David HausslerDavid Haussler

Center for Biomolecular Science and EngineeringCenter for Biomolecular Science and EngineeringUniversity of California, Santa CruzUniversity of California, Santa Cruz

The Human Genome ProjectThe Human Genome Projectand 100 Million Years of Human and 100 Million Years of Human

EvolutionEvolution

The human genome is a recipe for an The human genome is a recipe for an entire body and brainentire body and brain

• The genome is organized into The genome is organized into 23 pairs of human 23 pairs of human chromosomes (1-22 and the pair chromosomes (1-22 and the pair X,Y or X,X)X,Y or X,X)

• Each chromosome consists of Each chromosome consists of DNA – molecular string of A, DNA – molecular string of A, C, G, & T (bases), 3 billion in C, G, & T (bases), 3 billion in allall

• All cells in the body have the All cells in the body have the same DNA that was in the same DNA that was in the original fertilized egg original fertilized egg

• Genes are DNA sequence that Genes are DNA sequence that codes for proteins (only about codes for proteins (only about 1.5% of human genome)1.5% of human genome)

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

On July 7, 2000, UCSC posted On July 7, 2000, UCSC posted human genome on the webhuman genome on the web

Outgoing UCSC internet traffic for year 2000

The UCSC Genome Browser: a new kind The UCSC Genome Browser: a new kind of web-based genome microscopeof web-based genome microscope

• Data from all over the world are fed into Data from all over the world are fed into nightly updates of the UCSC browser database, nightly updates of the UCSC browser database, analysis, and displayanalysis, and display

• Every day, more than 7,000 biomedical Every day, more than 7,000 biomedical researchers use it to scan the genome at ever researchers use it to scan the genome at ever greater detail, dimension, and depth, making greater detail, dimension, and depth, making more than 300,000 web page requestsmore than 300,000 web page requests

Explore the genome at http://genome.ucsc.eduExplore the genome at http://genome.ucsc.eduUCSC Genome Bioinformatics Group

Large-scale Operations in Large-scale Operations in Genome EvolutionGenome Evolution

Zack Sanborn

Example: evolutionary history of a Example: evolutionary history of a mammalian chromosomemammalian chromosome

Jian Ma, Bernard Suh, Brian RaneyHistory of rat chromosome X

Example: evolutionary history of a Example: evolutionary history of a mammalian chromosomemammalian chromosome

Jian Ma, Bernard Suh, Brian RaneyHistory of rat chromosome X

Morpheus: new genes by segmental duplicationMorpheus: new genes by segmental duplication

Evan Eichler

Humanchromosome

Baboonchromosome

The demise of a gene

Codon TGG for amino acid tryptophan became a stop codon in this gene before 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 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.3) appear in all branches of life; this was the last in the hominid genome.

Jing Zhu, Zack Sanborn, Craig Lowe

Project to Project to reconstruct the reconstruct the evolutionary evolutionary history of the history of the genomes of genomes of placental placental mammalsmammals

Data from NHGRI

ComparativeGenome

SequencingProgram

Homo sapiens sapiensHomo sapiens sapiens

Homo sapiensHomo sapiens

Homo sapiens neanderthalensis

Homo/PanHomo/Pan

chimpanzee(Pan troglodytes)

Homo/Pan/GorillaHomo/Pan/Gorilla

Gorilla

HominidaeHominidae(great apes)(great apes)

orangutan

HomonoidaeHomonoidae(apes)(apes)

gibbon

CatarrhiniCatarrhini(old world monkeys(old world monkeys

and apes)and apes)

rhesus macaque

AnthropoideaAnthropoidea

marmoset

HaplorhinesHaplorhines

tarsier

PrimatesPrimates

bushbaby

EurachontaEurachonta

pygmy tree shrew

EuarchontogliresEuarchontoglires

mouse(Mus musculus

“genomicus”)

BoreoeutheriaBoreoeutheria

common shrew

EutheriaEutheria(placental mammals)(placental mammals)

elephant shrew

Tursiops truncates

Not all descendants of the eutherian ancestor are shrew-like

We found 49 genomic regions that showed We found 49 genomic regions that showed extremely accelerated evolution in humansextremely accelerated evolution in humans

