HW1 Due This Fri 10/21

http://cs273a.stanford.edu [Bejerano Fall11/12] 1

HW1 Due This Fri 10/21.

TA Q&A

Office Hours:•Preferred. Infinitely higher bandwidth.

E-mail:•Please reserve for (short) technicalities.•Discouraged questions:

–Is my answer correct? Am I on the right track?•You are experiencing genomic research.

No one tells us whether our answers are right or wrong. We QA ourselves. A lot. Do it too. Spot check elements in the UCSC Browser!

–Please debug this UNIX statement / output file for me.

Lecture 7

Chains & Nets cont’d

Genome Reconstruction

Genomic Conservation & Function

Sneak peek at other functional classes

Mutations

•Chromosomal Mutations:–Deletion

–Inversion

–Translocation

–Duplication

–(Nondisjunction)

4http://cs273a.stanford.edu [Bejerano Fall11/12]

Gene Families

Orthologs : Genes related via speciation (e.g. C,M,H3)

Paralogs: Genes related through duplication (e.g. H1,H2,H3)

Homologs: Genes that share a common origin (e.g. C,M,H1,H2,H3)

Species tree

Gene tree

SpeciationSpeciationDuplicationLoss

single

ancestral

Chaining (Paralogs)

Protease Regulatory Subunit 3

Netting (Ortholog)

Convert / LiftOver"LiftOver chains" are actually chains extracted from nets, or chains filtered by the netting process.

LiftOver – batch utility

Net highlights rearrangements

A large gap in the top level of the net is filled by an inversion containing two genes. Numerous smaller gaps are filled in by local duplications and processed pseudo-genes.

Drawbacks• Nets relentlessly try to fill in gaps

Heuristic guessof best chain!

True dog orthologjust hasn’t beensequenced

Retroposed Genes and Pseudogenes

And Retrogenes

Conservation Track Documentation

Useful in finding pseudogenes

Ensembl and Fgenesh++ automatic gene predictions confounded by numerous processed pseudogenes. Domain structure of resulting predicted protein must be interesting!

Cautionary Note 2

Same Region…

same in all

the other fish

A Rearrangement Hot Spot

Rearrangements are not evenly distributed. Roughly 5% of the genome is in hot spots of rearrangements such as this one. This 350,000 base region is between two very long chains on chromosome 7.

Drawbacks

• Inversions not handled optimally

> > > > chr1 > > > > > > > chr1 > > >

< < < < chr1 < < < <

< < < < chr5 < < < <

Chains

Nets > > > > chr1 > > > > > > > chr1 > > >

< < < < chr5 < < < <

Drawbacks

• High copy number genes can break orthology

Self Chain

From pairwise to multiple alignments

• Example: in 3D (three sequences):

• 7 neighbors/cell

F(i,j,k) = max{ F(i-1,j-1,k-1)+S(xi, xj, xk),F(i-1,j-1,k )+S(xi, xj, - ),F(i-1,j ,k-1)+S(xi, -, xk),F(i-1,j ,k )+S(xi, -, - ),F(i ,j-1,k-1)+S( -, xj, xk),F(i ,j-1,k )+S( -, xj, xk),F(i ,j ,k-1)+S( -, -, xk) }

Multidimensional DP

Progressive Alignment

• When evolutionary tree is known:

Align closest first, in the order of the tree In each step, align two sequences x, y, or profiles px, py, to generate a new

alignment with associated profile presult

E.g: Blastz – Multiz shown in UCSC browser

Anchor based alignment

Example:

Anchor based alignment

E.g: Enredo - Pecan shown in ENSEMBL browser

Reconstruct the Boreoeutherian ancestor

Ancestral Genome Reconstruction

Given: - Genomic sequences of several mammals - Phylogenetic tree

Find: The genomic sequence of all their ancestorsARMADILLO TGCTACTAATATTTAGTACATAGAGCCCAGGGGTGCTGCTGAAAGTCTTAAAATGCACAGTGTAGCCCCTCCTCC

