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Transcript
Chapter 15 The Human Genome Project and Genomics Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Genomics • Is the study of all genes in a genome • Relies on interconnected databases and software to analyze sequenced genomes and to identify genes • Impacts basic research in biology and generates new methods of diagnosis and treatment of disease Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Linkage refers to the transmission of two genes on the same chromosome How was linkage discovered? Standard dihybrid cross Find that observed ratios in the F2 progeny do not follow mendelian ratios. Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Fig. 5.11 Dihybrid Cross: purple flower Fig. P:5.11 L: long pollen, p: white flower l: round pollen P_L_: P_ll: ppL_ : ppll 9 : 3 : 3 : 1 Observed: hi low low Hypothesis: These two genes are somehow linked, and do not assort independently Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning hi Fig. 5.11 Two extremes Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Crossing over Disrupts Linkage and creates new combination of alleles (recombinants) Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Figure 5.10 Gene Linkage • Two or more genes do not show independent assortment • They tend to be inherited together • Located on the same chromosome • A measure of the degree of recombination gives relative distance between them Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Recombination Frequency (RF) = # of recombinant gametes/ total # of gametes • RF for a set of genes is proportional to the distance between the genes Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Figure 5.12 Linkage Maps. Linear maps from RF data RF of 1% between two genes: = 1 map unit or 1 centiMorgan (cM) apart. Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Genetic Mapping • Find linkages between genes • Measuring the frequency of crossing over to determine the relative distance between the genes • Linkage analysis is difficult to do in humans: only 5 human linkage groups were identified by 1969 • Unit of measure is a centimorgan (cM) 1cM = frequency of 1% recombination Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning General rules Recombination frequency is constant between two genes. Recombination frequency varies between different genes. NO Recombination = genes are very closely linked. Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Linked Genes Fig. 15.3 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Positional Cloning • Recombinant DNA-based method for mapping and cloning genes • No prior information about the gene product or its function is required • Maps cloned DNA sequences; most are markers not genes • 3,500 genes and markers identified in the late 1980s Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Genes ID-ed by Positional Cloning Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chromosome 1 Fig. 15.4 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Human Genome Project • Arose from methods developed for basic research recombinant DNA technology and DNA sequencing • It is an extension of genetic mapping by recombination frequencies • Took 13 years and $3 billion to complete Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Goals of Genomics Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Timeline of HGP Fig. 15.5 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Gene Sequencing Computers Fig. 15.7 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Sequencing a Genome Clone-by-Clone Method (used by public project) • A genomic library (a collection of clones) is developed • Physical maps are prepared • Clones are organized into overlapping groups • DNA cut with restriction enzymes • Each clone is sequenced and software assembles sequence from the libraries Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Clone-byClone Method Fig. 15.9a Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning How We Sequence a Genome Shear add plasmid vector+ Subclone Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning How We Sequence a Genome Transform into bacteria Grow bacteria Purify DNA Sequence DNA Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning How We Sequence a Genome Sequence read Feed all 30 M reads to assembly software Software compares all reads Assembles them together into consensus sequence Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning How to Do 30M Sequence Reads 30M reads, that’s a lot. Need robots... Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Sequencing a Genome Shotgun Cloning (used by private project) • Genomic library prepared • No genetic or physical maps are created • Restriction enzymes are used to cut DNA, and overlapping fragments are created • Clones selected at random from each library and sequenced • Assembler software programs organize information into genomic sequences Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Sequence of Beta-Globin Gene • Open reading frames (ORFs) are exons labeled in blue • Green indicates where transcription begins Fig. 15.10 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Facts About the Human Genome • Diploid, 23 chromosome pairs • 3 x 109 bases • ~30,000 genes • Genes represent ~1.5-2% of genome sequence • Non-genic functional sequences = ?? • Repetitive DNA = ~50% • 8% present in large recent duplications Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Functions of Human Genes Fig. 15.12 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Selected Genomes Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Genomics and Human Genetic Disorders Important questions that must be answered include • Where is the gene located? • What is the normal function of the protein encoded by this gene? • How does the mutant gene or protein produce the disease phenotype? Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Bioinformatics • Comparative genomics –Compares genomes • Structural genomics –Derives 3-D structures for proteins • Pharmacogenomics –Analyzes genes and proteins for therapeutic use Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Comparative Genomics *Using genomes of related species as keys to understanding genome evolution and function Key tools: Conserved sequences (both genes and not) Conserved order of sequences Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Evolution of Humans Mammals Increased Genomic and Developmental Complexity Chordate Body Plan Primates (Human) Rodents (Mouse) Reptiles Birds Amphibians Bony fish (Tetraodon) Cartilaginous fish Jawless vertebrates Cephalochordates Urochordates (Ciona) Hemichordates Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Mouse and Human Genomes Very similar biology Separated by ~75 million years of evolution Similarity at nucleotide level ~83% in genes ~60% between genes Shared gene content: 99% similar genes 96% similar genes in similar location Synteny- regions of genomes that share order of conserved features Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Syntenic Regions Between Human and Mouse • Identify sequences that are highly similar • Find their locations in each genome • Syntenic blocks: conserved order over long stretches • ~200 syntenic blocks between mouse and human • Span 95% of genome Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Humans have low rate of genetic variation ~100,000 BC, 104 humans 3000 generations Present day, 6 x109 humans • Humans: small species that grew large rapidly • Amount of variation implies 10,000 founders • Current variation in population ~10,000 individuals Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Proteomics Study of expressed proteins in a cell • Important in – Understanding gene function and its changing role in development and aging – Identifying proteins that are markers for diseases – Finding proteins that are targets for drugs in order to treat diseases and genetic disorders Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Studying Proteins in a Cell Fig. 15.15 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Ethical, Legal, and Social Implications (ELSI) Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Future Issues • Resources – Genome sequences – Libraries of cloned DNA sequences • Technology – New sequencing methods – Techniques of monitoring gene expression – Links to disease • Software for computational biology – Reveal protein-protein interactions in disease – Evaluate environmental factors on health Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Future Issues • Training – Scientists, physicians and scholars • Ethical, Legal, and Social Implications – Protection of human subjects and genomic information • Education – Healthcare professionals – Public – Develop reliable resources Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Grading for Discussions Background and Methods of topic History – place into context. Why is this being done 10 Discuss how it’s done Discuss the problems (if any) with the methods Applications 10 Issues and Prospects – Arguments for and against 40 Ethical Moral Social Legal Broader issues – eg. genetic diversity in the case of cloning What can and sho uld be done to address these issues Discuss conditions under which the issue could be justified All members of a group get the same grade Total of 60 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning