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Meeting Review

Life will never be the sameAnnual Genome Sequencing and Biology Meeting, Cold Spring Harbor Laboratory,USA. May 2000

M.A. Strivens*MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, UK

*Correspondence to:M. A. Strivens, MRC MammalianGenetics Unit and UK MouseGenome Centre, Harwell,Oxfordshire OX11 0RD,UK.E-mail: [email protected]

It seems appropriate that the Cold Spring HarborGenome Sequencing and Biology Meeting, whichwitnessed the creation of the Human GenomeOrganization (HUGO) in 1988, should this yearpresent three major advances in genomic science:the completion of the ®nished sequence of Droso-phila melanogaster; the announcement that 85% ofthe genome of Homo sapiens is now in draftsequence; and the complete, ®nished sequence of asecond human chromosome, chromosome 21. Othermajor sessions of the meeting focused on singlenucleotide polymorphisms (SNPs), ethical, legal andsocial implications (ELSI), as well as comparativeand functional genomics.

There is signi®cant debate as to whether thetechnique of `whole genome shotgun' sequencing1 isapplicable to the elucidation of larger genomes (e.g.human). Prior to the beginning of this year, thistechnique had only been demonstrated on smallmicrobial genomes (such as Haemophilus in¯uenzae,with a genome of approximately 1.8 Mb [1]) andthere had been considerable scepticism as towhether the technique would work in human orfruit ¯y. There was, therefore, considerable interestand excitement in the presentation by the BerkeleyDrosophila Genome Project (BDGP) and CeleraGenomics (Rockville, USA) on the full Drosophilasequence.

The crux of the whole-genome shotgun strategy isthe assembly technique. Gene Myers (Celera Geno-mics) reported on how the `double-barrelled' shot-gun2 approach had given a signi®cant advantage tothe computer algorithms employed in the assemblyof the ¯y genome. The assembly system employs abottom-up, nucleating strategy, initially assemblingsmall islands of sequence of high con®dence(diverting the assembly of repeat regions to laterstages) and then searching for other sequence(including orientation data from clone end-sequencing) to join the islands together. In addition,he con®rmed a less than 0.5% error rate in theautomated assembly of repeat sequences that are apotential problem for this type of system.

Gerry Rubin (BDGP) and Mark Adams (CeleraGenomics) presented material from the analysis ofthe genomic sequence, showing that the totalnumber of genes is approximately 13 600 (comparedwith approximately 15 000 seen in the smaller100 Mb Caenorhabditis elegans genome). In addi-tion, there was substantial variation of 0±30 genesper 50 kb (but without the clustering seen in C.elegans). There was also a general trend showing amarked decrease in gene density, G+C content andan increase in transposons in the 1 Mb portionadjacent to the centromeric heterochromatin. Gerry

1Where all genomic material is sequenced as small fragments and

resulting sequence fragments is reassembled by sophisticatedsoftware algorithms.

2This is where sequence is generated from both ends of shotgun

clones as well as a range of small insert libraries. These librarieshave a narrowly de®ned size range, so end-sequence data,provides important positional information for ordering andorientation of sequence fragments.

YeastYeast 2000; 17: 241±243.

Copyright # 2000 John Wiley & Sons, Ltd.

Rubin commented that it was remarkable that the¯y had only just over twice the number of genescompared with yeast, leading to the propositionthat the complexity of an organism's gene content isnot directly proportional to the complexity of theorganism itself.

This observation prompted spirited debate,centred on exactly how many genes would com-prise the human genome and, indeed, how onewould de®ne what comprised a single gene. Inresponse to this debate, Ewan Birney of theEuropean Bioinformatics Institute (EBI, UK) hascreated a sweepstake `Gene Sweep' (http://www.ensembl.org/genesweep.html), allowing bets to beplaced on what the eventual ®gure will be. It ischaracteristic of the current divergence in opinionthat guesses currently range from 27 000 to200 000. The sweepstake is open for another 2years with de®nitions and absolute gene numberbeing decided at the Cold Spring Harbor meetingsin 2002 and 2003, respectively.

In addition to the announcement of the comple-tion Drosophila genome, substantial progress hasbeen achieved in the production of the workingdraft of the human genome. Jane Rogers (SangerCentre, UK) presented the accelerated progress ofthe draft sequencing, now representing 85% of thehuman genome, with anything up to 97% in the®nal phase of checking (http://www.sanger.ac.uk/HGP/stats.shtml).

