Credits: Teaching resources from School of Forest Resources and
Environmental Science Michigan Tech University
1 SBL201 Lec 5 24-09-2014 Origin of terms Genomes and Genomics The term genome was used by German botanist Hans Winker in 1920 Collection of genes in haploid set of chromosomes Now it encompasses all DNA in a cell In 1986 mouse geneticist Thomas Roderick used Genomics for mapping, sequencing and characterizing genomes New terms: Functional genomics, transcriptomics, proteomics, metabolomics, phenomics (Omics) 2 SBL201 Lec 5 24-09-2014 What is the genome? Entire genetic complement of an organism 3 SBL201 Lec 5 24-09-2014 How many types of genomes are there in this world? Prokaryotic genomes Eukaryotic Genomes Nuclear Genomes Mitochondrial genomes Choloroplast genomes
4 SBL201 Lec 5 24-09-2014 Why should we study genomes? Each and everyone is a unique creation! Lifes little book of instructions DNA blue print of life! Human body has 10 13 cells and each cell has 6 billion base pairs (A, C, G, T) A hidden language/code determines which proteins should be made and when This language is common to all organisms
5 SBL201 Lec 5 24-09-2014 Genome sequence can tell us Everything about the organism's life Its developmental program Disease resistance or susceptibility How do we struggle, survive and die? Where are we going and where we came from? How similar are we to apes, trees, and yeast?
6 SBL201 Lec 5 24-09-2014 How will the study of Genomics impact this century? Biotechnology: more products GMOs: More food-More problems? Our society will not be the same! Individualized medicine Gene therapy Disease free life?
7 SBL201 Lec 5 24-09-2014 Now look at your neighbor What do you see? Someone is different than you! Could be that your friend differs in his/her sex, looks, nature, smartness, or simply the way he/she dresses and talks How much similarity you think you share with your friend at the gene level? 99.9% so we could fix genes if we want 8 SBL201 Lec 5 24-09-2014 Now look at your own hands and legs Do they look similar? No! But they contain the same DNA in each of their cells DNA makes RNA makes proteins Different genes are expressed differently in different cells, tissues and organs of an organism Having a gene does not mean it will be expressed. 9 SBL201 Lec 5 24-09-2014 Someone has a cancer gene! It is a normal gene that got mutated or changed and does not perform same job But having a gene does not mean you will get cancer Because environment has a big role in turning a gene on or off Different genes and their products also interact: microecosystem Genes do not work alone (G+E) 10 SBL201 Lec 5 24-09-2014 Genomics is the study of all genes present in an organism 11 SBL201 Lec 5 24-09-2014 Science of Genomics? A marriage of molecular biology, robotics, and computing Tools and techniques of recombinant DNA technology e.g., DNA sequencing, making libraries and PCRs High-throughput technology e.g., robotics for sequencing Computers are essential for processing and analyzing the large quantities of data generated 12 SBL201 Lec 5 24-09-2014 Origin of Genomics Human Genome Project Goal: sequence 3 billion base pairs High-quality sequence (<1 error per 10 K bases) ACGT Immensity of task required new technologies Automated sequencing Decision to sequence other genomes: yeast and bacteria Beginnings of comparative genomics
13 SBL201 Lec 5 24-09-2014 Technical foundations of genomics Molecular biology: recombinant-DNA technology DNA sequencing Library construction PCR amplification Hybridization techniques L o g
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Distance . . . . 14 SBL201 Lec 5 24-09-2014 Genomics relies on high-throughput technologies Automated sequencers Fluorescent dyes Robotics Microarray spotters Colony pickers High-throughput genetics 15 SBL201 Lec 5 24-09-2014 Sequencing genomes in Months and Years Sequencing genomes in Minutes (14 min precisely)!! Technology Revolution Sequencing bysynthesis nanotechnologyapproach
From a Few Billion $ to $5000 24-09-2014 SBL201 Lec 5 16 Industrial-scale Genomics Lab 2002 Paradigm Genetics, Inc. All rights reserve d. Used with permission. 17 SBL201 Lec 5 24-09-2014 Genome sequencing Analogy: Complete works of an author in partially understood language Two approaches Page by page All at once 18 SBL201 Lec 5 24-09-2014 Page-by-page sequencing strategy Sequence = determining the letters of each word on each piece of paper Assembly = fitting the words back together in the correct order
19 SBL201 Lec 5 24-09-2014 All-at-once sequencing strategy Find small pieces of paper Decipher the words on each fragment Look for overlaps to assemble
