The Development and Design of a Generic Genome

Analysis Environment: The G-language system

 

Arakawa Kazuharu

Faculty of Environmental Information, Keio University

 

Abstract

 

The short but grand history of bioinformatics has clarified the fact that it must gain higher efficiency in order for it to process the massive information that it faces in the future.

This paper introduces an attempt to solve the task which bioinformatics faces today by:

1.     Constructing an analyzing software developing environment aiming for the integration of the various individually developed conditions.

2.     Systematically accumulating existing analysis software techniques for analysis and their results.

3.     Constructing generic analysis packages which allow users to avoid redundancy in the process of analysis.

 

This document discusses the philosophy and the significance of the G-language project, and states in detail, the development and design of its G-language System.

 

1. Introduction

1.1 The significance of the G-language Project

 

The reading of the draft sequence of the human genome has finally been completed last year, bringing us to the opening of the post genome era.  This signifies that the importance of genome analysis, which searches for an ultimate understanding of life through analyzing digital data consisted of the four letters ga t c gh, will continue to increase. 

 Bioinformatics has been taking a great roll in science since the complete genome sequence of Mycoplasma Genetalium was made public in 1996, but its short history has clarified the fact that its systems must gain higher efficiency in order to process the massive information that it faces in the future.  Making new discoveries by exploring the massive genome data which is now constantly being produced requires a great amount of time and human resources.   In order to reconstruct the procedures of bioinformatics to have higher efficiency, the following points must be attained. 

 

 

1. The construction of an environment for the development of integrated analysis software.  Such software is now usually being developed individually under various conditions, with no common specifications.

1.       The Systematic accumulation of existing analysis software, procedures and their results.

2.       The construction of generic packages of analysis procedures that allow users to avoid redundancy in the process of analysis.

 

The first method saves time and cost necessary for the development of the new software.  Bioinformaticians who develop their own applied software for analyzing genome information usually need to develop their own versions of software for the most basic, commonly used methods.  Not only is this way generically inefficient, but it is also undesirable in terms of the flexibility of the software produced, in addition to its deficiency in ability for it to be shared and recycled.  This causes an unnecessary burden on developers, and wastes a great part of the resources in the field of bioinformatics.  A generic development platform suited for genome analysis which supports basic methods is capable of dramatically improving the efficiency of software development. 

  The second method allows researchers to choose and combine methods and software which match individual purposes by accumulating a pool of tools in a public domain within an integrated development system.  This way of increasing efficiency in research is only possible because bioinformatics uses various recyclable methods that are stored as software, a form fit for easy copying and distributing.  Connecting the pool of tools with bioinformatics databases, which are constantly enriched on the internet, will make it possible to make use of existing research results to the greatest extent. 

  The third method increases efficiency by constructing generic packages of analysis procedures which are otherwise repeated by handwork.  Non-generic software designed to comprehensively analyze basic data of the genome of a specific specie is likely to be useless for other species.  If such a package were to be developed on the generic integrated platform, countermeasures for unexpected difficulties can be taken easily simply by reconstructing part of the comprehensive analysis package.  The integration of existing analytic methods also have a great potential to be widely applied to new researches. 

  The attempt to construct a bioinformatics system actively rational with the conscious of the three points raised above is unprecedented.  This document discusses the G-language Project, which attempts to construct such a system, and Prelude (The developing code of The G-language Systemfs core version 0.1 to 1.0). 

 

1.2  Background

Before explaining the details of the G-language Project, projects similar to it are summarized below in order to clarify the significance and the tasks that The G-language Project faces. 

 

Bioperl

 

The Bioperl project attempts to make an integrated development environment as a group of Bio:: modules written in the programming language gPerl.h  It pays close attention to its functions such as its methods of input/output, coping with various formats of array databases, provides a number of useful methods along with genome information structs, and even using virtual memory when handling huge amounts of data like the human genome.  It also includes modules that use routine tools such as BLAST and FASTA for analysis.  The Bioperl project fulfills the first point mentioned in the previous section of this document, but it does not work for many irregular types of the Genbank database format, nor dose it have a reliable accuracy in parsing genome annotation data.  It lacks functions to fulfill the goals of the G-language Systems.  For example, it has little conscious to provide bioinformatics analysis tools other than those used most commonly.  Biopython, Biojava, Biocobra and Bioruby are projects similar to Bioperl. 

