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  1. 1. GENOMICS
  2. 2. WHAT IS GENOMICS? • Genomics is the sub discipline of genetics devoted to the – mapping, – sequencing , – and functional analysis of genomics.
  3. 3. WHAT IS GENOMICS? • The field includes studies of introgenomic phenomena such as heterosis, epistasis, pleiotropy and other interactions between loci and alleles within the genome.
  4. 4. WHAT IS GENOMICS? • How is Genomics different from Genetics? – Genetics looks at single genes, one at a time, like a picture or snapshot. – Genomics looks at the big picture and examines all the genes as an entire system.
  5. 5. HISTORY OF GENOMICS • Genomics can be said to have appeared in the 1980s, and took off in the 1990s with the initiation of genome projects for several biological species. • The most important tools here are microarrays and bioinformatics.
  6. 6. HISTORY OF GENOMICS cont… • Without a doubt, the introduction of the computers into molecular biology laboratories was one of the key factors in the development of the genomics. • Laboratory automation led to the production of large amounts of data, and the need of analysis ,combine and understand these resulted in development of “Bioinformatics”
  7. 7. RELATED DEVELOPMENTS • Bioinformatics and computational biology involves the use of techniques including – applied mathematics, – informatics, – statistics, – computer science, – artificial intelligence, – chemistry and biochemistry, to solve biological problems usually on the molecular level.
  8. 8. WHAT IS A GENOME? • The genome broadly refers to the total amount of DNA of a single cell (haploid cell in the case of a diploid organism) of an organism, including its genes. “The whole hereditary information of an organism that is encoded in the DNA”
  9. 9. WHAT IS A GENOME? Genes provide the information for making all proteins that are necessary for the expression of characters. Gene Protein Character Characters refers to how an organism looks, its physiology, its ability to fight infections and even its behavior.
  10. 10. • The genome is found inside every cell, and in those that have nucleus, the genome is situated inside the nucleus. It is a part of the DNA molecule.
  11. 11. • DNA sequencing techniques enables scientists to determine the exact order or sequence of the bases of a genome.
  12. 12. • The sequence information of the genome will show, • the position of every gene along the chromosome, • the regulatory regions that flank each gene, and • the coding sequence that determines the protein produce by each gene.
  13. 13. LOOKING AT A GENOME • • 1. 2. 3. 4. The key question about the genome is how many genes it contains. We can think about the total number of genes at four levels, corresponding to successive stages in gene expression: Genome Transcriptome Proteome Proteins
  14. 14. SOME QUICK FACTS ABOUT GENOMES • Individual genomes show extensive variation. • Not all genes are essential. In yeast and fly, deletions of <50% of the genes have detectable effects.
  15. 15. QUICK FACTS cont… • A substantial part of most eukaryotic nuclear genomes is made up of Repetitive DNA. – Repetitive DNA: individual sequence elements that are repeated many times over, either in tandem arrays or interspersed throughout the genome. – Single copy DNA: which includes most genes, and is made up of sequences that are not repeated elsewhere.
  16. 16. QUICK FACTS cont… • Extrachromosomal genes: – The mitochondria of all organisms, as well as the chloroplasts of all photosynthetic cells, contain DNA molecules that carry a limited number of genes. – These genes code for the RNAs and some of the proteins required in the organelle.
  17. 17. Genes and Proteins & the role of Introns • Introns: Derived from the term "intragenic regions", are non-coding sections of precursor mRNA (pre-mRNA). • Exons: Are coding sections that remain in the mRNA sequence.
  19. 19. INTRONS AND EXONS • Introns are common in eukaryotic pre-mRNA, but in prokaryotes they are only found in tRNA and rRNA. • Unlike introns, exons are coding sections that remain in the mRNA sequence.
  20. 20. INTRONS AND EXONS • It is now recognized that introns are "a complex mix of different DNA, much of which are vital to the life of the cell”. • Introns produce a major selection advantage and consequently are characteristic of higher, more developed organisms • The relationship of introns to cancer and their use as tumor markers is also being explored.
