A report on the 5th annual Advances in Genome Biology and Technology (AGBT) and Automation in DNA Mapping and Sequencing (AMS) meeting, Marco Island, USA, 4-7 February 2004

Kellis, Manolis

Genome Biology

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 The Changing Face of Genomics  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Kellis, Manolis. 2004. The changing face of genomics. GenomeBiology 5(5): 324.Published Version http://genomebiology.com/2004/5/5/324Accessed February 19, 2015 12:11:54 AM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:4553780Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAGenome Biology 2004, 5:324commentreviewsreportsdeposited researchinteractionsinformationrefereed researchMeeting reportThe changing face of genomicsManolis KellisAddress: The Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02138, and Computer Scienceand Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. E-mail: manoli@mit.eduPublished: 30 April 2004Genome Biology 2004, 5:324The electronic version of this article is the complete one and can befound online at http://genomebiology.com/2004/5/5/324© 2004 BioMed Central Ltd A report on the 5th annual Advances in Genome Biologyand Technology (AGBT) and Automation in DNA Mappingand Sequencing (AMS) meeting, Marco Island, USA, 4-7February 2004. The annual meeting on Advances in Genome Biology andTechnology was very different this year - in contrast toprevious years, only a handful of talks covered the latestlarge-scale sequencing projects and the next species to besequenced. This meeting took for granted that we cansequence, assemble and align complete genomes - achieve-ments that only a few years ago seemed daunting, if notunthinkable. The focus of the meeting has instead shiftedtowards the new challenges in genomics, particularly in theareas of gene regulation, cell dynamics and genome evolution. Cell regulation and organism developmentGiven the primary sequence of a species, a major goal ofcurrent genomics efforts is to understand the regulatorymechanisms and control circuitry of the cell. Towards thisgoal, Rick Young (Massachusetts Institute of Technologyand Whitehead Institute, Cambridge, USA) presented thecompletion of the yeast protein-DNA interaction map. Usingchromatin immuno-precipitation (ChIP) technology incombination with microarray ‘chips’ containing all intergenicregions, his group has undertaken a genome-wide study ofthe targets of all the roughly 200 transcriptional regulatorsin yeast under multiple environmental conditions. Theycharacterized the sequence-specificity of these regulatorsusing numerous motif-discovery tools, together withevolutionary sequence conservation and protein structureinformation. The resulting regulatory map revealed generalprinciples of regulation in yeast, including the organizationalarchitectures of promoter regions (single motif, multiplesites, multiple regulators or factor combinations), and thedifferent types of regulatory response to environmentalchanges (off/on, invariant, expanded or altered). The Younggroup also studied 20 chromatin regulators that do notdirectly recognize DNA sequences, but instead rely on theirassociation with transcription-factor partners for bindingand can keep a record of transcription by maintainingchromatin state. The Young lab is now moving this technologyinto studying transcriptional-regulator binding in thehuman genome, which will have applications to understandingdiseases from diabetes to cancer. Michael Levine (University of California, Berkeley, USA)presented work aiming to understand the cis-regulatorycircuitry of promoter regions in the fruitfly. He proposedthat enhancer complexity might be a better measure oforganismal complexity than overall gene count, and notedthat the majority of enhancer elements act cooperatively inhigher eukaryotes - autonomously-acting elements would infact be the exceptions. Levine’s group has studied thepromoter architecture of Drosophila developmental genesthat respond to different levels of the concentration gradientof the developmental protein Dorsal. Five activation levels,created by the combinatorial action of a three-response-levelactivator and a repressor, were detected for this set of genes.Levine and colleagues searched for conserved sequenceelements in the promoter regions of genes belonging to thesame activation level and discovered a common ‘grammar’ inthe organization of three basic enhancer elements. Searchingfor a similar regulatory grammar in the mosquito genomerevealed ten genes with similar putative regulatory clusters,two of which contain the same architecture, despite 230million years of divergence. Both Young and Levine have benefited from earlier work -classical studies of gene function in yeast and knowndevelopmental genes in the fly - that have set the foundationsfor future studies. In this spirit, Nancy Hopkins(Massachusetts Institute of Technology, Cambridge, USA)presented her research program that aims to systematicallyidentify all developmental genes in the zebrafish. Zebrafishis an appealing model for studying early vertebrate devel-opment because of its transparent body and the short time- a mere four days - between fertilization and free-swimminglarval stages. As reaching the adult stage takes another fourmonths, following multiple generations can, however, beprohibitively slow. To face this challenge, Hopkins andcolleagues have used insertional mutagenesis to createmosaic parents whose germ cells each contain a differentmutation. Following the fish with developmental defects andclassifying each mutation has allowed her group to screen32,000 founder fish, identify 550 mutants and 390 loci, 298of which have human homologs. As many as 20% of thesegenes have no previously known biochemical function,providing a great starting point for experimentation and newbiological discoveries. Additionally, the systematic approachallows one to estimate the total number of developmentalgenes, which Hopkins sets at 1,600, of which 25% havealready been isolated. The cost of identifying additional genesincreases as the study approaches saturation, however, andher group is not planning to pursue the systematic discoveryphase of the work. They are currently working on under-standing the genes identified and have revealed importantnew insights about genes involved in kidney, jaw, liver andmyeloid cell formation. Protein interactions and network evolutionBeyond the identification of genes involved in a developmentalprocess lies the major challenge of understanding the genes’dynamic patterns of behavior during development. JoshLaBaer (Harvard Medical School, Boston, USA) presented hislab’s proteomics work enabling such a pursuit, which theyhave approached