multiple sequence alignment
DESCRIPTION
Multiple Sequence Alignment. Definition. Given N sequences x 1 , x 2 ,…, x N : Insert gaps (-) in each sequence x i , such that All sequences have the same length L Score of the global map is maximum. Applications. Scoring Function: Sum Of Pairs . Definition: Induced pairwise alignment - PowerPoint PPT PresentationTRANSCRIPT
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CS273A
Lecture 17: Cross Species Comparisons
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Announcements• Your project should be coming along nicely!
TTATATTGAATTTTCAAAAATTCTTACTTTTTTTTTGGATGGACGCAAAGAAGTTTAATAATCATATTACATGGCATTACCACCATATACATATCCATATCTAATCTTACTTATATGTTGTGGAAATGTAAAGAGCCCCATTATCTTAGCCTAAAAAAACCTTCTCTTTGGAACTTTCAGTAATACGCTTAACTGCTCATTGCTATATTGAAGTACGGATTAGAAGCCGCCGAGCGGGCGACAGCCCTCCGACGGAAGACTCTCCTCCGTGCGTCCTCGTCTTCACCGGTCGCGTTCCTGAAACGCAGATGTGCCTCGCGCCGCACTGCTCCGAACAATAAAGATTCTACAATACTAGCTTTTATGGTTATGAAGAGGAAAAATTGGCAGTAACCTGGCCCCACAAACCTTCAAATTAACGAATCAAATTAACAACCATAGGATGATAATGCGATTAGTTTTTTAGCCTTATTTCTGGGGTAATTAATCAGCGAAGCGATGATTTTTGATCTATTAACAGATATATAAATGGAAAAGCTGCATAACCACTTTAACTAATACTTTCAACATTTTCAGTTTGTATTACTTCTTATTCAAATGTCATAAAAGTATCAACAAAAAATTGTTAATATACCTCTATACTTTAACGTCAAGGAGAAAAAACTATAATGACTAAATCTCATTCAGAAGAAGTGATTGTACCTGAGTTCAATTCTAGCGCAAAGGAATTACCAAGACCATTGGCCGAAAAGTGCCCGAGCATAATTAAGAAATTTATAAGCGCTTATGATGCTAAACCGGATTTTGTTGCTAGATCGCCTGGTAGAGTCAATCTAATTGGTGAACATATTGATTATTGTGACTTCTCGGTTTTACCTTTAGCTATTGATTTTGATATGCTTTGCGCCGTCAAAGTTTTGAACGATGAGATTTCAAGTCTTAAAGCTATATCAGAGGGCTAAGCATGTGTATTCTGAATCTTTAAGAGTCTTGAAGGCTGTGAAATTAATGACTACAGCGAGCTTTACTGCCGACGAAGACTTTTTCAAGCAATTTGGTGCCTTGATGAACGAGTCTCAAGCTTCTTGCGATAAACTTTACGAATGTTCTTGTCCAGAGATTGACAAAATTTGTTCCATTGCTTTGTCAAATGGATCATATGGTTCCCGTTTGACCGGAGCTGGCTGGGGTGGTTGTACTGTTCACTTGGTTCCAGGGGGCCCAAATGGCAACATAGAAAAGGTAAAAGAAGCCCTTGCCAATGAGTTCTACAAGGTCAAGTACCCTAAGATCACTGATGCTGAGCTAGAAAATGCTATCATCGTCTCTAAACCAGCATTGGGCAGCTGTCTATATGAATTAGTCAAGTATACTTCTTTTTTTTACTTTGTTCAGAACAACTTCTCATTTTTTTCTACTCATAACTTTAGCATCACAAAATACGCAATAATAACGAGTAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTTTCCTACGCATAATAAGAATAGGAGGGAATATCAAGCCAGACAATCTATCATTACATTTAAGCGGCTCTTCAAAAAGATTGAACTCTCGCCAACTTATGGAATCTTCCAATGAGACCTTTGCGCCAAATAATGTGGATTTGGAAAAAGAGTATAAGTCATCTCAGAGTAATATAACTACCGAAGTTTATGAGGCATCGAGCTTTGAAGAAAAAGTAAGCTCAGAAAAACCTCAATACAGCTCATTCTGGAAGAAAATCTATTATGAATATGTGGTCGTTGACAAATCAATCTTGGGTGTTTCTATTCTGGATTCATTTATGTACAACCAGGACTTGAAGCCCGTCGAAAAAGAAAGGCGGGTTTGGTCCTGGTACAATTATTGTTACTTCTGGCTTGCTGAATGTTTCAATATCAACACTTGGCAAATTGCAGCTACAGGTCTACAACTGGGTCTAAATTGGTGGCAGTGTTGGATAACAATTTGGATTGGGTACGGTTTCGTTGGTGCTTTTGTTGTTTTGGCCTCTAGAGTTGGATCTGCTTATCATTTGTCATTCCCTATATCATCTAGAGCATCATTCGGTATTTTCTTCTCTTTATGGCCCGTTATTAACAGAGTCGTCATGGCCATCGTTTGGTATAGTGTCCAAGCTTATATTGCGGCAACTCCCGTATCATTAATGCTGAAATCTATCTTTGGAAAAGATTTACAATGATTGTACGTGGGGCAGTTGACGTCTTATCATATGTCAAAGTCATTTGCGAAGTTCTTGGCAAGTTGCCAACTGACGAGATGCAGTAACACTTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCACAAACTTTAAAACACAGGGACAAAATTCTTGATATGCTTTCAACCGCTGCGTTTTGGATACCTATTCTTGACATGATATGACTACCATTTTGTTATTGTTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATGTTTTCAATGTAAGAGATTTCGATTATCTTATAGTTCATACATGCTTCAACTACTTAATAAATGATTGTATGATAATAAAG
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TerminologyOrthologs : 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
SpeciationDuplicationLoss
singleancestralgene
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Chains join together related local alignments
Protease Regulatory Subunit 3
likely ortholog
likely paralogsshared domain?
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Before and After Chaining
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Netting AlignmentsCommonly multiple mouse alignments can be found for a particular human region, eg including for most coding regions.