 

EMBOSS

 

EMBOSS is a set of genome analysis software provided by the Norwegian EMBnet.  EMBOSS methods and software for analysis are substantial in both number and quality, and has a simple standard for coding new software, enabling it to be used on various command lines.  This project too, though, has defects from the standpoint of the G-language Systems goals.  It has no concept of an integrated development environment, nor does it have a basic platform. 

 

Darwin

 

Darwin is a genome analysis environment provided by the Swiss ETH, which allow analysis to be executed as functions within its original script language.  Although this project has a history of over 5 years, it is not well approved of, because it has no particular methods that are superior to Bioperl, and it has an inflexible distribution license. 

 

In order to overcome the tasks that the projects stated above have yet settled, the G-language Project began in the year 2001, at the Institute for Advanced Biosciences of Keio University.  At this point, development of prototype version 0.5 has been completed.  The release of version 1.0-beta is planed in October on the internet http://www.g-language.org/. 

 

 

2 Program architecture

2.1 Design concept

When designing the G-language system, a generic genome analysis environment, the flexibility of the system should be most taken into consideration. If many and unspecified genome analysis methods and contents are developed by the unified system on the assumption that they are reused, a more flexible system design is desired. Moreover, it is indispensable that the various genome database files and the existing open source software can be broadly used in this system.

The program architecture of G-language System was designed as shown in Fig. 1, in which the flexibility of the system was taken into consideration as the first priority. This design consists of a three-layer structure, i.e. a user interface layer, a script module layer, and a core layer. Each layer is built as a completely separable independent system. Since various input and output make a structure object which consists of unified formats in a core layer, and the structure object itself is delivered to a script module layer, the data through the core layer can be treated without taking in account its form in a script module layer. In addition, by unifying the output from a script module layer, the result analyzed by various programs can be viewed without troubling with the different forms of the user interface layer.

The meaning of making G-language System into the independent three layer structure is not only the advantage of the communication between programs described above but also the simplicity of exchange of a layer in the system according to the situation. Bioperl, which is capturing the spotlight in the similar projects as described in the preceding chapter, has a function equivalent to the core of G-language System. Making each layer become independent in a design stage makes it possible to perform analysis by the script module layer using the core of Bioperl in G-language System. This enables a user to take in outstanding functions from the exterior flexibly and to make the favorite combination of systems. The epoch-making points of G-language System as an integrated system of bioinfomatics are that the various analysis techniques are accumulated in its script module layer, and that it has flexibility very much.

Fig. 1 Program architecture of G-language System

 

2.2 Architecture

The substance of G-language System is the module group of script language Perl [8]. Perl was developed by Larry Wall [9] and has been most generally used as a script language. Perl has a very flexible description and many useful modules accumulated by the Internet archive groups, such as CPAN [10]. In order to give flexibility widely as development environment, it becomes a big advantage that programming is easy and flexible and that there are many existing modules. Moreover, a script language which is good at character sequence processing is suitable for analyzing the genome database which is a document so to speak [11]. Thus the usage of a script language using rather than a compile language is advantageous.

However, it may be desirable for the core to be built by a compile language from a viewpoint of calculation efficiency, or by script languages which are more developed, such as Pyton or Ruby. Although these points had essential aspects, the G-language Project, in consideration of the situation such that the present developer is presently unfamiliar in languages other than Perl, the development language was unified to Perl.

The most general genome database format is a Genbank-form flat file database format [12]. Input and output of the other formats can be processed by supporting readseq, a database format conversion tool, in the core. Moreover, from a viewpoint of the amount of data and reference speed, the following strategies are adopted in the G-language System: a relational database can be used as standard, which is accessed by Pg modules in CPAN and gbk2pg, a part of Prelude core. The G-language System core holds data which pass these file input and output inside a program as a structure object, and it is used in a script module layer.

 

3 Mounting of G-language System

3.1 Prelude

Among the G-language System core layers, Prelude consists of (1) the G class which holds database information as a structure object as described in the preceding chapter, (2) the gbk2pg class interlocked with a relational database, and (3) the Rcmd class which communicate with R language, a statistics analysis language. The G class is a super class of all the systems of G-language System, and MT package in a script module layer is loaded as a library and a module in this class.  That is, the instance of the G class inherit G class automatically and can use the function of the MT package as a native function. Thus, the false program language that analysis is performed, which extends the system using a Perl language in the development environment of G-language System, is built by offering a diversified function from MT package. In the future, this false program language environment will be extended to a more advanced one by the script type user interface.