  21. 21. • Are genes uniformly distributed in chromosomes? – Some chromosomes are relatively poor in genes, and have >25% of their sequences as “deserts” – regions longer than 500 kb where there are no genes.
  22. 22. WHY SEQUENCE GENOMES? • Because there is a need to put information about the genomes of flora and fauna in the context of the fields that they serve. • Genomic sciences will serve those that choose genetic modification as a method for crop improvement as well as those that apply conventional breeding methods to improve and develop agricultural practices.
  23. 23. WHY SEQUENCE GENOMES? • This information is used by physiologists and scientists in research determining relationships between stress, genes and yield potential etc. • It can also be used to produce sufficient amounts of safe and nutritious food in times of increased population growth.
  24. 24. WHY SEQUENCE GENOMES? • It can be used to conserve and protect agricultural and other environments. • It can serve the farmer/producer under increasing financial pressure by providing higher yields through improve varieties.
  25. 25. WHY SEQUENCE GENOMES? • We need information and technology to – improve human health, – harness natural energy, – understand and react in a positive manner to global climate change, – clean up our environment and – ensure food safety.
  26. 26. ANTICIPATED BENEFITS OF GENOME RESEARCH • • • • Molecular Medicine Microbial Genomics Risk Assessment Bioarchaelogy, Anthropology, Evolution and Human Migration • DNA Identification (Forensics) • Agriculture, Livestock Breeding, and Bioprocessing
  27. 27. GENOME MAPPING • Genomes can be mapped by, – Linkage, – Restriction cleavage, or – DNA sequence.
  28. 28. LINKAGE MAP • A genetic / linkage map identifies the distance between mutations in terms of recombination frequencies. • A linkage map can also be constructed by measuring recombination between sites in genomic DNA.
  29. 29. RESTRICTION CLEAVAGE • A restriction map is constructed by cleaving DNA into fragments and measuring the distances between the sides of cleavage. • Large changes in the genome can be recognized because they affect the size or number of restriction fragments. Thus point mutations are difficult to detect.
  30. 30. DNA SEQUENCE • By analyzing the protein-coding potential of the sequence of the DNA. • The principle is to obtain a series of overlapping fragments of DNA, which can be connected into continuous map.
  31. 31. HUMAN GENOME PROJECT The Human Genome • The human genome is by far the most complex and largest genome. • Its size spans a length of about 6 feet of DNA, containing 30,000 to 40,000 genes.
  32. 32. HUMAN GENOME PROJECT The Human Genome • The DNA material is organized into a haploid chromosomal set of 22 and a sex chromosome.
  33. 33. HUMAN GENOME PROJECT • The US Human Genome Project is a 13 year effort, which is coordinated by the – Department of Energy (DOE) and – National Institutes of Health (NIH). • This project was launched in 1986 by Charles DeLisi and was originally planned to last for 15 years.
  34. 34. HUMAN GENOME PROJECT Goals • Identify the approximate genes in human DNA. • Determine the sequences of 3 billion chemical base pairs that make up human DNA. • Store this information in databases. • Improve tools for data analysis.
  35. 35. HUMAN GENOME PROJECT Goals • Transfer related technologies to the private sector. • Address the ethical, legal and social issues (ELSI), that may arise from the project.
  36. 36. HUMAN GENOME PROJECT Milestones 1986 1990 1994 The birth of the Human Genome Project. Project initiated as joint effort of US Department of Energy and the National Institute of Health. Genetic Privacy Act: to regulate collection, analysis, storage and use of DNA samples and genetic information is proposed.
  37. 37. HUMAN GENOME PROJECT Milestones 1996 1998 1999 2000 Welcome Trust joins the project. Celera Genomics formed to sequence much of the human genome in 3 years. Completion of the sequence of Chromosome 22-the first human chromosome to be sequenced. Completion of the working draft of the entire human genome.
  38. 38. HUMAN GENOME PROJECT Milestones 2001 2003 Analysis of the working draft are published. HGP sequencing is completed and Project is declared finished two years ahead of schedule.