Net finds best match mouse match for each human region.Highest scoring chains are used first.Lower scoring chains fill in gaps within chains inducing a natural hierarchy.
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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.
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Nets attempt to computationally capture orthologs
(they also hide everything else)
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Nets/chains can reveal retrogenes (and when they jumped in!)
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Nets
• a net is a hierarchical collection of chains, with the highest-scoring non-overlapping chains on top, and their gaps filled in where possible by lower-scoring chains, for several levels.
• a net is single-coverage for target but not for query.• because it's single-coverage in the target, it's no longer symmetrical.• the netter has two outputs, one of which we usually ignore: the target-
centric net in query coordinates. The reciprocal best process uses that output: the query-referenced (but target-centric / target single-cov) net is turned back into component chains, and then those are netted to get single coverage in the query too; the two outputs of that netting are reciprocal-best in query and target coords. Reciprocal-best nets are symmetrical again.
• nets do a good job of filtering out massive pileups by collapsing them down to (usually) a single level.
• GB: for human inspection always prefer looking at the chains!
[Angie Hinrichs, UCSC wiki]
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Before and After Netting
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Convert / LiftOver"LiftOver chains" are actually chains extracted from nets, or chains filtered by the netting process.
LiftOver – batch utility
Drawbacks
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• Inversions not handled optimally
> > > > chr1 > > >
> > > > chr1 > > >
< < < < chr1 < < < <
< < < < chr5 < < < <
Chains
Nets > > > > chr1 > > >
> > > > chr1 > > >
< < < < chr5 < < < <
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What nets can’t show, but chains will
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Same Region…
same in allthe other fish
Drawbacks
• High copy number genes can break orthology
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Gene Families
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Self Chain reveals (some) paralogs
(self net ismeaningless)
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The Biggest Challenge in Genomics…… is computational:
How does this encode this
Program Output
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Xkcd Take – It’s Actually Not That Bad
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Why compare to Chimp?
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Humans and Chimpanzees PossessMany Vastly Different Phenotypes
A: Chimp B: Human
A B
[Varki, A. and Altheide, T., Genome Res., 2005]
A B
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Disease Susceptibility Differences
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What human-chimp changes do we find?
Small
Large
Medium
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Large differences
Fusion (HSA 2) 18 pericentromeric inversions
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Medium Sized Differences
Gene families expandand contract
Mobile element insertionand mediated deletion
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Small Differences
1% difference at the base level
PhenotypeGenotype
Genetic basis of human phenotypes?N
umbe
r of r
earr
ange
men
ts
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Most mutationsare near/neutral.How do we know?4D sites, ARs.
The Genotype - Phenotype divide
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Can we find evolutionary patterns that are distinct enough to be phenotypically revealing?
