Initial analyses of the human genome:does it reveal anything new?Rebecca Lawrence, News & Features Editor

DDT Vol. 6, No. 5 March 2001 updatenews

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Detailed searches of the current draft of the human genome sequence for new candidate genes and paralogues of disease genes have had varying successes1–9. Disappointingly, in several instances, these searches have revealedlittle, if any, new information that hasnot already been discovered using traditional techniques.

These studies have been published inthe 12 February 2001 issue of Naturealongside a paper by the InternationalHuman Genome Sequencing Consortiumon the initial sequencing and analysis of the human genome10. The nine data-mining papers cover a variety of topics:cancer1, addiction2, gene expression3,immunology4, evolutionary genomics5,membrane trafficking6, the cytoskeleton7,the cell cycle8 and the circadian clock9.

The results of these attempts to minethe current draft of the human genomehave greatly varied in their success toobtain useful information. For example,no paralogues of known tumour sup-pressor genes were found from a searchfor the proteins predicted from the draftsequence1. Similarly, few novel cyclinsand no cyclin-dependent kinases (Cdks)were discovered8. By contrast, workersexamining the molecular componentsinvolved in addiction were able to iden-tify several new candidate genes2 andother teams have found many insightsinto the evolutionary genomics of thehuman genome5 and, more specifically,into the evolution of transport vesicles9.Similarly, a team examining the gen-omics of immunology found severalnovel proteins4, and more than 2000 hy-pothetical genes that encode transcrip-tional activators were discovered3. The

lack of success in finding new genes insome fields could either be becausethese new genes are currently in a frag-mented state in the draft sequence orjust because all the genes in these areashave already been found using tradi-tional methods.

Caution required?Many of the teams were cautious aboutthe information they gained from thedraft sequence. Although the searcheslocated numerous genes previously iden-tified by traditional methods (such as cytoskeletal genes7, tumour suppressorgenes1, clock loci9, cyclins and Cdks8),many other known markers4 and genes7

were not found. There are several poss-ible reasons for this, such as the fact thatmany of these genes might be currentlyrepresented as fragments that have notyet been assembled into full-length cod-ing sequences. Furthermore, there arecurrently many gaps in the gene annota-tion.

There was also disappointment thatcomparing sequenced genomes pro-duced little information about the cellcycle in general and was unable to helpexplain how differences have evolvedbetween the cell cycles of different or-ganisms8. A study searching for clockgenes identified new clock gene candi-dates but the team conducting thisstudy commented on the lack of infor-mation regarding their expression patterns or function9.

Other concerns came from a studythat mapped pairs of sequences (derivedfrom cDNA libraries constructed fromnormal and neoplastic tissue samples)from the same cDNA clone to the

genome. As expected, most of thesemapped to the same position in thegenome, but a few pairs mapped to twodifferent parts of the genome, suggest-ing a significant rate of false positives1.

Several limitations to the draft se-quence have also been highlighted bythese preliminary searches3. For exam-ple, the existence of a related gene sequence does not automatically meanthat there is a corresponding protein asthe sequence could be a non-expressedpseudogene. Furthermore, it is often difficult to decipher whether two relatedgenes are simultaneously expressed inone cell or differentially expressed. A fur-ther complicating factor is that manyfactors are components of multi-subunitcomplexes, making analysis difficultwithout associated biochemical studies.Moreover, relatively few clones havebeen sequenced from most of the li-braries and many of the libraries are notnormalized1.

Consortium analysis morepromisingA more global analysis of the drafthuman genome sequence by theConsortium itself has produced morepromising results10. Their rapid search ofthe draft sequence produced 286 potential paralogues of disease genes,demonstrating a potential for the rapididentification of disease gene paraloguesin silico. Furthermore, a search for paralogues of the classic drug target proteins in the draft sequence identified18 putative novel paralogues, which included possible dopamine receptors,purinergic receptors and insulin-likegrowth receptors. These all either

matched at least one expressed se-quence tag (EST) or contained long openreading frames (ORFs), and all showedhomology spanning multiple exons separated by introns, and are thereforenot pseudogenes. These could thereforerepresent interesting new candidatedrug targets.

