1. Genome Projects Maps Human Genome Mapping Human Genome Sequencing
Landmarks in Sequencing
Comparative Genomics
The Tree and Our Place on It

2. Genome Projects: Maps Cytogenetic maps Restriction maps
Low resolution (each band = several Mb)
Chromosome banding
Restriction maps
Rare-cutting restriction enzymes
Resolution - Several hundred kb
Clone contig maps
Overlapping YAC/cosmid clones
Resolution – 10s of kb to several hundred

3. Genome Projects: Maps STS maps EST maps DNA sequence
Sequence tagged site
PCR of known sequence to identify location
Resolution – 1 – 10s of kb
EST maps
Sequence cDNAs and locate on other physical maps
Resolution ~90 kb
DNA sequence
Resolution – 1 bp

5. Genome Projects: Maps Progress in human gene mapping
Slow when compared to Drosophila and mouse
Speed increased when non-coding markers began being used in conjunction with familial patterns of linkage

7. Genome Projects: Sequencing
Landmarks in genome sequencing

9. Genome Projects: Sequencing
Progress in human genome sequencing
Hierarchical vs. whole genome shotgun sequencing
Precision and accuracy
Repetitive DNA

10. 08_03.jpg
08_03.jpg

12. Genome Projects: Sequencing
Progress in human genome sequencing
Hierarchical vs whole genome shotgun sequencing
Landmark papers in Nature and Science (2001)
Venter et al Science 16 February 2001; 291:
Lander et al Nature 409 (6822):

13. Genome Projects: Sequencing
A typical high-throughput genomics facility

15. Genome Projects: Sequencing
BLAST/BLAT and other tools
BLAST - Basic local alignment search tool
Input a sequence and find matches to human or other organisms
publication information
DNA and protein sequence (if applicable)

20. Genome Projects: Sequencing
BLAST/BLAT and other tools
BLAT – BLAST-like alignment tool
A “genome browser”
Genomes available:
human, chimp, dog, cow, mouse, opossum, rat, chicken, Xenopus, Zebrafish, Tetraodon, Fugu, nematode (x3), Drosophila (x5), Apis (x3), Saccharomyces (yeast).
Off-slide show example: chr6:121,387, ,720,836

21. Genome Projects: BLAT BLAT and other tools
Off-slide show example: chr6:121,387, ,720,836
STS and RH markers
Known genes (alternative splices of genes)
Conservation with other genomes
Known single nucleotide polymorphisms (SNPs)
Repetitive DNA

22. Our Place in the Tree of Life: Genome Evolution
Endosymbiont hypothesis

24. Our Place in the Tree of Life: Genome Evolution
Gene duplication
Acquisition of novel functions

26. Our Place in the Tree of Life: Genome Evolution
Gene duplication
Paralogous chromosome segments
Ancient genome duplications
Hox gene clusters

28. Our Place in the Tree of Life: Genome Evolution
Concerted evolution –
members of a sequence of families in a species evolve together so that they maintain high similarities among themselves while diverging from members of other species
via gene conversion
example primate photoreceptors

30. X-linked pigment genes
Primate ancestor
X-linked pigment gene
Divergence
NWM
Gene duplication
X-linked pigment gene
OW primates
X-linked pigment genes

31. If duplication occurred before human-OWM split,
divergence between genes should be comparable (~7.1%)
Baboon divergence of exons 4 and 5 b/t genes = 11%
Human divergence of exons 4 and 5 b/t genes = 8%
Baboon divergence of intron 4 b/t genes = 0.5%
Human divergence of intron 4 b/t genes = 0.0%

32. Our place in the tree of life
Exon duplication and shuffling
Examples
May be mediated by mobile elements

34. Our Place in the Tree of Life: Genome Evolution
Mammalian phylogeny

36. Our Place in the Tree of Life: Genome Evolution
Conservation between mouse and man
Limited to subchromosomal regions
Variable rates of amino acid sequence divergence

39. Our Place in the Tree of Life: Genome Evolution
Human evolution
Determining our place in the tree
Cytogenetic analysis
Gene content analysis
Sequence analysis
Intron and exon sequences, mtDNA sequences
SINE analysis

41. Phylogenetic Inference Using SINEs

42. Phylogenetic Inference Using SINEs
Species A
Species B
Species C
Species D

43. Resolution of the Human:Chimp:Gorilla Trichotomy
(H,C)G
(H,G)C
(C,G)H
(H,C,G)

44. Phylogenetic Analysis
PCR of 133 Alu loci
117 Ye5
13 Yc1
1 Yi6
1 Yd3
1 undefined subfamily
PNAS (2003) 22:

45. Alu Elements and Hominid Phylogeny
PNAS (2003) 22:

46. Our Place in the Tree of Life: Genome Evolution
Human evolution
Coalescence analyses (mtDNA and Y chromosome)
Mutiregional vs. Out of Africa
Predictions of the Multiregional Hypothesis
Equal diversity in human subpopulations
No obvious root to the human tree
Predictions of the Out of Africa Hypothesis
Higher diversity in African subpopulations
Root of the human tree in Africa

49. Population Relationships Based on 100 Autosomal Alu Elements
Africa
Asia
Europe
S. India

50. Europe
Low diversity
0.1
0.1
0.6
Africa
High diversity
0.3
0.3
0.9
Australia
Low diversity

51. Our Place in the Tree of Life: Genome Evolution
Human evolution
Higher diversity in African subpopulations
Insulin minisatellite Table 12.6 in text
22 divergent lineages exist in the human population
All are found in Africa. Only 3 are found outside of Africa.