Species A
Species B
Problem #1:
Too many nucleotide changes between any pair of related species (or individuals).
The vast majority of these are near/neutral.
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Is it in our protein coding genes?
70-80% of all human-chimp orthologous proteins differ.On average they differ by 1-2 amino acids.• Which amino acid changes matter?• One can also compare non-synonymous amino acid
substitutions with synonymous changes, and look for proteins unusually enriched from the former.Those may be evolving under positive selection.
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Positive and negative gene selection in the human genome
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Candidate genes for human specific evolution
...
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What if we did an unbiased search?Human-specific substitutions in conserved sequences
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[Pollard, K. et al., Nature, 2006] [Beniaminov, A. et al., RNA, 2008]
Human
Chimp
Humanrapid change
HAR1:• Novel ncRNA• 18 unique human substitutions
conserved
Chimp
Different Unbiased Search: Loss vs Gain
Chimp
Humanrapid change • 4-18 unique human substitutions
• Pollard, K. et al., Nature, 2006• Prabhakar, S. et al., Science, 2008
conserved
Human Accelerated Regions
deleted!
Chimp
Human
conserved
Human Conserved Sequence Deletions
(hCONDELs)• Complete human loss of sequence• Likely to confer human-specific
phenotypes
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[McLean, Reno, Pollen et al., Nature, 2011]
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Identifying hCONDELs
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deleted!
Chimp
Human
conserved
hCONDEL genomic distribution
• Median size: 2.8kb• Not enriched in highly variable genomic regions• Most do not disrupt proteins: only 1 validated exonic deletion
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Deletions of functional non-coding DNAGene Gene Gene
GeneGeneGene
Gene Gene
GeneGene
( ) ( ) ( )
( )
( ) ( ) ( ) ( )
( )( )
Gene Gene
Gene with functione.g. “neuronal gene” Gene without function
( )hCONDEL Conserved element
[McLean et al., Nat. Biotechnol., 2010]
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Functional enrichments of hCONDELs
Ontology Term p-valueGene Ontology Steroid hormone receptor activity 3.73 x 10-4
InterPro Fibronectin, type III 1.01 x 10-4
Zinc finger, nuclear hormone receptor type 1.80 x 10-4
CD80-like, immunoglobulin C2 set 1.37 x 10-3
Entrez Gene Neuronal genes 1.11 x 10-4
Monoallelically-Expressed Genes Monoallelic expression 8.62 x 10-3
These enrichmentsare unique to hCONDELs
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hCONDEL near Androgen Receptor
The deletion appears fixed in humansand appears deleted in Neandertal.
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Androgen Receptor chimpanzee enhancer assay
[Phil Reno, David Kingsley]
Androgen Receptor
Human
Chimp
Genomic fragment Hsp68 promoter LacZ reporter gene
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The human deletion near AR acts as an enhancer within known AR expression domains
E16.5
Sensory whiskers
E16.5
Genital tubercle
E16.5
E16.5
Penile spines
8 weeksE16.5
Chi
mp
enha
ncer
Mou
se e
nhan
cer
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Androgen Receptor
Cell
AndrogenReceptor
Nucleus
Testosterone
AR+Tdimer
Androgen Receptor
Human
Chimp
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Androgen responsiveness in domains of expressionSensory whiskers Penile spines
Galago
Sen
sory
whi
sker
leng
th (m
m)
[Dixson, 1976]
Mice with Ar coding region mutations lack penile spines
[Murakami, 1987]
Sensory Penilewhiskers spines
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[Ibrahim & Wright 1983]
Could sequence loss lead to tissue gain?
• hCONDELs enriched for suppressors of cell proliferation or cell migration expressed in cortex (P=1.3 x 10-3)
Non-human mammals Humans
( )
Suppressproliferation
Do notsuppressproliferation
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The Genotype - Phenotype divide
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Can we find evolutionary patterns that are distinct enough to be phenotypically revealing?
Species A
Species B
Problem #1:
Too many nucleotide changes between any pair of related species (or individuals).
The vast majority of these are near/neutral.
Genotype -> Phenotype screens
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deleted!
Chimp
Human
conserved
Define a “dramatic” (non-neutral) genomic scenario:
hCONDEL
[McLean, Pollen, Reno et al, 2011]
Problem #2:
What is the phenotype?
Testing is Exciting… and Humbling
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These are “wild rides”: Often not what we expected, Often not what we can understand.Are we looking at the right place?Did we test at the right time?
[McLean, Pollen, Reno et al, 2011]
We are creating the humanized mice KOs
What about a tree of related species?
