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

2. 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

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

4. 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

5. Fig. 5.11 Fig. 5.11 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
Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

6. Fig. 5.11
Two extremes
Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

7. 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

8. 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

9. Figure 5.12 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

10. RF of 1% between two genes:
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

11. 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

12. Recombination frequency is constant between two genes.
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

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

14. 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

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

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

17. 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

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

19. Goals of Genomics
Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

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

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

22. 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

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

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

25. 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

26. 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

27. 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

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

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

31. 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

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

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

34. 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

35. 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

36. 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

37. Evolution of Humans Primates (Human) Rodents (Mouse) Reptiles Birds
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
Chapter 15 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

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

40. 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

41. 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

42. 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

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

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

45. 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

46. 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

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