Predicted impact of thecompleted sequenceAlthough there are a number concernsover the impact of the draft humangenome sequence as a resource to iden-tify novel genes and paralogues of dis-ease genes, there is more optimismabout the benefits of the completed sequence, which from the latest infor-mation available, has been estimated to contain 31,000–32,000 genes10.Suggestions from the teams reportedhere include an increase in the knowl-edge of the number of clock genes inmammals and a significant impact onthe study of circadian output systems9,and identification of many addiction vul-nerability genes2. Production of a reliableannotation of the genome and ‘clean’databases of human genes and proteinsshould enable rigorous analysis of thegenome to discover its evolution5.Meanwhile, it has been suggested thatresearch into the genomics of immunol-ogy are most likely to be successful using‘forward genetics’ that start from the al-tered immunological trait and identify thecausative gene, rather than using ‘reverse

genetics’ by systematically knocking outevery immunologically expressed gene4.

However, there are some that are lessoptimistic about the impact of the com-pleted human genome sequence. Theysuggest that, although it should revealuseful targets for the development ofnew therapies and will be essential forthe understanding of the cytoskeletonand associated molecular motors, it isunlikely to provide insight into molecularmechanisms due to the complexity ofproteins7. Similarly, the diversity of thestructure and function of cancer genesand the fact that many close relatives ofknown important cancer genes are notmutated in cancers means that search-ing for paralogues of these known genesis unlikely to be effective in identifyingnew candidate cancer genes1. Success inthis area is likely to require an increase inthe cancer genome sequence data avail-able. Most agree that to get significantlymore out of the human genome se-quence, there needs to be a marked im-provement in our ability to turn raw se-quence data into biological knowledge8.

There are even some concerns thathaving the full genome sequences couldhave a negative effect on research by de-laying studies on completing the mecha-nistic analyses required to understandphysiology7.

ConclusionsThe overall consensus seems to be thatsome initial information can be gained

from the draft sequence in certain fields.However, much care needs to be exer-cised when interpreting this informationdue to incomplete and sometimes in-correct assembly of some raw genomedata in the draft sequence. Furthermore, considerable work is still required to correctly identify all protein-coding segments and to remove intronic sequences. However, after completion ofthe human genome sequence, mostgroups agree that with the developmentof new technologies and strategies, itshould provide a source of much morevaluable information for the identifi-cation of novel targets and ultimately,for the development of new therapies.

References01 Futreal, P.A. et al. (2001) Cancer and

genomics. Nature 12 Feb02 Nestler, E.J. and Landsman, D. (2001)

Learning about addiction from the humandraft genome. Nature 12 Feb

03 Tupler, R. et al. (2001) Gene expression andthe human genome. Nature 12 Feb

04 Fahrer, A.M. et al. (2001) A genomic view ofimmunology. Nature 12 Feb

05 Li, W-H. et al. (2001) Evolutionary analysesof the human genome. Nature 12 Feb

06 Bock, J.B. et al. (2001) A genomic perspectiveon membrane compartment organization.Nature 12 Feb

07 Pollard, T.D. (2001) The human genome, thecytoskeleton and motility. Nature 12 Feb

08 Murray, A.W. and Marks, D. (2001) Cansequencing shed light on cycling? Nature 12 Feb

09 Clayton, J.D. et al. (2001) Keeping time withthe human genome. Nature 12 Feb

10 International Human Genome SequencingConsortium (2001) Initial sequencing andanalysis of the human genome. Nature 12 Feb

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What do YOU think the impact of thehuman genome sequence will be on drug discovery?

Have you had any experiences of data mining the draft sequence, successful or otherwise?

Do you have comparable experiences of data mining genome sequences from other species?

Please send your comments to Dr Rebecca Lawrence, News & Features Editor, Drug Discovery Todaye-mail: Rebecca.Lawrence@current-trends.com

Publication of letters is subject to editorial discretion.