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Human Genome Part I Development Team Paper No. : 16 Molecular Genetics Module : 29 Large scale analysis of genome: Human Genome Part I Development Team Principal Investigator: Prof. Neeta Sehgal Head, Department of Zoology, University of Delhi Co-Principal Investigator: Prof. D.K. Singh Department of Zoology, University of Delhi Paper Coordinator: Prof. Namita Agarwal Department of Zoology, University of Delhi Content Writer: Dr. Nidhi Garg Deshbandhu College, University of Delhi Content Reviewer: Dr. Surajit Sarkar Department of Genetics, South Campus, Delhi University 1 Molecular Genetics ZOOLOGY Large scale analysis of genome: Human Genome Part I Description of Module Subject Name Zoology Paper Name Molecular Genetics Zool 016 Module Name/Title Large scale analysis of genome Module Id M29: Human Genome: Part I Keywords Genome, Gene, Sequencing, Genetic and Physical Maps Contents 1. Learning Outcomes 2. Introduction 3. Human Genome Project (HGP) 4. History of Human Genome Sequencing 5. Budget of the Human Genome Project 6. Goals of the Human Genome Project 7. Summary 2 Molecular Genetics ZOOLOGY Large scale analysis of genome: Human Genome Part I 1. Learning Outcomes After studying this module, you shall be able to • Know how what genome is. • Learn about the history of the Human Genome Project. • Evaluate the importance of Human Genome Project. • Know the important goals of HGP and how well within the time frame they were achieved. 2. Introduction The genome is defined as the genetic material of an organism which comprises of DNA or it can be RNA in RNA viruses. The term genome was coined by Professor Hans Winkler of the University of Hamburg, Germany in 1920. The DNA is organized in the form of chromosomes. In haploid organisms such as bacteria, archaea, viruses and in organelles like mitochondria and chloroplasts, the genome consists of a single circular or linear chromosome. In a sexually reproducing diploid organism, the genome comprises of a two full sets of chromosomes in a somatic cell. The gametes of a diploid organism contain half the number of chromosomes due to meiosis. Some organisms may be triploid, tetraploid, pentaploid etc. and therefore, have multiple sets of chromosomes. The term genome thus, refers not only to the DNA present in the nucleus known as the "nuclear genome" but also to the DNA stored in mitochondria and chloroplast which is known as the "mitochondrial genome" and the "chloroplast genome". Sequencing the genome of an organism refers to the determination of the order of nitrogenous bases A, T, G and C in its genetic material. Thus, for a virus it may involve knowing the base composition of only a single chromosome whereas, for a bacterium it may involve sequencing both the chromosome and the plasmids which together comprise its genome. For sexually reproducing organisms, genome sequencing means determining the sequences of a complete set of autosomes and one of each type of sex chromosome. For example, the human genome consists of 22 pairs of autosomes and 2 sex chromosomes, therefore a complete genome sequence will comprise of 46 separate chromosome sequences. It is also important to determine the sequence of the mitochondrial or chloroplast DNA to have complete information about the genome of eukaryotic organisms. To sequence the genome of any organism genome projects are undertaken. Genome projects are scientific research projects initiated by research groups world over with the aim of sequencing the complete genome, annotating the protein-coding genes and decoding the essential features of a genome which either distinguishes it or relates it to another genome. Both the length of the genome as well as the total number of genes differ extensively from one species to another. The decision to sequence a genome by the research agencies depends upon the importance of that organism. It might be a model organism, may have commercial importance (example crop plant, livestock, yeast or enzyme producing bacteria) or significant importance to human health. Emphasis is also given to sequencing the genome of a species that will help in determining molecular evolution or phylogeny. The genome sequence provides information regarding the order of every nitrogenous base, whereas a genome map is less detailed than a genome sequence but identifies the landmarks and helps in navigating around the genome. Historically, for sequencing the eukaryotic genomes the common 3 Molecular Genetics ZOOLOGY Large scale analysis of genome: Human Genome Part I approach was to first map the genome to which gives information regarding the landmarks within the genome instead of sequencing the chromosome in one go. Mapping the chromosome allows sequencing to be done bit by bitas one already knows just about where a particular DNA fragment might be located on the chromosome. Currently, due to improvements in DNA sequencing technology it is possible to sequence the entire genome more quickly and in one go using methods such as the Shotgun approach. Sequencing of genomes has