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polyploidy and persistent genes hasinfluenced eukaryotic evolution sincethe nuclear genome originated. Para-logous gene families are found in allwell-studied eukaryotes and manyancient eukaryotic multigene familiesprobably arose primarily throughpolyploidy too.

To summarize, there is no needto invoke mechanisms that activelyselect for redundant genes to accountfor the extensive redundancy observedin vertebrate genomes. Rather, thepresent-day redundancy is simply aconsequence of ancestral polyploidy,coupled with the very slow elimi-nation, or gradual divergence, of theextra copies of certain classes of genethat do not tolerate deleterious pointmutations in the coding sequence.

AcknowledgementsWe thank K. Wolfe, D. Shields and

many colleagues at EMBL in the struc-tures, gene expression and cell diff-erentiation programmes for comment-ing on the ideas in this manuscript.

References1 Cooke, J. et al. (1997) Trends Genet.

13, 360–3642 http://www.gdb.org/Dan/tbase/

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(1996) Trends Genet. 12, 117–1184 Pieretti, M. et al. (1991) Cell 66,

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11 Lowell, C.A. and Soriano, P. (1996)Genes Dev. 10, 1845–1857

12 Xu, W., Harrison, S.C. and Eck, M.J.(1997) Nature 385, 595–602

13 Twamley-Stein, G.D. et al. (1993)Proc. Natl. Acad. Sci. U. S. A. 90,7696–7700

14 Ohno, S. (1985) Trends Genet. 1,160–164

15 Kimura, M. (1983) The NeutralTheory of Molecular Evolution,Cambridge University Press

16 Aparicio, S. et al. (1997) Nat. Genet.16, 79–83

17 Holland, P.W.H. (1997) Curr. Biol.7, 570–572

18 http://www.unibas.ch/dib/zoologie/research/spring.html

19 Spring, J. (1997) FEBS Lett. 400, 2–820 Ohno, S. (1970) Evolution by Gene

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Reply to Toby Gibson and Jürg SpringJONATHAN COOKE

j-cooke@ns1.nimr.mrc.ac.uk

NATIONAL INSTITUTE FOR MEDICAL RESEARCH, THE RIDGEWAY, MILL HILL, LONDON, UK NW7 1AA.

Gibson and Spring add a most inter-esting contribution to thinking aboutgenetic redundancy. They proposethat the accumulation of mutations in some genes (which have becomeredundant by duplication) occursmuch more slowly than predicted byOhno et al.1 if those genes encodeproteins that interact with multipleother molecules. The widespread per-sistence of such redundant duplicateswould therefore need no further ex-planation. This is because for suchgenes, the great majority of codingpoint mutations might be stronglyselected against because they givethe protein a competitive ‘dominant-negative’ interfering effect in relationto the normally functioning productor its relatives in the cell.

I agree that this could have beenof importance because many (usu-ally intracellularly acting) gene prod-ucts might partake of this property. Ihave even heard (somewhere) the

intellectually related proposal, thatcomplex cells contain so many proteinstructures that each must be undercontinual constraining selection toavoid acting as, in effect, an inadvert-ent precipitating antibody to one ofthe others! However, it is unlikely thatthis insight does, as they seem to feel,altogether ‘obviate the problem’ ofinvoking selective mechanisms formaintenance or evolution of the re-dundancy phenomena described byCooke et al.2 (not that we ourselves areconfident that our ideas are necessarily‘right’). Genes vary widely as to howmuch they might be expected to ex-hibit Gibson and Spring’s ‘dominant-negative constraint’ effect; a minority(including, certainly, their oncogeneexamples) can exhibit it strongly,while many (probably most enzymes,for example) will exhibit it little or notat all. Most genes perhaps will haveparticular, limited relative incidencesof dominant interfering mutations and

in this regard these authors’ illustra-tive use of the duplicated HOX-typehomeobox transcription factors isinteresting. Such dominant effects areindeed known in homeoproteins but,as in most classes of transcription fac-tor, constitute a small proportion of allpoint mutations. Large stretches of thesequence of vertebrate HOX para-logues outside the DNA-binding do-main indeed show evolutionary driftrates that approximate the baseline‘molecular clock’ and thus reveal littleconstraint. The evidence is that verte-brate duplicates in the ancestral HOMcomplex, both within the cluster andthen into the replicate clusters of ‘para-logues’, have been supported by posi-tive selection in terms of the additionalcomplexity of body regionalizationthus allowed for. The latter has oc-curred through subtle divergence inboth the expression domain of theduplicates and probably the batteriesof downstream genes controlled by

Genetics in profileIBC’S CONFERENCE ON GENETIC PROFILING AND DIAGNOSTICS, SAN DIEGO, CA, USA, 29–30 OCTOBER, 1997.