  39. 39. HUMAN GENOME PROJECT • Whose DNA is being sequenced? – Used samples from of blood (female) and sperm (male) from a large number of people. – Celera Genomics collected samples from individuals who were Hispanic, Asian, Caucasian, and African-American. – The donor identities were protected.
  40. 40. HUMAN GENOME PROJECT • The first step towards sequencing the genome is creating maps. • Maps are of various types: – Genetic Linkage Maps – Physical Maps – Contig Maps
  41. 41. HUMAN GENOME PROJECT Sequencing • Chromosomes broken down into much shorter pieces. • Each short piece is used as a template to generate a set of fragments. • The fragments in a set are separated by gel electrophoresis. • The final base at the end of each fragment is identified.
  42. 42. HUMAN GENOME PROJECT Sequencing • Automated sequencers analyze the resulting electropherograms giving the output as a four-colour chromotogram. • After the bases are “read”, computers are used to assemble the short sequences into long continuous stretches.
  43. 43. A CLOSER LOOK AT THE HUMAN GENOME • The human genome contains 3164.7 million nuckeotide bases ( approx. 3 billion A,C,T and G). • The average gene is made up of 3000 bases, but sizes of genes vary greatly.
  44. 44. A CLOSER LOOK AT THE HUMAN GENOME • The total number of genes is estimated at around 30000. • Almost all (99.9%) nucleotide bases are exactly the same in all the people.
  45. 45. A CLOSER LOOK AT THE HUMAN GENOME • Less than 2 % of the genome codes for protein.
  47. 47. A CLOSER LOOK AT THE HUMAN GENOME • Repeated sequences that do not code for proteins (“junk DNA”) make up at least 50% of the genome. • Repetitive sequences fall into five classes: 1. Transposons 2. Processed pseudogenes 3. Simple sequence repeats 4. Segmental duplications 5. Tandem repeats form blocks of one type of sequence
  49. 49. A CLOSER LOOK AT THE HUMAN GENOME • The sequence of human genome emphasizes the importance of transposons. • Most of the transposons in the human genome are nonfunctional; very few are currently active. • They have played an active role in shaping the genome.
  50. 50. A CLOSER LOOK AT THE HUMAN GENOME • Some present genes originated as transposons, and evolved into their present condition after losing the ability to transpose. • Almost 50 genes appear to have originated like this.
  51. 51. A CLOSER LOOK AT THE HUMAN GENOME • The human genome’s gene-dense “urban centres” are predominantly composed of C and G bases. • The gene-poor “deserts” are rich in A and T bases. • Genes appear to be concentrated in random areas along the genome, with vast expanses of non-coding DNA in between.
  52. 52. A CLOSER LOOK AT THE HUMAN GENOME • Stretches of up to 30000 G and C bases repeating over and over occur adjacent to gene-rich areas, forming a barrier between the genes and the “junk” DNA. • Chromosome 1 has the most number of genes (2968) and Y chromosome the least (231).
  53. 53. SEQUENCING THE GENOMES OF OTHER ORGANISMS • The sequence of many organisms have been carried out and is still being carried out at a rapid pace. • There are many medical, genetic and commercial reasons for sequencing the genomes of various organisms.
  54. 54. • As of September 2007 the complete sequence was known of, – 1879 viruses, – 577 bacterial species, and – roughly 23 eukaryotic species (of which about half are fungi).
  55. 55. PROKARYOTIC GENOMES Escherichia coli Genome • Escherichia coli considered as model bacteria. • Model organism for studying many essential processes of life. • The E. coli strain K-12 genome was sequenced.
  56. 56. Escherichia coli Genome • 4639 kb in length • Comprises approximately 4288 genes. – 1897 genes coding for known proteins – 397 unidentified open-reading frames • The 4288 genes take up approximately 80% of the DNA molecule with the remaining 20% being made up of intergenic regions.
  57. 57. • Note on the genomes of other bacteria: – The basic features of gene organization, with numerous operons but few repeated genes, appear to be the same in all bacteria. – Many of the bacteria with larger genomes have more complex life cycles. – The bacteria with the smallest genomes are mostly obligate parasites.
