ggtgccagggaaagggcaggaggtgagtgctgggaggcagctgaggtcaacttctttt...

http://bejerano.stanford.edu 1

GGTGCCAGGGAAAGGGCAGGAGGTGAGTGCTGGGAGGCAGCTGAGGTCAACTTCTTTTGAACTTCCACGTGGTATTTACTCAGAGCAATTGGTGCCAGAG

GCTCAGGGCCCTGGAGTATAAAGCAGAATGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCGAAAGACCTGTTGGAGGCTATGAATGC

AATCAAGGTGACAGACAACTGGTGCAATGATGGTAGTGGAAATGGAGGAGAGGGGATTGATTCAAGATGCATTTAGGACCAAGAATCGGGAGCTTGTGAA

CGTGTGTATGAGTACTGTAGACGGAGTGGGTGTGTCATCAGAGAAGATCTGAGCATTTGGGCTTGCTCTCCTCAGAGGCCCTGCGAGTGGAGTTCAGCTT

TTCCTCATGGGGCAAATCTCACTTTCGCTCCAGTTCCTGGGGCTCAGAGTCCCTGGCCCAGATGCCTCTTGCCATCTCATCTTCACCCTGCCTGGCTTCC

CTTGCTTGTTCCAGGATTGTTTCATAAAGAGGGATGTGGTTGGTCTTTAACCCTATGAATGCTGGCTGAGGATGCCTGCGGAACCTGTAGTGAAGCTTTC

AGGGGCTGCTCGGGTTCTGGCTGGTAGGTGAACACTGTCCATCTTGCCGGCTGGGACACAGTGACTCTGGGTAGTTGTGTAAGAGAGGGGCCCTTGGCAG

ACAAACAGGTTCTTCTCTGTTGGTGGGCCAGCCAGCAGGTCAGTGGGAAGGTTAAAGGTCATGGGGTTTGGGAGAACTGGGTGAGGAGTTCAGCCCCATC

CCCCGTAAAGCTCCTGGGAAGCACTTCTCTACTGGGGCAGCCCCTGATACCAGGGCACTCATTAACCCTCTGGGTGCCAGGGAAAGGGCAGGAGGTGAGT

GCTGGGAGGCAGCTGAGGTCAACTTCTTTTGAACTTCCACGTGGTATTTACTCAGAGCAATTGGTGCCAGAGGCTCAGGGCCCTGGAGTATAAAGCAGAA

TGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCT

CTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAG

GAAAGACCTGTTGGAGGCTATGAATGCAATCAAGGTGACAGACAACTGGTGCAATGATGGTAGTGGAAATGGAGGAGAGGGGATTGATTCAAGATGCATT

TAGGACCAAGAATCGGGAGCTTGTGAACGTGTGTATGAGTACTGTAGACGGAGTGGGTGTGTCATCAGAGAAGATCTGAGCATTTGGGCTTGCTCTCCTC

AGAGGCCCTGCGAGTGGAGTTCAGCTTTTCCTCATGGGGCAAATCTCACTTTCGCTCCAGTTCCTGGGGCTCAGAGTCCCTGGCCCAGATGCCTCTTGCC

ATCTCATCTTCACCCTGCCTGGCTTCCCTTGCTTGTTCCAGGATTGTTTCATAAAGAGGGATGTGGTTGGTCTTTAACCCTATGAATGCTGGCTGAGGAT

GCCTGCGGAACCTGTAGTGAAGCTTTCAGGGGCTGCTCGGGTTCTGGCTGGTAGGTGAACACTGTCCATCTTGCCGGCTGGGACACAGTGACTCTGGGTA

GTTGTGTAAGAGAGGGGCCCTTGGCAGACAAACAGGTTCTTCTCTGTTGGTGGGCCAGCCAGCAGGTCAGTGGGAAGGTTAAAGGTCATGGGGTTTGGGA

GAAACTGGGTGAGGAGTTCAGCCCCATCCCCCGTAAAGCTCCTGGGAAGCACTTCTCTACTGGGGCAGCCCCTGATACCAGGGCACTCATTAACCCTCTG

GGTGCCAGGGAAAGGGCAGGAGGTGAGTGCTGGGAGGCAGCTGAGGTCAACTTCTTTTGAACTTCCACGTGGTATTTACTCAGAGCAATTGGTGCCAGAG

GCTCAGGGCCCTGGAGTATAAAGCAGAATGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCGAAAGACCTGTTGGAGGCTATGAATGC

AATCAAGGTGACAGACAACTGGTGCAATGATGGTAGTGGAAATGGAGGAGAGGGGATTGATTCAAGATGCATTTAGGACCAAGAATCGGGAGCTTGTGAA

CGTGTGTATGAGTACTGTAGACGGAGTGGGTGTGTCATCAGAGAAGATCTGAGCATTTGGGCTTGCTCTCCTCAGAGGCCCTGCGAGTGGAGTTCAGCTT

TTCCTCATGGGGCAAATCTCACTTTCGCTCCAGTTCCTGGGGCTCAGAGTCCCTGGCCCAGATGCCTCTTGCCATCTCATCTTCACCCTGCCTGGCTTCC

CTTGCTTGTTCCAGGATTGTTTCATAAAGAGGGATGTGGTTGGTCTTTAACCCTATGAATGCTGGCTGAGGATGCCTGCGGAACCTGTAGTGAAGCTTTC

AGGGGCTGCTCGGGTTCTGGCTGGTAGGTGAACACTGTCCATCTTGCCGGCTGGGACACAGTGACTCTGGGTAGTTGTGTAAGAGAGGGGCCCTTGGCAG

ACAAACAGGTTCTTCTCTGTTGGTGGGCCAGCCAGCAGGTCAGTGGGAAGGTTAAAGGTCATGGGGTTTGGGAGAACTGGGTGAGGAGTTCAGCCCCATC

CCCCGTAAAGCTCCTGGGAAGCACTTCTCTACTGGGGCAGCCCCTGATACCAGGGCACTCATTAACCCTCTGGGTGCCAGGGAAAGGGCAGGAGGTGAGT

GCTGGGAGGCAGCTGAGGTCAACTTCTTTTGAACTTCCACGTGGTATTTACTCAGAGCAATTGGTGCCAGAGGCTCAGGGCCCTGGAGTATAAAGCAGAA

TGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCT

CTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAGACGTGAGCAGGTGAGCAGCTGGGGCTGTCTGCTCTCTGTGCCCAG

The Bejerano Lab:

How the Human Genome Does Its Thing

Dept. of Electrical Engineering

Stanford University

Harendra Guturu

Why Genomics?

•This century is owned by Genomics.

•Huge impact on everybody’s life.

•And science’s understanding of life.

•Genomics is a computational science.