@The flexibility of G-language System makes it possible to replace a core layer by Bioperl as described in the preceding chapter. However, there is a big meaning in daring develop Prelude, considering problems such that Bioperl is not designed as an integrated system and does not support R language which is useful in statistics analysis.  In addition, its structure object with database information cannot respond to the irregular form of Genbank. Now, Prelude can conquer these problems and play role sufficient as a core of a bioinfomatics integrated system, which posseses many fundamental techniques of genome sequence analysis such as intron, exon, and so on as a native function are supported as a native function, and holds a memory which can be operated with the pointer of a file handle so that a huge database format such as human genome can be treated. The Perldoc documentation explaining the detailed function of G class is appended to the end of the book.

 

 

 

Fig. 2 Prelude core in G-language System

 

3.2 MT package

The MT package is a set of the various bioinfomatics analysis techniques, and is constituted as several modules which are collected based on functional relation in the inside. As described in the preceding chapter, a user is provided with the MT package as a native function because it is loaded as a library from G class, a super class from the inherited class and an instance of Prelude.

Furthermore, the relation between the functions in MT package is the homage.  That is, the function, in which the several functions of the minimum unit (for example, which calculates GC skew) are created and packed, and performs batch processing. The bacterial complete coverage analysis system, which is mounted in the present G-language System, integrates/unifies the function in this MT package and is itself offered as a function of MT package. The integrated system software exists based on the design of such a general-purpose script module layer.

Fig. 3 Outline on MT package

 

3.3 Example of System Mounting: MT::System::Mutation_finder

An example of system mounting is shown below in order to introduce how the G-language System functions. The flow of gMT::System::mutation_finderh method, a system which explores mutation information from two different bacterial genome databases, is shown in Fig. 4.  (1) sequence homology analysis by BLAST is performed for every gene from the genome data, (2) mutations of homologous genes are investigated based on the result, and (3) the site of the mutation and its influence on translation and secondary structure are analyzed and outputted.

The mutation_finder method of the MT::System class is called on the G-language System, and the genome data structure object is read during Prelude activation. Based on these data, the mutation_finder method calls another MT method groups inside, performs each analysis, and returns an output. Furthermore, each method such as MT::uni-all_blaster, MT::bi-bi_clustalwer, and MT::RNAfolder calls BLAST, ClustalW, and RNAfold which are the external programs from the inside, respectively. If complicated processing is realized under the unified environment where the MT package is the general-purpose method group based on a Prelude structure object which  constitutes a multiplex structure, development cost will decrease and the reusability of the individual method will increase. This hints a possibility that the MT method located in the lowest layer is used as composition parts of a different system. Because input and output of the MT::System are the Prelude structure object which is common to the G-language System, it can be performed without troubling to the file of a different format, and is effective as a general-purpose analysis system.

Fig. 4 Program figure of MT::System::mutation_finder

 

4.       Discussions

 

4.1 Plans for further Development

 

The development of The G-language System is now at version 0.5; There are still many tasks to be tackled before the beta release in October: 

 

l         The preparation of documentation

l         The development of user friendly UI

l         Exhaustive function checking

l         The construction of analytic packages from existing MT modules

l         The enrichment of the MT::System class

 

There must be an additional increase of basic analysis tools prior to the The G-language Systems formal release in December. 

 

4.2 Distinction

 

At the opening of the post genome era, many projects similar to the G-language Project are launched.  Therefore the G-language Project must become distinctive from the others.   Providing a system replete with high quality applications, solving the 3 tasks which bioinformatics faces stated in chapter 1, focusing on constructing a system to satisfy both low end and high end users (not intermediate users), and inviting developers from the public, will be the most important keys to the success of the G-language Project. 

In order to clarify the merits of this unprecedented generic analysis environment constructed by combining two independent pieces of software, Prelude and the MT modules, it is necessary to arrange the UI environment to make the system open to low end users.

The G-language System is available to the public domain (GPL) with an open source copy left concept, and the G-language Project invites you to be part of the development of its system.