  58. 58. Escherichia coli Genome • Benefits of the genome project: – Role of small proteins found in E. coli. – To identify proteins that are crucial to E. coli. – By comparing the genes, we can infer how particular genes originated. – Sequence information of strain K-12 of E. coli can be used to compare with the deadly E. coli designated O157:H7, which has also been sequenced.
  59. 59. EUKARYOTIC GENOMES Saccharomyces cerevisiae Genome • One of the most important fungal organisms used in biotechnological processes. • Considered as a model eukaryotic organism. • The first eukaryotic organism to have its entire genome sequenced
  60. 60. Saccharomyces cerevisiae Genome • 16 chromosomes (2n) • Approximate genome size – 15520 kb • 5885 potential protein-coding genes.
  61. 61. Caenorhabditis elegans (Nematode) Genome • Is an often used simple model for multicellular organisms. • 19099 known and predicted genes. • One gene per 5076 bp.
  62. 62. Drosophila melanogaster (Fruit Fly) Genome • Has been the most important tool for genetics studies in the twentieth century. • Second multicellular organism to have its genome sequenced. • Genome is about 180 Mb in size • 4 chromosomes (2n) • 13601 predicted genes
  63. 63. Drosophila melanogaster (Fruit Fly) Genome • Interestingly, the Drosophila genome contains genes that are similar to 177 of 289 human genes that are responsible for diseases.
  64. 64. Arabidopsis thaliana (Thale / Mouse Ear Cress) Genome • Used as a model plant in plant research. • This was the first ever plant to be completely sequenced. • 10 chromosomes (2n).
  65. 65. Arabidopsis thaliana (Thale / Mouse Ear Cress) Genome • Spans 125 Mb • Contains a total of 25498 genes and code for 11601 proteins – Of these proteins, 35% are unique to plants • Of the total genes, 9% were classified experimentally, while 30% were unclassified. • At least 70% of the genes are duplicated.
  66. 66. Arabidopsis thaliana (Thale / Mouse Ear Cress) Genome • Impacts of plant genetics and research: – Greatly simplify the process of forward genetics. – Study of human diseases. – Improve food crops.
  67. 67. Oryza sativa L. (rice) Genome • One of the ,most important food crops in the world. • Scientists use rice as a model plant in cereal genomics. • 24 chromosomes (2n).
  68. 68. Organism Type Genome size Number of genes predicted Oryza sativa Rice ssp. indica 420 Mb 32 – 50000 Oryza sativa Rice ssp.japonica 466 Mb 46022 – 55615
  69. 69. Mus musculus (Laboratory Mouse) Genome • The sequence of the mouse genome is important for understanding the contents of the human genome and it also serves as a key experimental tool for biomedical research. • 20 chromosomes (2n)
  70. 70. Mus musculus (Laboratory Mouse) Genome • The draft sequence was generated by assembling the sevenfold sequence coverage from female mice of the B6 strain. • Genome size is 2.5 Gb. • Seem to contain about 30000 protein-coding genes.
  71. 71. COMPARING THE GENOMES OF DIFFERENT ORGANISMS • Why Compare? – Need to better understand the individual genomes – To understand the functioning of individual genes – To derive a comparative study of basic functions – To better understand evolutionary processes
  72. 72. COMPARATIVE CEREAL GENOMICS • Rice is now considered as the model system for studying cereal genomics because of its relationship to other cereals. • It is extremely difficult to carry out studies at the molecular level of wheat, maize, barley and rye. • Gene content in rice is comparable to other grass plants and gene order and sequences have been conserved during evolution.
  73. 73. COMPARATIVE CEREAL GENOMICS • The conservation of the order of genes (Synteny) allows the identification of linkages between plant families through their genomes. • This will provide information to understand the structure and evolution pattern of genes and genomes.
  75. 75. COMPARATIVE CEREAL GENOMICS • Through the identification of different loci, the existence of synteny will assist in isolating an important gene in the small genome of rice and use it as a probe to isolate the corresponding homologue in a plant with a much larger genome such as wheat or maize.