COW GCCTCTCTTTCTGCCCTGCAGGCTAGAATGTATCACTTAGATGTTCCAAATCAGAAAGTGTTCAGCCATTTCCATACC

HORSE GTCACAATTTAGGAAGTGCCACTGGCCTCTAGAGGGTAGAAGACAGGGATGCTAATAATCATCCCACGTCATCCTACAGTGCTCAGAACAGCACCCCTACCCTCACCCC

CAT GTCACAGTTTAGGGGGTACTACTGGCATCTATCGGGTGGAGGATAGGGATACTGATAATCATTCTACAGTGCACAGGACAGTACCCCTACTTTCACCCC

DOG GTCACAATTTGGGGGATACTACTGGCATCTAATGGGTAGAGGACAGGGATACTGATAATTGCTTTACAGTGCACAGGACAGCACCCTTATCTTCACCCC

HEDGEHOG GTCATAGTTTGATTATATGGGCTTCTTAGTAGACAAAGAAAAAGATGTTCTGGTAGTCATTCTGCTTTCCATATGATAGCACTCCCATCTTCACTTC

MOUSE GTCACAGTTTGGAGGATGTTACTGACATCTAGAGAGTAGACTTTAAAGATACTGATAGTCACCCCATTGTGCACCTCC

RAT GTCACAATTTGGAGGATGTTACTGGCATCTAGAGAGTAGACTTTAAGGACACTGATAATCATACTATGCTGCACTTCC

RABBIT ATCACAATTTGGGGAACACCACTGGCATCTCGGGTAGCAGGCCAGGCATGCTGGTAATTATACTACAGTGCACAGTACAGTTCCCCACATCCCGCACC

LEMUR ATCACAATTGGGGGTGCCACGGTCCTCCAGTGGGTAGAGAACAGGGAGGCTGATAACCACCCTGCAGTGCACAGGGCAGTGCCCCACTCCCACCAC

MOUSE-LEMUR ATCACAGTTGGGGGATGCCACTGGCCTCAAGTGGGTAGAGAACAGGGAGGCTGAAAACCACCCTGCAGAGCACGGGGCAGTGCCTTCACCACCACTCC

VERVET GTCAGAATTTGGGGGATGCTTCTGGCTCTACTTGGGTAGAGAAACAGGGATGCTTATAATCATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCC

MACAQUE GTCAGAATTTGGGGGATGCTTCTGGCTCTACTTGGGTAGAGAAACAGGAATGCTTATAATCATCCTACAGTGCACAGGTCAGTACCCCCACCCACACTCC

BABOON GTCAGAATTTGGGGGATGCTTCTGGCTCTACTTGGGTAGAAAAACAGGGATGCTTATAATCATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCC

ORANGUTAN GTCACGATTTGGGAGATGCTTCTGGCTCGACTTGGGTAGAGAAGCGGGGATGCTTATAATCATCCAACAGTGCACAGGACAGTACCCCCACCCACACTCC

GORILLA GTCACGATTTGGGGGATGCTTCTGGCTCAACTTGGGTAGAGAAGTGGGGATGCTTATACTCATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCC

CHIMP GTCACGATTTGGGGGATGCTTCTGGCTCAACTTGGGTAGAGAAGCGGGGATGCTTATAATCATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCC

HUMAN GTCACGATTTGGGGGATGCTTCTGGCTCAACTTGGGTAGAGAAGCGGGGATGCTTATAATCATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCC

Mutational operations• Small-scale : Substitutions, deletions, insertions (inc. transposons)

• Large scale: Genome rearrangement, segmental/tandem duplications(*): Heterochromatin non-included

All of it: Functional,

non-functional, introns,

intergenic, repeats,

everything*!

