7.3. Human Genome Project and Impacts on Medical Sciences

pp. 139-140 in Bioethics and the Impact of Human Genome Research in the 21st Century

Author: Nobuyoshi Shimizu (Keio University School of Medicine)

Editors: Norio Fujiki, Masakatu Sudo, and Darryl R. J. Macer
Eubios Ethics Institute

Copyright 2001, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.

On May 8, 2000, we as a member of the international consortium of human genome project (HGP) announced that the draft sequencing of the entire human genome of 3 billion base pairs has been finished and the proposed goal of complete understanding the estimated 100,000 human genes is within reach. We have been involved in the HGP by taking responsibility for analyzing several targeted regions of human chromosomes 22, 21, 8 and 6 to find new genes which are associated with important biological and medical problems. Human chromosomes 22 and 21 were the first and second chromosomes whose sequences were completely determined and extensively analyzed for the presence of genes. In fact, 545 and 225 genes each were found in these two chromosomes, for which we made substantial contributions (1, 2).

Our gene finding strategy combines several advanced molecular techniques such as exon trapping, cDNA capture and genomic sequencing (3). We constructed a high quality BAC library and chromosome-specific cosmid libraries and developed efficient PCR-based screening and high fidelity digital hybridization methods to construct BAC/cosmid DNA contigs (4). We utilize the shotgun sequencing method to completely determine the genomic DNA sequence with no gaps and high accuracy (> 99.999%) (5). The recovered genomic sequences are routinely subjected to homology search and analysis of protein coding potential using computer programs GRAIL, MZEF and GENSCAN. Putative exon sequences are used as probes to screen corresponding cDNA clones or as primers to amplify cDNA fragments from appropriate cDNA libraries by PCR. Eventually, the entire gene structure is determined and the function of its product is predicted. The candidate gene was confirmed as a disease causing pathogenic gene by extensive mutation analysis of the patient's DNA.

For chromosome 22, we analyzed the peri-centromeric region of 7.1 Mb and identified over 45 genes (1, 6). These genes include CESK1, hSNF5/INI1, BCR, GGT, GGTR, GSTT, DDCT, BID and CECR1. Also, many pseudogenes include NF-1-like, ALD-like, GGT-related, BCRL2 and POM121. In addition, we found that the IGL gene cluster consists of 36 functional Vl genes and 83 Vl pseudogenes, 7 VJ genes, 7 VC genes and 13 non-Ig genes/pseudogenes including VPREB and TOP3B (5). Particularly interesting genes found from chromosome 22 include CESK1 (t-complex protein-1 q-like) which is located at the most centromeric region and this together with BID (a regulatory subunit of calcium channel protein) and CECR1 (a growth factor) appear to be candidate genes for cat eye syndrome. hSNF5/INI1seems responsible for rhabdoid tumor development. It is also noteworthy that 7 sites of LCR22 (low copy repeat 22) consisting of BCR and GGT are strongly associated with the chromosomal breakpoints of certain diseases (6).

For chromosome 21, we analyzed four separate regions of 6.5 Mb and found 45 new genes and 15 pseudogenes. These new genes include C21orf5, DSCR5, DSCR6, ZNF295, UMODL1, TMPRSS3, UBASH3A, TSGA2, SLC37A1, PDE9A, WDR4, SNF1LK, H2BSF, AGPAT3, TRPC7, AIRE, DNMT3L, SIM2, MNB and 18 members of KAP gene family (2, 7). We determined the precise genomic structures of 24 known genes including ADAMTS1, ADAMTS5 and HSF2BP. There are several genes of medical importance. SIM2 (single-minded 2) encoding a PAS family transcription factor and MNB (minibrain) encoding a dual specific protein kinase were the first two genes discovered as candidate genes for the mental retardation of Down syndrome patients (8, 9). AIRE (auto-immune regulator) encoding a transcription factor with SAND and PHD finger motifs was proven to be a pathogenic gene for an autoimmune disease called APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) and it was the first transcription factor found to be involved in the mechanism of immune tolerance (10). TRPC7 (transient receptor potential-related channels 7) encoding a putative Ca++ channel transmembrane protein is considered to be a good candidate for bipolar affective disorder (11). TMPRSS3 encoding a putative transmembrane serine protease was found to be responsible for the autosomal recessive nonsyndromic deafness DFNB10 (12).

