisoquine 4-hydroxylase ( CYP2D ) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene.Am J Hum Genet. 1989; 45: 889-904PubMed Google Scholar At least 74 CYP2D6 alleles (http://www.imm.ki.se/cypalleles/cyp2d6.htm, accessed Jan 11, 2000) are responsible for the 200-fold variability in metabolism of probably 100 or more drug and chemical substrates to which humans can be exposed. Most of the known variant alleles are inactive and give rise to the poor metaboliser (PM) phenotype, which constitutes 1–19% of human populations.3Hadidi H Guzey C Idle JR Pharmacogenetics and toxicological consequences of human drug oxidation and reduction.in: Ballantyne B Marrs T Syversen T General and applied toxicology. second edn. Macmillan Reference, Basingstoke1999: 215-250Google Scholar One of these, CYP2D6*5, comprises a 12-1 kb deletion that includes the entire CYP2D6 gene,5Steen VM Molven A Aarskog NK Gulbrandsen A-K Homologous unequal cross-over involving a 2-8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytochrome P450 CYP2D6 gene.Hum Mol Genet. 1995; 12: 2251-2257Crossref Scopus (68) Google Scholar and is the second most common inactivating allele in the UK population.3Hadidi H Guzey C Idle JR Pharmacogenetics and toxicological consequences of human drug oxidation and reduction.in: Ballantyne B Marrs T Syversen T General and applied toxicology. second edn. Macmillan Reference, Basingstoke1999: 215-250Google Scholar The sequence of chromosome 22 that HGP has deposited on the internet (http://www.sanger.ac.uk/HGP/Chr22/, accessed Jan 4, 2000) carries the CYP2D6*5 allele (ie, does not contain the CYP2D6 gene). Fortunately, this gene locus has been very well studied. But what of the thousands of yet undiscovered genes that are the mission of the HGP? Gene deletion is not an uncommon form of human polymorphism. Given the problems that Dunham and colleagues discuss1Dunham I Shimizu N Roe BA et al.The DNA sequence of human chromosome 22.Nature. 1999; 402: 489-495Crossref PubMed Scopus (906) Google Scholar in ab initio gene prediction from new DNA sequence data, we believe there is a strong possibility that some new human genes of medical importance will be missed by HGP simply because nature has chosen to delete them on one of our pair of chromosomes, as was the case with CYP2D6. Clearly failsafe procedures will be required to minimise this possibility.