1. The Human Genome Project and 100 Million Years of Human Evolution
David Haussler
Center for Biomolecular Science and Engineering University of California, Santa Cruz

2. The human genome is a recipe for an entire body and brain
The genome is organized into 23 pairs of human chromosomes (1-22 and the pair X,Y or X,X)
Each chromosome consists of DNA – molecular string of A, C, G, & T (bases), 3 billion in all
All cells in the body have the same DNA that was in the original fertilized egg
Genes are DNA sequence that codes for proteins (only about 1.5% of human genome)
The reference human genome sequence is a computer file of about 3 billon bases

3. To what extent does a person’s genome define them?

4. On July 7, 2000, UCSC posted human genome on the web
Outgoing UCSC internet traffic for year 2000

5. The UCSC Genome Browser: a new kind of web-based genome microscope
Data from all over the world are fed into nightly updates of the UCSC browser database, analysis, and display
Every day, more than 7,000 biomedical researchers use it to scan the genome at ever greater detail, dimension, and depth, making more than 300,000 web page requests
Explore the genome at
UCSC Genome Bioinformatics Group

6. Large-scale Operations in Genome Evolution
Zack Sanborn

7. Example: evolutionary history of a mammalian chromosome
Roughly 200 segments, we also have 1,000 and 50,000.
History of rat chromosome X
Jian Ma, Bernard Suh, Brian Raney

8. Example: evolutionary history of a mammalian chromosome
Roughly 200 segments, we also have 1,000 and 50,000.
History of rat chromosome X
Jian Ma, Bernard Suh, Brian Raney

10. Morpheus: new genes by segmental duplication
Figure 2: Human vs. Baboon Duplication Architecture. The organization of five LCR16 (low copy repeats on chromosome 16) segmental duplications is compared between human and baboon. In humans, the duplications range in size from kb, are % identical and are distributed in different permutations to 27 different map positions shown along the ideogram. In baboons (and other Old World monkeys), the corresponding segments are not duplicated and map to a single locus. The data suggest a dramatic expansion of segmental duplications during hominoid evolution on this chromosome. Note: The LCR16a duplication (red) contains a novel gene family (morpheus) that shows positive selection only in humans and the great-apes.
Baboon
chromosome
Human
chromosome
Evan Eichler

11. The demise of a gene Jing Zhu, Zack Sanborn, Craig Lowe
This was the last protein with the Pfam domain Acyl_transf_3
Interpro: IPR Acyltransferase 3
GO:transferase activity, transferring groups other than amino-acyl groups
There are 925 protein in interpro with this domain, covering all branches of life. Mouse has 2. Human and chimp have none.
Codon TGG for amino acid tryptophan became a stop codon in this gene before the human-chimp ancestor, killing the gene. Proteins of this type (acyltransferase 3) appear in all branches of life; this was the last in the hominid genome.
Jing Zhu, Zack Sanborn, Craig Lowe 11

12. Project to reconstruct the evolutionary history of the genomes of placental mammals
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Data from NHGRI
Comparative
Genome
Sequencing
Program

13. 12 key nodes in human evolution (+neanderthal and human itself makes 14)
Homo sapiens sapiens

14. Homo sapiens neanderthalensis
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Neanderthal picture:
Homo sapiens

15. chimpanzee (Pan troglodytes) Homo/Pan
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Chimp picture:
Homo/Pan

16. Gorilla Homo/Pan/Gorilla
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Mountain gorilla
Homo/Pan/Gorilla

17. orangutan Hominidae (great apes)
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Hominidae
(great apes)

18. gibbon Homonoidae (apes)
12 key nodes in human evolution (+neanderthal and human itself makes 14)

19. rhesus macaque Catarrhini (old world monkeys and apes)
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Rhesus macaque

20. marmoset Anthropoidea
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Common marmoset (Callithrix jacchus)
Anthropoidea

21. tarsier
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Haplorhines

22. bushbaby
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Lesser bushbaby, Galago moholi
Primates