Katie Pollard and Sofie SalamaHuman Accelerated Region 1

HAR1 produces a structured RNA HAR1 produces a structured RNA sequence that is expressed in the fetal brainsequence that is expressed in the fetal brain

Jakob Pedersen

Computational prediction of structure conserved throughout amniotesComputational prediction of structure conserved throughout amniotes

New interactions in New interactions in the human version the human version of this geneof this gene

The six layers of the cerebral cortex are The six layers of the cerebral cortex are

built during fetal brain developmentbuilt during fetal brain development

Image: www.thebrain.mcgill.ca

During development, the During development, the cerebral cortex is built cerebral cortex is built “inside-out” by neurons “inside-out” by neurons migrating radially from migrating radially from the subventricular zone to the subventricular zone to the pial surface. This the pial surface. This process is guided by the process is guided by the neurodevelopmental gene neurodevelopmental gene Reelin.Reelin.

HAR1 is expressed in the same cells as Reelin (the HAR1 is expressed in the same cells as Reelin (the Cajal-Retzius neurons), and during the same period Cajal-Retzius neurons), and during the same period

of development (8-20 GW)of development (8-20 GW)

Nelle Lambert, Marie-Alexandra Lambot, Sandra Coppens, Pierre Vanderhaeghen

We are pursuing the hypothesis that HAR1 We are pursuing the hypothesis that HAR1 functions in cortical development and was functions in cortical development and was

involved in the evolution of the human braininvolved in the evolution of the human brain

Grand challenge of human Grand challenge of human molecular evolutionmolecular evolution

Reconstruct the evolutionary historyReconstruct the evolutionary historyof each base in the human genomeof each base in the human genome

• Discover functional elements of the genomeDiscover functional elements of the genome

• Find the human evolutionary innovations Find the human evolutionary innovations

• Map the important human genetic variationMap the important human genetic variation

• Map the genome adaptations in individual cancer Map the genome adaptations in individual cancer tumors that make them dangeroustumors that make them dangerous

The UCSC TeamThe UCSC Team

Sofie SalamaJim Kent

Katie Pollard and Gill Bejerano

Adam Siepel

Extended CreditsExtended Credits Thanks to Jim Kent, Sofie Salama, Gill Bejerano*, Katie Thanks to Jim Kent, Sofie Salama, Gill Bejerano*, Katie

Pollard*, Adam Siepel*, Robert Baertsch, Galt Barber, Hiram Pollard*, Adam Siepel*, Robert Baertsch, Galt Barber, Hiram Clawson, Mark Diekhans, Jorge Garcia, Rachel Harte, Angie Clawson, Mark Diekhans, Jorge Garcia, Rachel Harte, Angie Hinrichs, Fan Hsu, Donna Karolchik, Sol Katzman, Andy Hinrichs, Fan Hsu, Donna Karolchik, Sol Katzman, Andy Kern, Bryan King, Robert Kuhn, Victoria Lin, Andre Love, Kern, Bryan King, Robert Kuhn, Victoria Lin, Andre Love, Craig Lowe, Yontao Lu, Jian Ma, Chester Manuel, Courtney Craig Lowe, Yontao Lu, Jian Ma, Chester Manuel, Courtney Onodera, Jakob Pedersen, Andy Pohl, Brian Raney, Brooke Onodera, Jakob Pedersen, Andy Pohl, Brian Raney, Brooke Rhead, Kate Rosenbloom, Krishna Roskin,Rhead, Kate Rosenbloom, Krishna Roskin, Zack Sanborn, Zack Sanborn, Kayla Smith, Mario Stanke, Bernard Suh, Paul Tatarsky, Kayla Smith, Mario Stanke, Bernard Suh, Paul Tatarsky, Archana Thakkapallayil, Daryl Thomas, Heather Trumbower, Archana Thakkapallayil, Daryl Thomas, Heather Trumbower, Jason Underwood, Ting Wang, Erich Weiler, Chen-Hsiang Jason Underwood, Ting Wang, Erich Weiler, Chen-Hsiang Yeang, Jing Zhu, and Ann Zweig, in my group at UCSC Yeang, Jing Zhu, and Ann Zweig, in my group at UCSC