AndreÂ Rosenthal (Institut fuÈr Molekulare Bio-technologie, Germany) reported the work of aninternational consortium of labs [2] producing a®nished sequence for human chromosome 21. Thischromosome has almost 20 disease loci associatedwith it, in addition to the trisomy that gives rise toDown's syndrome. From the analysis of the ®nishedsequence, the consortium identi®ed 127 genes ofknown function and 98 putative genes (including59 pseudogenes). Approximately 40% of this chro-mosome is composed of repetitive elements, withsome apparently very gene-poor areas totallingapproximately 10 Mb. One of the most startling ofthe gene-poor regions was a 7 Mb region on 21q,where only one gene, as yet, has been detected.Using the number of genes identi®ed from thecompleted sequence from human chromosomes 21and 22, an extrapolation was done showing that(theoretically) the human genome could contain aslittle as 40 000 genes.

In addition to the intense experimental effort,

several sessions focused on the bioinformaticstechniques being designed to analyse the explosionof raw data from the sequencing and mappingcentres. One of the principal problems with the highoutput of the various genome projects concerns thedegree and appropriateness of annotation assignedto a sequence. This is exacerbated by the constantlyevolving draft sequence. Ewan Birney (EBI, UK)presented the Ensembl (http://www.ensembl.org/)system, which is capable of de®ning features ondraft sequence (assigning them stable identi®ers),maintaining those features and identi®ers as draftsequence progresses to its ®nal ®nished form. Thissystem is clearly a valuable tool in the earlyidenti®cation and exploitation of novel genes andregulatory elements. Comparative sequence analy-sis3 is also becoming a viable tool for the dissectionof novel genomic regions where sequence is avail-able in a number of species. Greg Elgar (HumanGenome Project Resource Centre, UK) presentedcomparative analysis between the compressedgenome of the puffer-®sh, Fugu, with a number ofloci in mouse and man, demonstrating the power ofthis technique in identifying new genes and con-served regions in these species. In addition, to aidthis type of approach, tools are being developed toalign and visualize multi-species sequence compar-isons, e.g. the Vista tool (Kelly Frazer, LawrenceBerkley National Laboratory, USA). This toolis capable of visualizing long-range alignmentsbetween several species and can be used to de®nestatistical cut-offs for conserved elements.

The keynote speech was, appropriately, deliveredby Francis Collins (National Human GenomeResearch Institute, USA), who has played a pivotalrole in the organisation of the Human GenomeProject and who clearly relished the prospect ofdelivering this address. He urged the assembledaudience not to lose sight of the ultimate goals ofthe genome project; in the near-term this means thegeneration of high-quality, annotated sequence, thatis made available to all. In the longer term, therequirement is to begin to use the data generated topump-prime the next phase of genomic science ±seeing that this, in turn, is translated into advancesin basic medical science.

Given the potential impact of even the draftsequence on the whole of science and society, Dr

3The alignment of sequence from syntenic regions in order to

identify evolutionary conserved regions, such as conserved exonsand regulatory regions.

242 M. A. Strivens

Copyright # 2000 John Wiley & Sons, Ltd. Yeast 2000; 17: 241±243.

Collins, ®nished his address with 10 `exhortations'(see below) to the assembled scientists to `attend tothe broader social context' of the Human GenomeProject. This involves both the education of schooland college students and ensuring the understand-ing of the general public:

1. Cut out the lights, close the door, and get outof the lab. Spread your wisdom. Turn your barnapkins into genetic primers.

2. Volunteer to be a resource to local scienceteachers. Make yourself available to speak toelementary and secondary school students. Getinvolved in setting state and local scienceeducation standards. Alert local high schoolbiology teachers to the NHGRI curriculumsupplement on human genetic variation andHGP educational video documentary and CDROM to be released this Fall.

3. Be an ambassador for science ± speak toRotary, Chamber of Commerce, church groupor local bar association. Volunteer to providetechnical assistance to local science museumsand programmes.

4. Reward and foster community outreach activ-ities by those who work for you, e.g. students,trainees and faculty.

5. Personalize scienti®c application, e.g. watchyour language - make the Book of Life under-standable to your Aunt Betty and nephewJimmy.

6. Establish links with the schools of business,law, public health and education at yourinstitution.

7. Start a DNA Day on your campus, at yourhospital, or within your community.

8. Engage your community in a discussion ofgenetics. Use mistakes and over-simpli®cationsin the press to improve local genetic literacythrough letters to the editor. Write op-eds.

9. Get to know the ELSI issues and offer yourexpertise to state and federal policy makers.Share your concerns about the importance ofprotecting the privacy and fair use of geneticinformation.

10. Share ideas. Let me ± and others ± know whatworks in your community.

Acknowledgements

My thanks to Francis Collins (NHGRI, USA) for providing

me with extracts from his keynote lecture.

References

1. Fleischmann RD et al. 1995. Whole-genome random sequen-

cing and assembly of Haemophilus in¯uenzae. Science 269:

496±512.

2. Hattori M et al. 2000. The DNA sequence of human

chromosome 21. The chromosome 21 mapping and sequen-

cing consortium. Nature 405: 311±319.

Life will never be the same 243

Copyright # 2000 John Wiley & Sons, Ltd. Yeast 2000; 17: 241±243.

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