The scientific platform for this meet-ing was recent technological advancesthat offer the potential to assess theintegrity of the genome and patternsof gene expression in a comprehen-sive manner and to apply that knowl-edge to disease characterization andmanagement (for additional discus-sion of comprehensive gene expres-sion technologies see Refs 1, 2). Thiswould be a particularly important ad-vance for diseases, such as cancer,that can arise through diverse mol-ecular mechanisms influenced byenvironmental factors. Whereas can-cer is, at present, most often classifiedby body location and histology, it isclear that tumors that appear similarcan be profoundly different at the mol-ecular level, requiring different dis-ease management strategies. Although

excellent progress has been made inidentifying genes associated with can-cer and other complex human dis-eases, the new technologies offer thepromise of looking much more exten-sively to identify additional geneticchanges associated with these dis-eases. The hope is that by character-izing all changes related to the gen-ome, and comparing disease andnormal states, key indicators, or finger-prints, will be identified that can formthe basis for all phases of diseasemanagement, including risk assess-ment, prevention, early detection,diagnosis, prognosis and develop-ment of therapeutic strategies.

Underlying the new scientificopportunity are limited numbers ofdocumented examples of specificgenetic changes related to cancer that

are informative for disease prognosisand potential response to therapeuticregimes. That such examples alreadyexist raises the hope that by casting amuch wider net we will be betterpositioned to identify the most infor-mative genetic features related to dis-ease origination and progression (foradditional perspectives on geneticprofiling as applied to cancer seeRefs 3, 4).

Conference attendees were treatedto dazzling exhibits of new technol-ogies that offer the promise of assayingthe expression of all cellular transcripts(including transcript processing) inparallel. These technologies rangefrom oligonucleotide and cDNA arrayson various types of solid supports, tomass spectrometric and gel-based ap-proaches (Fig. 1). The degree of so-phistication already developing aboutthe issues associated with applyingthe new approaches to understandinghuman disease was particularly strik-ing. For example, while it seems likelythat gene expression profiling at thetranscript level will provide valuableinsight, it was also recognized thatwithout similar tools for protein analy-sis the full potential of genetic profil-ing would not be realized. It is alreadyknown that in cancer some importantevents are directly correlated withpost-translational processing of pro-teins. While tools for comprehensiveprotein analysis are at a relatively earlystage of development, there is cer-tainly the vision of new technologicalapproaches for profiling of cellularproteins. These include technologiesfor (1) identifying all expressed pro-teins and their post-translational modi-fications (two-dimensional gels cou-pled with mass spectrometric analysis);(2) deciphering protein networks

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them. Thus, while double knockoutsof HOX paralogues can certainly showa superadditive phenotype (reveal-ing redundant role overlap) no cur-rently available HOX null mutant isentirely phenotypeless. Space had

constrained us from considering themin our article, but the HOX gene clus-ters, though a special case, support thescenario of selection-mediated survivalof duplicates, with genuinely redun-dant genes being of rare incidence.

References1 Ohno, S. et al. (1985) Trends Genet.

1, 160–1642 Cooke, J., Nowak, M.A., Boerlijst, M.

and Maynard-Smith, J. (1997) TrendsGenet. 13, 360–364

Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0168-9525/98/$19.00PII: S0168-9525(97)01366-8

MEETING REPORTS

Unique repressed

Inte

nsity

Inte

nsity

Unique induced

Normal cell line

Genes

Malignant cell line

Upregulated

Dow

nreg

.

FIGURE 1. DNA microarrays can be used to monitor differential gene expression in tumorcells (in this case breast cancer) versus normal cells. Data from Affymetrix’ human

expression array, courtesy of David Mack, PhD, Affymetrix, Inc.