And to Webb Miller, Nadav Ahituv, Manny Ares, Mathieu And to Webb Miller, Nadav Ahituv, Manny Ares, Mathieu Blanchette, Rico Burhans, Michele Clamp, Richard Gibbs, Blanchette, Rico Burhans, Michele Clamp, Richard Gibbs, Eric Green, Haller Igel, John Karro, Eric Lander, Kerstin Eric Green, Haller Igel, John Karro, Eric Lander, Kerstin Lindblad-Toh, Jim Mullikin, Tom Pringle, Eddy Rubin, Lindblad-Toh, Jim Mullikin, Tom Pringle, Eddy Rubin, Armen Shamamian, Pierre Vanderhaeghen, and many other Armen Shamamian, Pierre Vanderhaeghen, and many other outside collaboratorsoutside collaborators

Single nucleotide polymorphisms (SNPS)Single nucleotide polymorphisms (SNPS)

• When we compare the genomes of many people, we see ~3 When we compare the genomes of many people, we see ~3 million variable bases (SNPs). That is one every 1000 million variable bases (SNPs). That is one every 1000 bases.bases.

• Each SNP is a change that happened only once. Each SNP is a change that happened only once.

• The more ancient the SNP, the more common – most SNPs The more ancient the SNP, the more common – most SNPs come from before the time of a population bottleneck about come from before the time of a population bottleneck about 100,000 years ago, before our ancestors migrated out of 100,000 years ago, before our ancestors migrated out of Africa.Africa.

• Each of your kids has about 175 new DNA changes, but Each of your kids has about 175 new DNA changes, but nearly all changes are lost within 20 generations.nearly all changes are lost within 20 generations.

• SNPs inherited together with no recombination form SNPs inherited together with no recombination form “haplotype blocks”.“haplotype blocks”.

Polymorphism Data is Used to Polymorphism Data is Used to Help Locate Disease GenesHelp Locate Disease Genes

• With new genotyping technology, there has been With new genotyping technology, there has been a revolution in our ability to discover disease-a revolution in our ability to discover disease-related genes. New discoveries have been made related genes. New discoveries have been made for diabetes, cancer, cardiovascular disease, auto for diabetes, cancer, cardiovascular disease, auto immune diseases, and neurological diseases.immune diseases, and neurological diseases.

• The ability to interactively explore the genome The ability to interactively explore the genome on the web is accelerating biomedical research on the web is accelerating biomedical research and will eventually help us to better diagnose and will eventually help us to better diagnose and cure disease.and cure disease.

Genomes and the Central Dogma Genomes and the Central Dogma of Molecular Biologyof Molecular Biology

The Tree of LifeThe Tree of Life

DNA -> DNA (molecular evolution)DNA -> RNA -> protein (molecular cell biology)

Neutral drift:Neutral drift: a genetic change that does not affect the organisma genetic change that does not affect the organism

Browser: Kent et al; conservation track: Siepel and Rosenbloom

• Mutations occur all the time in protein-coding regions; some do not Mutations occur all the time in protein-coding regions; some do not change the protein, so do not affect the fitness of the organismchange the protein, so do not affect the fitness of the organism

• Changing the third DNA base in this codon does not change the Changing the third DNA base in this codon does not change the amino acid it encodes, alanine (A)amino acid it encodes, alanine (A)

Negative selection:Negative selection: rejecting a change that decreases fitnessrejecting a change that decreases fitness

Browser: Kent et al; conservation track: Siepel and Rosenbloom

• Some mutations would change the protein and thereby reduce fitness Some mutations would change the protein and thereby reduce fitness

• Such changes are rejected by natural selection, and the DNA is conservedSuch changes are rejected by natural selection, and the DNA is conserved

Positive selection:Positive selection: a genetic change that increases fitnessa genetic change that increases fitness

Browser: Kent et al; conservation track: Siepel and Rosenbloom; FOXP2 results: Enard et al, Nature, 2002

• Some mutations have a positive effect: This change from C to A in the gene 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 FOXP2 changed the amino acid from threonine (T) to asparagine (N) , which may have improved fitnessmay have improved fitness

• Possible role in the evolution of speechPossible role in the evolution of speech