Reconstruction algorithm

1) Identify orthologous regions in each species

2) Compute multiple genome alignment

ARMADILLO ----------------TGCTACTAATAT-----T-TAGTA-CATAGAG-CC-CAGGGGTGCTGCTGAAA----------GTCTTAAAATGCACAGTGTAGCCCCTCCTCC------------ACAAAGAATTAACTAGCCCAGAATGTCAGGA--------GT--A-CCAAG

COW GCCTCTCTTT-----------CTGCCCTGCAGGC-TAGAA-TGTATCA-CT-TAGATGTTCCAA---------------ATCAGAAAGTGTTCAG----------CCATTTCCATACCACC----AGGAGCTA-CAATGTTGGGCTGCAGCTA--------TTTGGATCAAA

HORSE GTCACAATTTAGGAAGTGCCACTGGCCT-----C-TAGAG-GGTAGAA-GA-CAGGGATGCTAATAATCATCCCACGTCATCCTACAGTGCTCAGAACAGCACCCCTACCCTCACCCCATCAACAAAGAATTATCCAGCCCAAAATGCCAATA--------GT--GCCCAGA

CAT GTCACAGTTTAGGGGGTACTACTGGCAT-----C-TATCG-GGTGGAG-GA-TAGGGATACTGATAATC----------ATTCTACAGTGCACAGGACAGTACCCCTACTTTCACCCCACAA-CAAAGAATTATCCAGCCCAAAATGCCAACA--------GT--GCTCAGA

DOG GTCACAATTTGGGGGATACTACTGGCAT-----C-TAATG-GGTAGAG-GA-CAGGGATACTGATAATT----------GCTTTACAGTGCACAGGACAGCACCCTTATCTTCACCCCAAAAGCAAAGTATTATCCAGCCCCAAATGCCAATG--------GT--GCTCAGA

HEDGEHOG GTCATAGTTT----GATTATATGGGCTT-----CTTAGTA-GACAAAGAAA-AAGATGTTCTGGTAGTC----------ATTCTGCTTTCCATATGATAGCACTCCCATCTTCACTTCCAAAATTAAGAGTCATCATACTCAGTGTGCCAATA--------TG--GCCCAGA

MOUSE GTCACAGTTTGGAGGATGTTACTGACAT-----C-TAGAG-AGTAGAC-TT-TAAAGATACTGATAGTC----------ACCCCATTGTGCAC---------------------CTCCAACAATAATGGCTCATCGAAACCTAAATGCCAATCTGCCAATTAT--GTCCATG

RAT GTCACAATTTGGAGGATGTTACTGGCAT-----C-TAGAG-AGTAGAC-TT-TAAGGACACTGATAATC----------ATACTATGCTGCAC---------------------TTCCAACAATAATGGCTCATCTAGACCTAAATACCAATCTGCCAATTAT--ATCCATG

RABBIT ATCACAATTTGGGGAACACCACTGGCAT-----C-TCGGGTAGCAGGC----CAGGCATGCTGGTAATT----------ATACTACAGTGCACAGTACAGTTCCCCACATCCCGCACCAACAACA--GGTTTATGCTGCCCAAAGTGCCAGTGTGC-----------CCACG

LEMUR ATCACAA-TTGGGGG-TGCCACGGTCCT-----C-CAGTG-GGTAGAG-AA-CAGGGAGGCTGATAACC----------ACCCTGCAGTGCACAGGGCAGTGCC-CCACTCCCACCACAACAATGGAGAATTATTGGGCCCCAAATGCCAATA--------GT--GCCCAAG

MOUSELEMUR ATCACAG-TTGGGGGATGCCACTGGCCT-----C-AAGTG-GGTAGAG-AA-CAGGGAGGCTGAAAACC----------ACCCTGCAGAGCACGGGGCAGTGCCTTCACCACCACTCCAACAACGGAGAATTATTGGGTCCCAAATGCCAATA--------GT—-GCCCAGG