  76. 76. COMPARATIVE CEREAL GENOMICS • Such studies will – Make an important contribution to cereal breeding. – Be the basis for maximizing the breeding potential of all cereal plants. • Rice will serve as the “reference” genome for comparative studies and a donor of genes for biotech manipulations.
  77. 77. COMPARATIVE ANALYSIS OF THE HUMAN AND MOUSE GENOMES • The mouse genome is 14% smaller than the human genome. • At the nucleotide level, approximately 40% of the human genome can be aligned to the mouse genome. • The mammalian genome is evolving in a non-uniform manner.
  78. 78. • The mouse and human genomes seem to contain about 30000 protein-coding genes. • Mouse-human sequence comparisons allow an estimate of the rate of protein evolution in mammals. • Similar types of repeat sequences have accumulated in the corresponding genomic regions in both species.
  79. 79. GENERAL GENOMIC COMPARISONS • Unlike the human’s seemingly random distribution of gene-rich areas, many other organisms’ genomes are more uniform, with genes evenly spaced throughout. • Although humans appear to have stopped accumulating repeated DNA over 50 million years ago, there seems to be no such decline in rodents.
  80. 80. GENERAL GENOMIC COMPARISONS Organism Genome Size (Bases) Estimated Genes Human (Homo sapiens) 3 billion 30,000 Laboratory mouse (M. musculus) 2.6 billion 30,000 Thale cress (A. thaliana) 100 million 25,000 Roundworm (C. elegans) 97 million 19,000 Fruit fly (D. melanogaster) 137 million 13,000 Yeast (S. cerevisiae) 12.1 million 6,000 Bacterium (E. coli) 4.6 million 3,200 Human immunodeficiency virus (HIV) 9700 9
  81. 81. GENOMES AND EVOLUTION • Comparisons of the human genome sequence with sequences found in other species is revealing about the process of evolution. • Comparisons of different genomes show a steady increase in gene number as additional genes are added to make eukaryotes, make multicellular organisms, make animals, and make vertebrates.
  82. 82. GENOMES AND EVOLUTION • Most of the genes that are unique to vertebrates are concerned with the immune or nervous system.
  83. 83. GENOMES AND EVOLUTION • We see, therefore, that the progression from bacteria to vertebrates requires addition of groups of genes representing the necessary new functions at each stage.
  84. 84. GENOMES AND EVOLUTION • Comparing the human proteome in more detail with proteomes of other organisms, – 46% of the yeast proteome, – 43% of the worm proteome, and – 61% of the fly proteome is represented in the human proteome. • A key group of approx. 1300 proteins is present in all four proteomes.
  85. 85. • The common proteins are housekeeping proteins required for essential functions.
  86. 86. ISSUES OF CONCERN Ethical, Legal and Social issues of the Human Genome Project • Fairness in the use of genetic information. • Privacy and confidentiality of genetic information. • Psychological impact, stigmatization, and discrimination. • Reproductive issues. • Clinical issues. • Uncertainties associated with gene tests for susceptibilities and complex conditions.
  87. 87. ISSUES OF CONCERN Ethical, Legal and Social issues of the Human Genome Project • Fairness in access to advanced genomic technologies. • Conceptual and philosophical implications. • Health and environmental issues. • Commercialization of products. • Education, Standards, and Quality control. • Patent issues.
  88. 88. ISSUES OF CONCERN • Some questions to consider: – Who should have access to your genetic information? – How does knowing your predisposition to disease affect an individual? – Should screening be done when there is no treatment available?
  89. 89. ISSUES OF CONCERN Example situation: Human Gene Prospecting in Iceland • The human gene pool of Iceland is much more homogenous than the gene pools of most other populations.
  90. 90. Human Gene Prospecting in Iceland cont. • Iceland’s national health service has kept superb medical records since 1915. • deCODE Genetics, a private company has an exclusive license from the government of Iceland to construct and analyze a genetic database derived from the country’s health records.