•“There is gold in them thar hills”


Organism – Cell - Genome


1013 different cells in an adult human.

The cell is the basic unit of life.

DNA = linear molecule inside the cell that carries instructions needed

throughout the cell’s life ~ long string(s) over a small alphabet

Alphabet of four (nucleotides/bases) {A,C,G,T} Strings of length 104-1011

...ACGTACGACTGACTAGCATCGACTACGACTAGCAC...

“instruction” Genome:


One Cell, One Genome, One Replication

Every cell holds a copy of all its DNA = its genome.

The human body is made of ~1013 cells.

All originate from a single cell through repeated cell divisions.

cell

genome =

all DNA

chicken ≈ 1013 copies

(DNA) of egg (DNA)

chicken

egg egg

egg

cell

division

DNA strings =

Chromosomes


The Genome Has Been Had

2001

HGC Celera

Getting the “blueprint of life”

Former

graphics

programmer


TTATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATACATATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTCAGTAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTCCGTGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAGATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACTAGCTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATGATAATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAAAAGCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAATTGTTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAATTCTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGGATTTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGATTTTGATATGCTTTGCGCCGTCAAAGTTTTGAACGATGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAATCTTTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATGAACGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATCATATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAAAAGAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCAGCATTGGGCAGCTGTCTATATGAATTAGTCAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACTTTAGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAG...TTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTTTCCTACGCATAATAAGAATAGGAGGGAATATCAAGCCAGACAATCTATCATTACATTTAAGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAAGAGTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATACAGCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACAACCAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATCAACACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCGTTGGTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCTTCTCTTTATGGCCCGTTATTAACAGAGTCGTCATGGCCATCGTTTGGTATAGTGTCCAAGCTTATATTGCGGCAACTCCCGTATCATTAATGCTGAAATCTATCTTTGGAAAAGATTTACAATGATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAAT


We need to store the genome


We need to understand the genome

Genomes, Genes & Proteins

http://bejerano.stanford.edu/ 9

• The human genome encodes 20,000 genes.

• Gene = genomic substring that encodes HOW to make a

protein, an independent short linear molecule.

• A cell is made of proteins and run by proteins.

• Different cells are very different from each other,

because different cells express different genes.

...ACGTACGAC...ACTAGCATCGACTACGACTAGCAC... Genome Gene

Protein Cell [1,0,0,1] [1,1,0,0]

[0,1,1,1]

Genomic Switches


• The human genome encodes >1,000,000 genomic

switches that control these 20,000 genes.

• Gene = genomic substring that encodes

HOW to make a protein.

• Genomic switch = genomic substring that encodes

WHEN, WHERE & HOW MUCH of a protein to make.