VERVET GTCAGAATTTGGGGGATGCTTCTGGCTC-----T-ACTTG-GGTAGAG-AAACAGGGATGCTTATAATC----------ATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTATCGAAGAATCATTGAACCCAAAATGTTAATA--------GT--GTCCAGG

MACAQUE GTCAGAATTTGGGGGATGCTTCTGGCTC-----T-ACTTG-GGTAGAG-AAACAGGAATGCTTATAATC----------ATCCTACAGTGCACAGGTCAGTACCCCCACCCACACTCCAGTATCGAAGAATCATTGGACCCAAAATGCTAATG--------GT--GTCCAGG

BABOON GTCAGAATTTGGGGGATGCTTCTGGCTC-----T-ACTTG-GGTAGAA-AAACAGGGATGCTTATAATC----------ATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTATCGAAGAATCATTGGACCCAAAATGTTAATG--------GT--GTCCAGG

ORANGUTAN GTCACGATTTGGGAGATGCTTCTGGCTC-----G-ACTTG-GGTAGAG-AAGCGGGGATGCTTATAATC----------ATCCAACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTAATGAAGAATCACTGGACCCAAAATGTTAATG--------GT--GTCCAGG

GORILLA GTCACGATTTGGGGGATGCTTCTGGCTC-----A-ACTTG-GGTAGAG-AAGTGGGGATGCTTATACTC----------ATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTAATGAAGAATCATTAGACCGAAAATGTTAATG--------GT--GTCCAGG

CHIMP GTCACGATTTGGGGGATGCTTCTGGCTC-----A-ACTTG-GGTAGAG-AAGCGGGGATGCTTATAATC----------ATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTAATGAAGAATCATTAGACCGAAAATGTTAATG--------GT--GTCCAGA

HUMAN GTCACGATTTGGGGGATGCTTCTGGCTC-----A-ACTTG-GGTAGAG-AAGCGGGGATGCTTATAATC----------ATCCTACAGTGCACAGGACAGTACCCCCACCCACACTCCAGTAATGAAGAATCATTAGACCTAAAATGTTAATG--------GT--GTCCAGG

• Goal: Phylogenetic correctness• Two nucleotides are aligned if and only if

they have a common ancestor.

Reconstruction algorithm3) Reconstruct insertion/deletion history

• Find most likely explanation for gaps observed

3) Reconstruct insertion/deletion history • Find most likely explanation for gaps

observedARMADILLO ----------------TGCTACTAATAT-----T-TAGTA-CATAGAG-CC-CAGGGGTGCTGCTGAAA----------GTCTTAAAATGCACAGTGTAGCCCCTCCTCC------------ACAAAGAATTAACTAGCCCAGAATGTCAGGA--------GT--A-CCAAG

3) Reconstruct insertion/deletion history – Find most likely explanation for gaps

observed

• This defines the presence/absence of a base at each position of each ancestor

NNNNNNNNNNNNNNNNNNNNNNNNNNNN-----N-NNNNN-NNNNNNN-NN-NNNNNNNNNNNNNNNNN----------NNNNNNNNNNNNNNNNNNNNNNNNNNNNNN

GTCACAATTTGGGGGATGCTACTGGCAT-----C-TAGTG-GGTAGAG-AA-CAGGGATGCTGATAATC----------ATCCTACAGTGCACAGGACAGTGCCCCCACCCCCACTCCAACAACAAAGAATTATCCGGCCCAAAATGCCAATA--------GT--GCCCAGG

4) Infer max.-like. nucleotide at each position

• Ancestral sequences are inferred!

Reconstructing Cancer Genomes

• GleevecTM (Novartis 2001) targets BCR-ABL oncogene.

• Change gene structure and regulatory “wiring” of the genome.

• Create “bad” novel fusion genes and break “good” old genes.