Additional example is the gene named PARKIN which was identified from chromosome 6 and found to be responsible for an inherited Parkinson's disease called AR-JP (autosomal-recessive juvenile parkinsonism) (13). PARKIN was a giant gene of over 1.5Mb but it encodes an ordinary protein of 50 KDa having ubiquitin-like domain and RING finger domain. Parkin protein was found to be a ubiquitin-ligating enzyme and appears to play a key role in the proteasome-mediated system for protein degradation in the neuronal cells in the substantia nigra of brain.

Thus, we have found a large number of new genes although we still need to establish the physiological function of individual gene products. It is however obvious that many of these genes and their products could serve as good targets for the biomedical studies which will ultimately contribute to the development of enhanced diagnostic and therapeutic regimens. The information on the human genes is rapidly increasing and these enormous amounts of information are being deposited in various computer databases. Along this line, we have developed a distributed database system MutationView which accommodates genomic informations such as disease-associated gene mutations, clinical phenotypes and diagnostic methods (14).

The outcomes of HGP are enormous and have already given significant impacts on the human biological and medical sciences. This new medical science includes studies on the common diseases such as diabetes and hypertension with the aids of polymorphic nature of individual DNA sequences. The convenient technologies for gene diagnosis of individual genomes will greatly facilitate the order-made medical treatment and preventive medicine, and may influence on the dignity of man. In this symposium, I will review the frontiers of HGP and discuss its influences on the 21st century society.

References

1) Nature 402:489-496, 1999.

2) Nature 405:311-319, 2000.

3) The First Intl. Conf. on Electrophoresis, Supercomputing and The Human Genome, pp.212-218, 1991; Genomics, 13:109-114, 1992; Keio Symposia for Life Science and Medicine, vol. 2 Neural Development, pp.535-540, 1999.

4) Gene, 191:69-79, 1997; Genomics, 49:209-217, 1998.

5) Genome Res., 7:250-261, 1997; J. Exp. Zool., 288:120-134, 2000.

6) Genomics, 51:472-475, 1998; Genomics, 62:90-94, 1999; Genomics, 64:277-285, 2000.

7) BBRC 225: 608-616, 1996; BBRC 235:185-190, 1997; Genomics, 42:528-531, 1997; Hum. Genet., 103:386-392, 1998; BBRC 271:693-698, 2000; Genomics, 65:293-298, 2000; Eur. J. Pediatr., 159:18-22, 2000.

8) Nature Genet., 10:9-10, 1995; Genomics, 35: 136-143, 1996; Genome Res., 7:615-624, 1997.

9)BBRC 225: 92-99, 1996; BBRC 250:704-710, 1998; Genomics 62:165-171, 1999.

10) Nature Genet., 17:393-398, 1997; DNA Res., 4:45-52, 1997; Mol. Endocrinol., 12:1112-1119, 1998; Immunol. Today, 19:384-386, 1998; Hum. Genet., 103:428-434, 1998; BBRC 257:821-825, 1999; BBRC 255:483-490, 1999; Hum. Mutat., 13:69-74, 1999; J. Biol. Chem., 276:16802-16809, 2000; Eur. J. Immunol., 30:1884-1893, 2000.

11) Genomics, 540:124-131, 1998.

12) Genomics, in press.

13) Nature, 392:605-608, 1998; BBRC, 249(3):754-758 (1998); Ann. Neurol., 44:935-941 (1998); BBRC, 249:754-758 (1998); Ann. Neurol., 45:655-657, 1999; Ann. Neurol., 45:668-672, 1999; Mamma. Genome, 11:417-421, 2000; Parkinsonism & Related Disorders, 5:163-168 (1999); Neurogenet., 2:207-218, 2000; Nature Genet., 25:302-305, 2000.

14) Nuc. Acids Res., 27:358-361, 1999; Hum. Mutat., 15:95-98, 2000; Nucl. Acids Res., 28:364-368, 2000.


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