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Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 The Human Genome Project and Genomics.

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Presentation on theme: "Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 The Human Genome Project and Genomics."— Presentation transcript:

1 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 15 The Human Genome Project and Genomics

2 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

3 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

4 How was linkage discovered? Standard dihybrid cross Find that observed ratios in the F2 progeny do not follow mendelian ratios. Linkage refers to the transmission of two genes on the same chromosome

5 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Fig Dihybrid Cross: P: purple flower p: white flower L: long pollen, l: round pollen P_L_: P_ll: ppL_ : ppll 9 : 3 : 3 : 1 Observed : hi low low hi Hypothesis: These two genes are somehow linked, and do not assort independently

6 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Fig Two extremes

7 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Crossing over Disrupts Linkage and creates new combination of alleles (recombinants) Figure 5.10

8 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning 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

9 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 Figure 5.12

10 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Linkage Maps. Linear maps from RF data RF of 1% between two genes: = 1 map unit or 1 centiMorgan (cM) apart.

11 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

12 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning General rules  Recombination frequency varies between different genes.  Recombination frequency is constant between two genes. NO Recombination = genes are very closely linked.

13 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Linked Genes Fig. 15.3

14 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

15 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Genes ID-ed by Positional Cloning

16 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chromosome 1 Fig. 15.4

17 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

18 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

19 Goals of Genomics

20 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Timeline of HGP Fig. 15.5

21 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Gene Sequencing Computers Fig. 15.7

22 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

23 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Clone-by- Clone Method Fig. 15.9a

24 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning How We Sequence a Genome Shear Subclone + add plasmid vector

25 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

26 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

27 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning 30M reads, that’s a lot. Need robots... How to Do 30M Sequence Reads

28 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

29 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

30 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Sequence of Beta-Globin Gene Fig Open reading frames (ORFs) are exons labeled in blue Green indicates where transcription begins

31 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Facts About the Human Genome Diploid, 23 chromosome pairs 3 x 10 9 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

32 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Functions of Human Genes Fig

33 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Selected Genomes

34 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?

35 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

36 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

37 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Evolution of Humans Hemichordates Urochordates (Ciona) Cephalochordates Chordate Body Plan Jawless vertebrates Increased Genomic and Developmental Complexity Bony fish (Tetraodon) Cartilaginous fish Amphibians Primates (Human) Reptiles Birds Rodents (Mouse) Mammals

38 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

39 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

40 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

41 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Humans have low rate of genetic variation Humans: small species that grew large rapidly Amount of variation implies 10,000 founders Current variation in population ~10,000 individuals ~100,000 BC, 10 4 humans Present day, 6 x10 9 humans 3000 generations

42 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

43 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Studying Proteins in a Cell Fig

44 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Ethical, Legal, and Social Implications (ELSI)

45 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

46 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

47 Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning All members of a group get the same grade


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