become more affordable due to steady reduction in the cost in terms of cost per base pair. 3. Human Genome Project The HGP was a collaborative project between several countries that aimed to know the sequence of 3 billion base pairs comprising the human DNA. It also involved both identifying and mapping the total number of genes in the human genome. The HGP was both proposed and funded by the US government and till date is the world's largest collaborative project. Although, the planning of the project started in 1984 but the work began in 1990 and the complete genome was announced in 2003. In 1998 Craig Venter founded the Celera Genomics, a company that took up the sequencing project parallel to HGP that was privately funded. The sequencing was carried out in the twenty institutes mentioned below. The International Human Genome Sequencing Consortium included the following institutes: 1. The Whitehead Institute/MIT Center for Genome Research, Cambridge, Mass., U.S. 2. The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U. K. 3. Washington University School of Medicine Genome Sequencing Center, St. Louis, Mo., U.S. 4. United States DOE Joint Genome Institute, Walnut Creek, Calif., U.S. 5. Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, Houston, Tex., U.S. 6. RIKEN Genomic Sciences Center, Yokohama, Japan 7. Genoscope and CNRS UMR-8030, Evry, France 8. GTC Sequencing Center, Genome Therapeutics Corporation, Waltham, Mass., USA 9. Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany 10. Beijing Genomics Institute/Human Genome Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China 11. Multimegabase Sequencing Center, The Institute for Systems Biology, Seattle, Wash. 12. Stanford Genome Technology Center, Stanford, Calif., U.S. 13. Stanford Human Genome Center and Department of Genetics, Stanford University School of Medicine, Stanford, Calif., U.S. 14. University of Washington Genome Center, Seattle, Wash., U.S. 15. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan 16. University of Texas Southwestern Medical Center at Dallas, Dallas, Tex., U.S. 17. University of Oklahoma's Advanced Center for Genome Technology, Dept. of Chemistry and Biochemistry, University of Oklahoma, Norman, Okla., U.S. 18. Max Planck Institute for Molecular Genetics, Berlin, Germany 4 Molecular Genetics ZOOLOGY Large scale analysis of genome: Human Genome Part I 19. Cold Spring Harbor Laboratory, Lita Annenberg Hazen Genome Center, Cold Spring Harbor, N.Y., U.S. 20. GBF - German Research Centre for Biotechnology, Braunschweig, Germany. These international institutions played a vital role in quick and effective completion of the HGP. In the United States, where the project was founded the major contributors were 1. The U.S. Department of Energy (DOE)- It was the center for the discussion of the HGP as early as 1984. 2. National Institutes of Health (NIH)- It first participated in the project in 1988, by creating the Office for Human Genome Research, which was upgraded in 1990 to the National Center for Human Genome Research and then later on in 1997 it was named as the National Human Genome Research Institute (NHGRI). The funding for the HGP came from not only the US government through the NIH and DOE but, also from a UK based charity organization known as the Wellcome Trust, and several organizations located world over. The UNESCO played a significant role in involving the developing nations in the HGP. 4. History of Human Genome Sequencing The HGP arose because of two important perceptions that arose in the early 1980s. The first was to sequence complete genomes which would result in accelerated biomedical research, as it would allow the researchers to solve problems in an all-inclusive and unbiased fashion. The second insight was the requirement to build infrastructure through communal effort, something that no one had attempted in biomedical research so far. Important projects that played a vital role in crystallizing these insights were: 1. In between 1977 and 1982, the complete genomes of bacterial viruses ØX174 and ƛ, the animal virus SV407 and the human mitochondrion were sequenced. These sequencing projects demonstrated the practicability of assembling small sequences into complete genomes. The data generated led people to value the complete set of genes and other functional elements for further research and analysis. 2. Botstein and colleagues in 1980, launched a program which could generate a human genetic map which made it feasible to find genes causing disease of unknown function on the basis of only their inheritance patterns. 3. In the mid-1980s, Olson and Sulston launched programs that created physical maps of clones containing sequences that covered the yeast and worm genomes. This allowed the separation of genes and regions on the basis of their chromosomal position. The history of the HGP dates back to 1985 when, Robert Sinsheimer in the May of 1985 organized a workshop for discussing the sequencing of the human genome, but the NIH was not interested in his proposal.
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