[1,0,0,1] [1,1,0,0]

[0,1,1,1]

Gene

Gene

Gene

Gene

B

N

B N

H

H

Lab Focus


• Genes take up 2% of the human genome.

• Genomic switches take up >10%.

• 99% of genomic switches were never seen before

the human genome was sequenced 10 years ago.

• My lab studies these switches.

[1,0,0,1] [1,1,0,0]

[0,1,1,1]

Gene

Gene

Gene

Gene

B

N

B N

H

H


Combinatorial Regulatory Code

Gene

2,000 different proteins can bind specific DNA sequences.

A regulatory region encodes 3-10 such protein binding sites.

When all are bound by proteins the regulatory region turns “on”,

and the nearby gene is activated to produce protein.

Proteins

DNA

DNA

Protein binding site


Transcription Factor Language


Infer Codes (Machine Learning)

limb Gene

All Transcription Factors


Gene with Gene without

Predict Codes (Statistics)

Gene Annotation (e.g. “neuronal gene”) We think we found

a new code!

What is it doing?


Quick: What Do Regulatory Regions Have in Common?

(Algorithmics, Data Structures)

Find associations with molecular pathways, human diseases, etc.

19

Share Tools & Discoveries (web programming, GUIs)

Dave Bristor

Pick a genome

assembly

Input BED

regions of

interest

http://great.stanford.edu

http://bejerano.stanford.edu

GREAT Web Stats: Catching On

http://bejerano.stanford.edu/

.stanford.edu

20

1st Nature citation

Up 500 days 40,000 job submissions from 3,500 IPs


Every Genome is Different

DNA Replication is imperfect – between individuals of the

same species, even between the cells of an individual.

...ACGTACGACTGACTAGCATCGACTACGA...

chicken

egg ...ACGTACGACTGACTAGCATCGACTACGA...

functional junk

TT CAT

“anything

goes”

many changes

are not tolerated chicken

This has bad implications – disease,

and good implications – evolution.

23

Drift & Negative Selection

Neutral Drift Negative Selection

time population

Don’t

Care Function!

This is how Cancer starts



Developmental Defects

genome

gene

protein

Limb Malformation

Over 300 genes already

implicated in limb malformations.


Genetic Causes

genome

gene

NO protein

made

Limb Malformation

HANDFUL of cases known (limb, deafness, etc).


Modular Regulation: Disease Implications


Explain Non-Syndromic Limb Patients

120 non syndromic limb patients and growing.

limb

30

Drift, Negative & Positive Selection

Neutral Drift Positive Selection Negative Selection

time population


human

mouse

rat

chimp

chicken

fugu

zfish

dog

tetra

opossum

cow

macaque

platypus

Comparative Genomics

t

*

what made

us human?


Primate Evolution

33 33

Phenotype Genotype

Which genomic changes mattered?

Size of difference

No.

of diffe

rences

4%


Compartmentalized: Most Likely to Evolve?

Chimp Human


Identifying regulatory elements

uniquely lost in human

Why deletions?

• Likely to confer a phenotype

• May contribute to both loss

and gain events.

36

Hsp68 promoter LacZ Reporter Gene

Human

Chimpanzee

Androgen Receptor Chimpanzee Enhancer Assay

[Phil Reno, David Kingsley]

Genomic Fragment

Facial Vibrissae

Genital Tubercle

E16.5 http://bejerano.stanford.edu

37

Androgen Responsiveness and Domains of Expression

Facial vibrissae Penile spines

http://bejerano.stanford.edu


Summary

The Human Genome is mostly unexplored

We study the genomics regions that turn genes on and off.

In other words we study the control layer of the human genome

Research opportunities in:

• Algorithms

• Data Analysis

• Visualization

• NLP

GENOMICS DEVELOPMENT EVOLUTION


Interested? Check us out

Many Computational Biology

class are offered on campus.

See

http://bejerano.stanford.edu/

http://compbio.stanford.edu/

http://cs273a.stanford.edu/

[email protected]


Questions, Please…


Sequence Conservation implies Function

(but which function/s?...)

human

mouse

mammalian ancestor

..GCTTTGGGAATGACTAGCATCGACTATTTAG..

..CACGGTGGACTGACTA-CATCGACTACGACC..

functional region!

Comparative Genomics of related species highlights:


Human Genome:

3*109 letters

Human Genome full of Conserved Non-Coding Elements

1.5% known

function >50% junk

3x more functional DNA than known!

compare to other species

>5% human genome functional

~106 genomic loci do not code for protein

What do all these regions do then?

Even the most conserved regions are not coding.

ggtgccagggaaagggcaggaggtgagtgctgggaggcagctgaggtcaacttctttt...

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