23. pygmy tree shrew Eurachonta
12 key nodes in human evolution (+neanderthal and human itself makes 14)

24. (Mus musculus “genomicus”)
mouse
(Mus musculus “genomicus”)
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Mus musculus genomicus !!
Euarchontoglires

25. common shrew Boreoeutheria
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Common shrew Sorex araneus

26. elephant shrew Eutheria (placental mammals)
12 key nodes in human evolution (+neanderthal and human itself makes 14)
Macroscelidea

27. Not all descendants of the eutherian ancestor are shrew-like
Tursiops truncates
Not all descendants of the eutherian ancestor are shrew-like

28. We found 49 genomic regions that showed extremely accelerated evolution in humans
Katie Pollard and Sofie Salama
Human Accelerated Region 1

29. Computational prediction of structure conserved throughout amniotes
HAR1 produces a structured RNA sequence that is expressed in the fetal brain
New interactions in the human version of this gene
Computational prediction of structure conserved throughout amniotes
Jakob Pedersen

30. The six layers of the cerebral cortex are built during fetal brain development
During development, the cerebral cortex is built “inside-out” by neurons migrating radially from the subventricular zone to the pial surface. This process is guided by the neurodevelopmental gene Reelin.
Human embryo looks human at this stage (roughly Carnegie stage 23), but is only about 1 inch long
Image:

31. HAR1 is expressed in the same cells as Reelin (the Cajal-Retzius neurons), and during the same period of development (8-20 GW)
At 19GW, HAR1F and reelin show the
same pattern in the MZ/SGL (arrows), and HAR1F remains expressed in the
upper CP (arrowheads), whereas the HAR1F sense probe shows no signal.
Lower panels centred on the MZ illustrate double in situ hybridization/
immunohistochemistry experiments. Lower left and middle panels show
that HAR1F (in dark blue) and reelin (in dark brown) are co-localized in
most cells, corresponding to Cajal–Retzius neurons (black arrows),
although some reelin-positive cells do not express HAR1F (brown arrows).
The lower right panel illustrates that HAR1F cells (blue arrows) seem to be
mainly distinct from interneurons (brown arrows) expressing vesicular
GABA transporter (vGAT). Scale bar: 250 microns.
Nelle Lambert, Marie-Alexandra Lambot, Sandra Coppens, Pierre Vanderhaeghen

32. We are pursuing the hypothesis that HAR1 functions in cortical development and was involved in the evolution of the human brain
Optional movie:
Method: peroxidase-driven tyramide signal amplification (TSA). You directly conjugate horseradish peroxidase (HRP) to (RNA? Or oligodeoxynucleotides (ODNs) and use these probes to study the transcript of interest.
This movie shows takes you on a tour from the bottom to top of nuclei  from a group of mouse neuroblastoma cells, Neuro-2A.  These have been  transfected with a vector that encoded the predicted full length HAR1  transcript. We are visualizing the HAR1 using a FISH probe against  the structured region of the molecule.  To our surprise, though the  HAR1 RNA is a capped, spliced and polyadenylated transcript, we do  not see it in the cytoplasm.  Instead, it collects in individual  spots in the nucleus.  This is especially evident in the cell at the  center of the movie which has the highest expression. We are  currently performing experiments to co-localize these bodies with  known nuclear subcompartments and also figure out whether HAR1 gets  stuck in the nucleus or has already left the nucleus after splicing  and has been re-imported ... a biogenesis pathway similar to snRNAs.