• Example: translocation in leukemia.

promoter

promoter ABL gene

BCR genepromoter

Chromosome 9

Chromosome 22

BCR-ABL oncogene

Complex Tumor Genomes

1) What are detailed architectures of tumor genomes?

2) What rearrangements/duplications produce these architectures and what is the order of these events?

3) What are the novel fusion genes and old “broken” genes?

Tumor Genomes Projects

Tumor genomeHuman genome

1) Identify recurrent aberrations

2) Identify temporal sequence of aberrations

3) Use these data for tumor diagnostics and therapeutics

Mutation, selection

Tumor genome 2

Tumor genome 4

Tumor genome 3

Meet Your Genome contd.

[Human Molecular Genetics, 3rd Edition]

Sequence Conservation implies Function

•(but which function/s?...)

anotherspecies

commonancestor

...CTTTGCGA-TGAGTAGCATCTACTATTT...

...ACGTGGGACTGACTA-CATCGACTACGA...

functional region!

Comparative Genomics of Distantly related species:

Note: the inverse “no conservation no function”is a much weaker statement given current knowledge

Vertebrates: what to sequence?

you are here

, Opossum

, Lizard

, Stickleback

too far

sweet spot

too close

Which species to compare to?

Too close and purifying selection will be largely indistinguishable from the neutral rate.

Too far and many functional orthologs will diverge beyond our ability to accurately align them.

The Dawn of Whole Genome Comparative Genomics

2001 2002

40% DNA alignable95% coding genes shared

More Species Have Joined Since

How They Measuredall human-mouse alignmentshuman-mouse

ancestral repeats alignment

Difference: 5% of

Human Genome

[Mouse consortium, Nature 2002]

Conserved elements in the Human Genome

all human-mouse alignmentshuman-mouse ancestral repeats alignment

Difference: 5% of

Human Genome

[Mouse consortium, Nature 2002]

election

human-mouse ancestral repeats alignment

85%id on average

UltraconservationUltraconservation

Ultraconserved Elements

[Bejerano et al., Science 2004]

481 elements perfectly conserved (100%id) over

200bp or more between human, mouse and rat.

Ultraconserved Elements: Why?

Hundreds of long substrings identical between amniotes they must have rejected many different changes.

But... all functions we understand in our genome are encoded using redundant codes.

E.g. Protein Coding Genes:

DNA – 108 letters over alphabet of 4.

Protein – 102 letters over alphabet of 20.

Coding: 3 DNA letters → 1 Protein letter.

[Bejerano et al., Science 2004]

No known function requires this much conservation

CDS ncRNA TFBS

PhastCons Conserved Elements

http://cs273a.stanford.edu [Bejerano Fall11/12]

Other Ways to Measure: indel resistance, rejected subst

[Lunter et al, 2006]

[Cooper et al., 2005]

, Opossum

, Lizard

, Stickleback

Phylogenetic Shadowing

you are here

too close

“too close” can actually be a boon

if you have enough closely related genomes

HumanGenome:

3*109 letters

What They Found

[Science 2004 Breakthrough of the Year, 5th runner up]

1.5%known

function >50%junk

3x more functional DNA than known!

compare to other species

>5% human genome functional

~106 regions do not code for protein

What do they do then?

Gene regulation = when/where to make protein

•gene (how to)•control region(when & where)

~103 letters

Vertebrate Gene Regulation

•gene (how to)•control region(when & where)

proximal: in 103 letters

distal: in 106 letters

DNA binding

proteins

unicellular

multicellular

Unicellular vs. Multicellular

Most Non-Coding Elements are likely cis-regulatory

“IRX1 is a member of the Iroquois homeobox gene family.

Members of this family appear to play multiple roles

during pattern formation of vertebrate embryos.”

gene deserts

regulatory jungles

Central Dogma of Biology:

RNA is an Active Player:

Transcripts, transcripts everywhere

Human Genome

Transcribed (Tx)

Tx from both strands

Leaky tx?

Functional?

HW1 Due This Fri 10/21

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