by developing a ‘protein-expression clonerepository’ that contains full-length protein-coding sequencesfor every gene in a number of model organisms, includingyeast, bacteria and human. These protein-coding sequencesare inserted into ‘master’ clone vectors and can be easily trans-ferred to specialized vectors for expression studies, taggingwith green fluorescent protein (GFP) to study localization,two-hybrid assays to determine protein interactions, orexpression in constructs to detect protein modification statesby mass spectroscopy. The system architecture is designed tobe flexible, modular, reliable, comprehensive and catalogued.Mark Vidal (Harvard Medical School, Boston, USA) describeda similar system for understanding the worm proteome. Hislab is now mapping the localization of all 19,000 worm geneproducts across development, and so building ‘chronograms’of gene expression from the head to the tail. The patterns ofprotein localization can then be clustered across space andtime, thus constructing the dynamic aspect of the protein-interaction network of the worm. Vidal’s group has currentlycompleted 10% of the interactome matrix, and is movingtowards completeness with the goal of understanding not onlythe components of the interactome but also protein behaviorsduring complex organismal tasks. The protein-interaction network of a species provides thefoundation for understanding the organism’s responses toenvironmental changes and developmental signals. Acrossevolutionary time, these responses change and the regulatorycircuits shift towards new ones. Lisa Stubbs (LawrenceLivermore National Laboratory, Livermore, USA) presentedwork aimed at understanding the evolution of such regulatorymechanisms across species. Her group studied the KRAB-ZNFfamily of chromatin-interacting zinc-finger transcriptionalregulators. These proteins arose 400 million years ago, afterdivergence of land vertebrates from fish, and have recentlyundergone lineage-specific expansions in the human andmouse lineages via tandem duplications and deletions.Researchers shy away from using traditional comparativegenomics tools for the analysis of such expanding genefamilies, as orthologous pairs are hard to determine. In theabsence of orthology information, Stubbs constructed multiplealignments of all paralogous gene copies within each speciesin turn, rather than across species. This clever methodology,although atypical, yielded biologically meaningful intergenicsequence elements that are highly conserved across paralogs,and which can be shown, on the basis of reporter assays, toindeed act as enhancers. This approach also allowed theidentification of species-specific elements that have arisensince the divergence of the mouse and human lineages.Stubbs’ group is now working out the protein-level differencesbetween paralogs, with the goal of understanding howstructural changes affect function, in particular with respectto tissue-specific regulation and parental imprinting. Human divergence and diversityDifferences between more closely related species can bemuch more subtle than the protein family expansionsobserved between human and mouse. For example, divergencebetween human and chimp shows as few as 12 changes every1,000 nucleotides, which makes biological signal discovery areal challenge. Mike Zody (Massachusetts Institute ofTechnology and Broad Institute, Cambridge, USA) presented avery interesting way to use such a close relative to revealinsights into recent evolutionary history. Assuming thatneutral divergence between species and neutral diversitywithin species are driven by the same underlying mutationalmechanisms, Zody and colleagues used human-chimpdivergence information to model the background mutationrate for each region of the genome. Using this information,they were able to distinguish regions of low within-humandiversity that were due to selective sweeps (where a favorablemutation becomes incorporated into the genome veryquickly), rather than simply to a lower mutation rate. Theseregions of low diversity were confirmed by genotypingnucleotide polymorphisms in humans of different ethnicityand building allele-frequency profiles. FOXP2, a well-knowngene involved in language development, showed only amoderate signal for selection, whereas some regions that aredevoid of annotated genes showed very strong evidence of324.2 Genome Biology 2004, Volume 5, Issue 5, Article 324 Kellis http://genomebiology.com/2004/5/5/324Genome Biology 2004, 5:324selection, raising new questions about what type of geneticelements may be under selection in the human genome. With the aim of understanding human variation and howgenetic differences may relate to phenotypic differences,Joanna Mountain (Stanford University, USA) presentedher work relating language similarities to populationpolymorphisms. In particular, she has studied the geneticrelationships of two geographically isolated populations inAfrica, both of which speak with clicking languages(Khoisan). Using a multitude of metrics across various lociand populations, she found that the genetic data clearlysupport an evolutionarily distinct group for each of the twolanguages. To explain the results, Mountain put forwardthree possibilities: that the two languages arose indepen-dently, that they traveled across populations, or that insteadthe ancestral language was click-based and all interveninggroups lost the click sounds. One advantage to such clicklanguages might be the ability to communicate whilehunting without alerting the prey. The use of moderngenomics tools in the population genetics of language evolutionillustrates how diverse the genomics field has become, andthat, in fact, the maturity of genomics as a science hasmoved its applications well beyond the boundaries of themodern laboratory. Overall, the meeting showcased a wide range of innovativetalks, combining ground-breaking technological inventionswith important scientific applications. The attendance wasunusually low this year, especially on the industry side,witnessing the tight economic situation in the USA andinternationally. At the same time, the changing focus of themeeting is evidence of a maturing field. Genomics hasmastered its initial challenges, and is now extending its armsto embrace a growing number of fundamental questions in thestudy of life.commentreviewsreportsdeposited researchinteractionsinformationrefereed researchhttp://genomebiology.com/2004/5/5/324                                                   Genome Biology 2004, Volume 5, Issue 5, Article 324 Kellis  324.3Genome Biology 2004, 5:324

The Changing Face of Genomics

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The Changing Face of Genomics

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