33. Grand challenge of human molecular evolution
Reconstruct the evolutionary history
of each base in the human genome
Discover functional elements of the genome
Find the human evolutionary innovations
Map the important human genetic variation
Map the genome adaptations in individual cancer tumors that make them dangerous

34. Katie Pollard and Gill Bejerano
The UCSC Team
Katie Pollard and Gill Bejerano
Jim Kent
Sofie Salama
Adam Siepel

35. Extended Credits
Thanks to Jim Kent, Sofie Salama, Gill Bejerano*, Katie Pollard*, Adam Siepel*, Robert Baertsch, Galt Barber, Hiram Clawson, Mark Diekhans, Jorge Garcia, Rachel Harte, Angie Hinrichs, Fan Hsu, Donna Karolchik, Sol Katzman, Andy Kern, Bryan King, Robert Kuhn, Victoria Lin, Andre Love, Craig Lowe, Yontao Lu, Jian Ma, Chester Manuel, Courtney Onodera, Jakob Pedersen, Andy Pohl, Brian Raney, Brooke Rhead, Kate Rosenbloom, Krishna Roskin, Zack Sanborn, Kayla Smith, Mario Stanke, Bernard Suh, Paul Tatarsky, Archana Thakkapallayil, Daryl Thomas, Heather Trumbower, Jason Underwood, Ting Wang, Erich Weiler, Chen-Hsiang Yeang, Jing Zhu, and Ann Zweig, in my group at UCSC
And to Webb Miller, Nadav Ahituv, Manny Ares, Mathieu Blanchette, Rico Burhans, Michele Clamp, Richard Gibbs, Eric Green, Haller Igel, John Karro, Eric Lander, Kerstin Lindblad-Toh, Jim Mullikin, Tom Pringle, Eddy Rubin, Armen Shamamian, Pierre Vanderhaeghen, and many other outside collaborators

36. Single nucleotide polymorphisms (SNPS)
When we compare the genomes of many people, we see ~3 million variable bases (SNPs). That is one every 1000 bases.
Each SNP is a change that happened only once.
The more ancient the SNP, the more common – most SNPs come from before the time of a population bottleneck about 100,000 years ago, before our ancestors migrated out of Africa.
Each of your kids has about 175 new DNA changes, but nearly all changes are lost within 20 generations.
SNPs inherited together with no recombination form “haplotype blocks”.

37. Polymorphism Data is Used to Help Locate Disease Genes
With new genotyping technology, there has been a revolution in our ability to discover disease-related genes. New discoveries have been made for diabetes, cancer, cardiovascular disease, auto immune diseases, and neurological diseases.
The ability to interactively explore the genome on the web is accelerating biomedical research and will eventually help us to better diagnose and cure disease.
Collins: SIFTER project stores linkage and association results mapped to golden path coordinates. Custom tracks containing markers they have genotyped or plan to genotype,
And other info delineating the boundaries of the region that is likely to contain the disease gene. (unpublished)

38. Genomes and the Central Dogma of Molecular Biology

39. The Tree of Life DNA -> DNA (molecular evolution)
DNA -> RNA -> protein (molecular cell biology)

40. Neutral drift: a genetic change that does not affect the organism
Note: alanine (A) is 4 fold degenerate, so all 3rd position changes there are presumably neutral. Same with threonine change in mouse.
Mutations occur all the time in protein-coding regions; some do not change the protein, so do not affect the fitness of the organism
Changing the third DNA base in this codon does not change the amino acid it encodes, alanine (A)
Browser: Kent et al; conservation track: Siepel and Rosenbloom

41. Negative selection: rejecting a change that decreases fitness
Some mutations would change the protein and thereby reduce fitness
Such changes are rejected by natural selection, and the DNA is conserved
Browser: Kent et al; conservation track: Siepel and Rosenbloom

42. Positive selection: a genetic change that increases fitness
OMIM : one of these two changes in exon 7 creates a potential phosphorylation site for protein kinease C and a minor change in secondary structure (not sure which one).
Enard, W.; Przeworski, M.; Fisher, S. E.; Lai, C. S. L.; Wiebe, V.; Kitano, T.; Monaco, A. P.; Paabo, S. :
Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418: , PubMed ID :
Some mutations have a positive effect: This change from C to A in the gene FOXP2 changed the amino acid from threonine (T) to asparagine (N) , which may have improved fitness
Possible role in the evolution of speech
Browser: Kent et al; conservation track: Siepel and Rosenbloom; FOXP2 results: Enard et al, Nature, 2002