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(####) mam## i##m ^i#i#a##m 141 :## X4ff?/oy —k>?- ?l&8 m 143 5 x./is (NEDO) (m) x/ft/ryyxhv-m^ (JBA) mmADNA%#^DNAy-ir>y>ym#(o^%(:zo, #< % Cfi6DNA<7m&@a#lf'-?/<-%#, fc-c, C<7)#^:»DNA^mmK^I^6, mef^R^L, #m - ##&#"?-c#to -E-LT^fi6 7 h9-^e#%t&ctcz ^ yemmmcf&mf & c & e g % c, &%#2:i####<?)m^ »&^at%Ad'&mm%efT-3to #c, me yyA###m#ijm%ms /</f^T^yny i). j: o#Lv^^yy m^tzhz.h zmwhtz^o (#) ;</f >y^ hu-m^ # : t* @± k h y y A#$f t > ? -0:^ : mm m& &&%#%####%# &####& 4>s n& HTB M2 m# gg mfc $iJX tty/ A##ft > 'b&QWM a#:m^c&c#%mr (tt)a^M#pif ±e#%m iWifl i- amman:##) #%^agy-y -vy-y - 7^0- #±m(W ##y%yA#%gg /W/NSAMS&m mem## 7 7;i/7y7/</ftTy(%) :±m ±@ £is B£ #A my##m #m /W tyyy sm mm > y - /Wf yy y ay —— me #E n^m % $#m# ## i^m c hyv /< /f t ^ -f /f * : (m/<^ t/f >y% h v -m^ $#@# f>y% h v-m^ %#§G^ urn %# Summary The Human Genome Project has advanced to the stage where U.S., U.K., German and French scientists are now engaged in large-scale human genome sequencing programs. The complete base sequences of yeast and several other microbial genomes have already been determined, and new life science areas based on such data is rapidly expanding. Thus this report takes a life and information science perspective of the technological developments needed to apply genome information to a wide variety of industries. Chapter 1 provides an overview of the genome map as well as sequence and function information at the current level of development of international research on genome analysis and highlights issues confronting the efforts. The information obtained from genome analysis is being compiled in databases which will enable us in the future to simulate diverse biological systems on computers. The analysis of genome structures requires a new system that integrates existing analytical methods and executes them much more quickly on a much greater scale and in a more well organized manner. The methodologies for analyzing genome functions have not been established and need to be further developed and refined. The efforts to analyze gene functions have so far primarily focused on individual genes. The new challenges are to perceive biological manifestations as expressions of entire systems while elucidating how sets of genes interact to control the expression of discrete genes. Chapter 2 reviews the current status of the technologies that analyze and make use of genome information. It also discusses (1) prediction and identification of gene regions in genome sequences, (2) techniques for searching and selecting useful genes, (3) technologies for predicting the expression of gene functions, and (4) technologies that predict gene-product structure and functions. — 1 — On predicting and identifying gene regions in genome sequences, the report discusses the sequences characteristic of eukaryotic gene regions as well as different approaches and pending issues for predicting gene regions using information science methodologies. The report finds that linear models, especially the hidden Markov model, are most suited to genome model constructions. Differences in prokaryote and eukaryote transcription and control mechanisms are compared together with their associated analytical techniques. In the area of techniques used to search for and select useful genes, the report describes fluorescent differential display (FDD), molecular indexing and cDNA microarray technologies which are critical for rapid analysis of gene expression profiles. The report covers gene searching technologies with an examination of the positional cloning method which identifies genes responsible for an expressed trait based on the fact that genes lose intrinsic functions through mutations. Experiments on humans and other primates are limited by ethical and financial considerations. However, important knowledge about useful genes can be obtained using mutants of organisms that are carefully selected for a particular purpose. Discussed here are unique approaches using microorganisms, nematodes, fruit flies and mice to find useful genes. In covering technologies that predict gene-function expression, the report initially reviews methods that reveal transcription-controlling regions for cloning. This is followed by a discussion of methods for analyzing transcription ­ controlling regions. Since gene transcription is controlled by interactions between DNAs and proteins or between proteins, information about many transcription-controlling factors is registered in databases. Many models for simulating the mechanisms for controlling the expression of genes have also been proposed. However, these models are only at the stage of evaluation for usefulness. We still need better models that can be applied to a variety of -ii- complicated processes. Since proteins are synthesized based on gene information, the technologies for predicting gene-product structures and functions are discussed. The two most commonly used methods to analyze the structures of synthesized proteins are examined including nuclear magnetic resonancing applied to proteins in solution and X-ray crystallography which determines protein structures in their crystalline state. To predict the three-dimensional structure of a protein from its amino acid sequence, the 3D-1D alignment method is widely used. The method predicts the initial 3D structure of a protein by comparing the data from the target protein with those from known 3D structures and by selecting the one that fits best. This approach is taken because statistical calculation is impracticable for predicting 3D protein structures that sets of amino acid residues can form. Improving the techniques of gene destruction and expression suppression- useful in clarifying gene functionsis still required. The report reviews the homology and motif search methods which are widely used to predict the function of a protein from its amino acid sequence. It also discusses integrated database systems incorporating data on amino acid sequences, functions including protein sequence motifs as well as 3D protein structures. Turning to the course of future research, Chapter 3 recommends that Japan's industry, government and academic sectors should focus their leading technologies and expertise on developing new technologies, collecting more data and interpretation in order to clarify the inter-gene information networks, a subject which will be of utmost importance when the DNA sequences of major organisms have been determined. It also calls for more research on gene data processing technologies so that inter-gene information networks can be simulated on computers using protein databases on amino acid sequences, structures and functions. -in - Chapter 4 gives examples of how the research project discussed in this report can affect industry and society. The focus is on sectors such as pharmaceuticals, diagnostics, diagnostic and analytical instruments, laboratory equipment, chemicals, food, agriculture, animal husbandry, fishery, electronics, environmental protection, information technologies. The final chapter cites the need to develop technologies for interpreting and using genome information through multidisciplinary cooperation among professionals in genetic biochemistry, computer and information sciences, precision engineering and other fields. The unprecedented nature of this project demands unique research infrastructures, periodic review of project targets and progress while keeping up to date on the latest findings in this fast developing area. — iv — (:%oa,&a&#"cv'ao coz 9 ^^%Tc*-oT. y v A##eg; < mmcf&mt #%omfu:f&c-cyvA#^. y-y>xi##, ##m#c^v'-c WmLto y/AM#f(:j:c"C#6fi&m#(±y-^/<-%<l:$^c)c60, #$, eft < ^.1^- hT#&to^i:m $fi&o yyAo#3m##[:^v^(±m#oR#^i#5^.
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