20 SBL201 Lec 5 24-09-2014 Genome size and gene number Amoeba dubia: 670 billion base pairs 21 SBL201 Lec 5 24-09-2014 Lessons from sequencing Variability of genome structure: Non- coding (junk?) Duplication events Transposons Microsatellites Repetitive DNAs 1 2 3 4 5 22 SBL201 Lec 5 24-09-2014 Functional Genomics Once we know the sequence of genes, we want to know the function The genome is the same in all cells of an individual, except for random mutations However, in each cell, only a subset of the genes is expressed The portion of the genome that is used in each cell correlates with the cells differentiated state 23 SBL201 Lec 5 24-09-2014 Gene-by-gene approach to understand biological processes Analogous to understanding circuitry by following wires Choose one wire Follow circuit to transistor Follow from transistor to capacitor Follow from capacitor to power source Do again 24 SBL201 Lec 5 24-09-2014 Genomics provides a parts list Provides list of all parts Parts list in itself doesnt say how the machine works Can use to get global picture e.g., RNA expression 25 SBL201 Lec 5 24-09-2014 Expression microarrays Global expression analysis RNA levels of 30x10 3
genes in the genome analyzed in parallel Compare with Northern blot Microarrays contain more information by many orders of magnitude 26 SBL201 Lec 5 24-09-2014 Biological networks: Systems Biology Food chain Neuronal network Transcriptional network 27 SBL201 Lec 5 24-09-2014 Regulatory network of sea urchin development 28 SBL201 Lec 5 24-09-2014 Future of sequencing We have the genome! Whats next? (post genome era) Sequencing costs Dropping each year Could go down to <$1,000/genome Opens possibility of sequencing genomes of individuals: 23andMe Greatly facilitates comparative genomics 30 SBL201 Lec 5 24-09-2014 Comparative Genomics What is conserved between species? Genes for basic processes Understand the uniqueness between different species Their adaptive traits What makes closely related species different? Analyzing & comparing genetic material from different species to study evolution, gene function, and inherited disease 31 SBL201 Lec 5 24-09-2014 What is compared? Gene location Gene structure Exon number Exon lengths Intron lengths Sequence similarity Gene characteristics Splice sites Codon usage Conserved synteny 32 SBL201 Lec 5 24-09-2014 Figure 1 Regions of the human and mouse homologous genes: Coding exons (white), noncoding exons (gray}, introns (dark gray), and intergenic regions (black). Corresponding strong (white) and weak (gray) alignment regions of GLASS are shown connected with arrows. Dark lines connecting the alignment regions denote very weak or no alignment. The predicted coding regions of ROSETTA in human, and the corresponding regins in mouse, are shown (white) between the genes and the alignment regions. 33 SBL201 Lec 5 24-09-2014 Improved disease diagnostics from genomics Microarray analysis of gene expression from four different types of tumors Grouping of gene expression patterns shows very clear differences among the tumors Used to tailor therapy to individuals
34 SBL201 Lec 5 24-09-2014 Pharmacogenomics: drug therapies tailored to individuals Design therapies based on the individuals genome Subtle, but important, differences in genomes Cause differences in how one responds to drugs Identify those who will suffer harmful side effects from particular drugs
35 SBL201 Lec 5 24-09-2014 Prescreening based on genomes All patients with same diagnosis 1 Remove Toxic and Nonresponders Treat Responders and Patients Not Predisposed to Toxic 2 36 SBL201 Lec 5 24-09-2014 Genomics applied to agriculture Sequencing of crop- plant genomes Gene discovery for useful traits Genomewide regulatory networks to improve traits
37 SBL201 Lec 5 24-09-2014 Farm-animal genomics Genome sequencing of pigs, cows, sheep, and poultry EST sequencing Agricultural pathogens Potential bioterrorism agents 38 SBL201 Lec 5 24-09-2014 Ethical issues raised by genomics (ELSI) (Ethical legal, societal implications) Individuals genome holds key to disease susceptibility Potential for misuse recognized by founders of Human Genome Project 39 SBL201 Lec 5 24-09-2014 Genetic testing in the workplace Major railroad company decided to perform DNA tests on employees Wanted to identify susceptibility to carpal tunnel syndrome Equal Employment Opportunity Commission filed suit to block action 40 SBL201 Lec 5 24-09-2014 Genetic modification of humans Once we know the genes responsible for particular diseases, should we cure the diseases? Should we also modify genes responsible for traits such as height or beauty? Should we allow the cloning of human beings? 41 SBL201 Lec 5 24-09-2014