  91. 91. Human Gene Prospecting in Iceland cont. • deCODE Genetics has a deal with the Swiss pharmaceutical giant Hoffman-LaRoche. • To the people of Iceland, the contract specifies that Hoffman-LaRoche must provide free of charge all drugs, diagnostic tests and other products resulting from this research.
  92. 92. Human Gene Prospecting in Iceland cont. • The key issue in the ongoing debate in Iceland is the question of presumed consent and informed consent.
  93. 93. ISSUES OF CONCERN “Will the poor get poorer whilst losing their valuable genetic resources, and the rich get richer? Will the exorbitantly expensive research into genomics and proteomics limit this powerful technology to the rich only? Can we manage without this technology? Will someone sequence the tea genome, for example? Should we not do it first, being so famous for Ceylon tea? Can we not use this technology to identify and isolate those wonderful genes from our traditional rice varieties and transfer them to present day varieties? Can we not manipulate the rubber genome to produce better quality rubber and lead the world market?”
  94. 94. THE FUTURE • Future Challenges – What we still don’t know – Beyond the HGP: – – – – – – – – – Gene number, exact locations, and functions Gene regulation DNA sequence organization Chromosomal structure and organization Noncoding DNA types, amount, distribution, information content, and functions Coordination of gene expression, protein synthesis, and posttranslational events Interaction of proteins in complex molecular machines Predicted vs experimentally determined gene function Evolutionary conservation among organisms
  95. 95. THE FUTURE • Future Challenges – What we still don’t know – Beyond the HGP: – Protein conservation (structure and function) – Proteomes (total protein content and function) in organisms – Correlation of SNPs (single-base DNA variations among individuals) with health and disease – Disease-susceptibility prediction based on gene sequence variation – Genes involved in complex traits and multigene diseases – Complex systems biology including microbial consortia useful for environmental restoration – Developmental genetics, genomics
  96. 96. THE FUTURE Functional Genomics Trasnscriptomics Proteomics Structural Genomics Experimental methodologies and Comparative Genomics
  97. 97. THE FUTURE Genomes to Life: A DOE Systems Biology Program Exploring Microbial Genomes for Energy and the Environment HapMap Chart genetic variation within the human genome
  98. 98. THE FUTURE • What does the future hold for us? • How far will this new science take us? • What will become the boundary of man?
  99. 99. THE FUTURE “We still do not have in our hands the answer to a most fundamental question: What makes us human…?”
  100. 100. The staff of the Department of Biotechnology of the Faculty of Agriculture and Plantation Management. GROUP MEMBERS Ikram Mohideen 066020 Prof. D.P.S.T.G. Nimhani Perera Attanayake B.Sc. (Agric) 066119 (Peredeniya), Ph.D. (Birm) Kokila Harshanie 066092 Janaki Gunathilake 066016 Prof. E.R.K. Perera Damith Dharmarathne B.Sc. Hons.(Agric), M.Sc. 066066 (VPI & SU, USA), Ph.D.(VPI & SU, USA), Janaka Sampath 066094 Postdoctoral Animal Biotechnology (VPI & Pubudu Gokarella 066013 SU, USA) Nushri Jamal Mohamed 066115 Thilini Priyadharshani 066049 Prof. Athula Perera B.Sc. (Agric) (Sri Lanka), Sandun Ranasinghe 066084 M.Sc.(Japan), Ph.D.(UK), Postdoctoral training – Biotechnology & Biosafety(UK, USA,
  101. 101. REFERENCES Book based research Perera, A. “Secrets of the Genomes” 1st edition, 2005. Brown,T.A “Genomes” 8-10 Snustad,Simmons.“Principles of Genetics”.3rd edition, 514-541 Kumar,H.D.”Molecular Biology”, Lewin ,“Genes III”, 236-277 Lewin ,“Genes VIII”,52-69 Domingo,Esteban; Holland, J.J; Ahlquist,Paul. “RNA Genetics” volume 1 “Genomics & Bioinformatics”, 8-25 Journal based research Beachy,R.N(Ph.D), President & Director, Donald Donforth Plant