The Genom of Homo sapiens.pdf

500 OLSONwill respond to perturbations. This talk generated a vigorousdiscussion of where we really are on the path fromthe types of heuristic models that have dominated molecularbiology since the early days of the lac operon to truepredictive modeling. During this discussion, Peter Little(Cotsapas et al.) advocated the stringent standard thatpredictions must be non-obvious, quantitative, and falsifiable;speaking for many skeptics, he indicated that hehad yet to see any results from systems biology that meetthis test.This debate captured one clear axis of tension at themeeting. Certainly there was optimism that the referencedata, computational and experimental tools, and globalperspective of genome research will successfully shift thecenter of gravity of biology toward the analysis of increasinglycomplex aspects of life. However, balancing thesense of new possibilities was a clear recognition that thechallenges ahead are immense. Hence, one question thathovered over CSHSQB LXVIII was “If total victory in developinga molecular understanding of life remains a distantdream, what are the more proximate goals of the genomicera?” One answer is that genome researchers mayincreasingly pursue practical goals. In his overview of futuredirections in genome research, Collins (Collins) advocatedan increased focus on achieving medical benefits,and many other speakers described efforts in this direction.HUMAN GENETICSMost medically related genome research continues tobe directed toward the elucidation of pathogenic mechanisms.Although population-based and case-control studiesreceived most of the attention, Porteous (Porteous etal.) described family-based approaches to schizophreniaand bipolar affective disorder. These diseases, and psychiatricdisorders in general, have proven particularlyfrustrating targets for “positional cloning.” By analyzingone extended family with multiple cases of bipolar affectivedisorder, Porteous’s group has defined a candidateregion on Chromosome 4. Even when supporting evidencefrom other families is also used, the candidate regionspans several megabase pairs. Interestingly, the audiencevoted for immediate sequencing of affectedchromosomes across the entire region as the preferrednext step in the search for causal mutations.D. Cox reported on one actual effort to carry out awhole-genome-association scan. His project sought toidentify genetic variants contributing to the occurrence ofcirrhosis in heavy drinkers. Cox expressed the view thatthe technology still did not exist to allow such scans to becarried out by genotyping individual samples at an adequatedensity of SNPs. However, by pooling case andcontrol samples, Cox’s group identified a modest numberof SNPs that defined potential “disease-enhancing” loci.All the SNPs were common in both case and control populations:Hence, if they prove to be true positives, themodel for enhancement of disease susceptibility must involvethe combinatoric effects of many loci.Most talks on whole-genome-association scans focusedon technology and infrastructure rather than applications.Chee (Fan et al.) and Kwok (Kwok and Xiao)both described advances in genotyping methods that addressone of the major obstacles to such studies. Othertalks addressed the question of how SNPs should be chosenfor association studies. Goldstein (Goldstein et al.)expressed optimism that as few as 10 5 SNPs might be sufficientfor whole-genome scans, at least in some populations.D. Altshuler reported on haplotype mapping inmultiple populations. On the whole, his studies suggestthat SNPs which adequately capture diversity in African,Asian, and European populations also work well in morenarrowly defined groups. Linkage disequilibrium extendsover the longest distances in Native Americans and PacificIslanders, and these populations also have the leasthaplotype diversity of all groups examined. Bertranpetit(Bertranpetit et al.) expressed skepticism about the adequacyof SNPs acquired in a few major populations tocapture worldwide diversity. In a study of linkage disequilibriumon Chromosome 22, his group found substantialheterogeneity in allele frequencies for many SNPsand the extent of linkage disequilibrium between SNPs indifferent populations.ETHICAL AND SOCIAL ISSUESDiscussions of social concerns about current approachesto human genetics were interspersed with thoseof technical issues. Jan Witkowski moderated an interactivepanel that sought to explore the sensitive issues surroundingsuch work. The panel largely explored familiartopics: potential conflicts of interest for scientists whostraddle the divide between academic and commercial research,the risk that geneticists will reinforce racialstereotypes as they characterize human-population structure,and the need for more realism in discussing thehealth relevance of advances in genome research.Nonetheless, I perceived an unspoken tension at themeeting that transcended these traditional ethical, legal,and social issues. A brief exchange between Ewan Birneyand David Altshuler, following Altshuler’s talk, was exemplary.Birney asked whether, in designing the haplotype-mappingproject, it would not have made sense tocollect some phenotypic data about the individuals whosegenomes were being mapped. In this way, assessment ofthe number and choice of SNPs required for wholegenome-associationscans could be informed by simultaneousefforts to associate these SNPs with phenotypes.Altshuler responded that this approach was impossiblebecause of Institutional Review Board restrictions on thehaplotype-mapping project.In my summary talk, I revisited this point. While acknowledgingthat Altshuler’s reply was factually correct,I expressed the view that the tight restrictions underwhich most current research on human genotype–phenotypecorrelations is conducted are largely self-imposed bygeneticists. From a scientific standpoint, Birney’s point isincontrovertible. However, there is a comfort level, towhich human geneticists have perhaps too readily ac-