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What if we could find evolutionary patterns that were distinct enough to be phenotypically revealing?
ancestor
Species A
Species H
Genomes:Inherited and Modified.
Traits:Come and Go.
Species B...
ancestral trait information
Trait information is no longer under selection
Erodes away over evolutionary time
ancestor
What happens when an ancestral trait “goes”?
Phenotype Genome
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ancestral trait information
Trait information is no longer under selection
Erodes away over evolutionary time
ancestor
Phenotype Genome
A lot of DNA and many traitsvary between any two species.
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ancestral trait information
Trait information is no longer under selection
Erodes away over evolutionary time
ancestor
Phenotype Genome
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A lot of DNA and many traitsvary between any two species.
What about independent trait loss?
vitamin C synthesis, tail, body hair,dentition features, etc. etc.
ancestral trait information
Trait information is no longer under selection
Erodes away over evolutionary time
ancestor
Phenotype Genome
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matches trait presence/absence pattern
The PG screen
[Hiller et al., 2012a] 54
The PG screen
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Capture the independent genomic switch from purifying selection neutral evolution
in all and only the trait loss species.
Robust to: Different trait disabling times.Different trait disabling mutations.
Forward Genetics:Search for mutations that segregate with a trait of interest
Forward Genomics:Search for regions that are lost only in species lacking the trait
phenotype genotype
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Branding ;-)
But does it work?
Vitamin C Synthesis
synthesize vitamin C cannot synthesize vitamin C
rats & mice human
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vitamin C synthesis was lost3-4 times independently in mammalian evolution
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The Vitamin C synthesis “phenotree”
Fwd Genomics asks:Do one or moregenomic locilook like THAT?
We quantify divergence by comparing sequences to the reconstructed ancestral sequence
reconstruct ancestral sequence
ancestor
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species 1
outgroup
species 2
ACCCTATCGATT-CA
ACCCTATCGATTGCA
TCCGTATCG-TT-CA
species 1
species 2
14 identical bases
11 identical bases
Mutation in species 1 or 2?
species 1species 2
93%79%
percent of identical bases: more diverged
Insertion in species 1 or deletion in species 2 ?
ACCCTATCGATTGCA
TCCGTATCG-TT-CA
ACTCT-TCGATT-AA
Sequencing errors mimic divergence
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high sequencing error rate
treat species 2 as missing data
sequence quality scores
ancestor ACCCTATCGATT-CAATGG
ACCCTATCGATTGCAAGGGspecies 1
species 2
89% identical bases
61% identical basesTCCGTAACG--T-CTATCG
Assembly gaps mimic divergence
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?????????species 1
Sanger reads
assembly gap
conserved region
treat species 1 as missing data
species 2species 3species 4species 5
...
Reconstruct the evolutionary history of all conserved regions, coding and non-coding
85%
70%
93%
matrix: 33 species x 544,549 regions
544,549 conserved regions
• Reconstruct ancestral sequence• Measure extant species divergence• Avoid
• Low quality sequence• Assembly gaps
• Seek perfect phenotree match
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reconstructancestrallocus
We quantify the match to the vitamin C pattern by counting the number of species that violate the pattern
Percent identity0 100
Percent identity0 100
1 violation
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Regions matching the vitamin C trait are clustered
these conserved regions are all exons of a single gene
544,549 conserved regions
no. o
f vio
latin
g sp
ecie
s
012345
7
910
6
no match
perfect match
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This gene is more diverged in all non-vitamin C synthesizing species
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What is the function of this gene ?
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encodes the enzyme responsible for vitamin C biosynthesis
Vitamin C pattern
Gulo - gulonolactone (L-) oxidase
33 genomes X 544,549 regions
Note: 1. No likely shared
disabling mutation.2. We learned about
both evolution and function.
The Power of Forward Genomics
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Vitamin C pattern
Gulo - gulonolactone (L-) oxidase
33 genomes X 544,549 regions
Forward genomics works.Can it work for continuous traits?With only two independent losses?And many unknown values?
BileBile is a fluid produced by the liver that aids the digestion of lipids in the small intestine.
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Bile Phospholipids
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Different mammals have remarkably different levels of biliary phospholipids:
ABCB4 is a phospholipid transporter
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Find “Cure” Models for Human Disease
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Human ABCB4 mutations lower patient biliary phospholipid levels to guinea pig levels but are detrimental. Our discovery: Guinea pig and horse have inactivated the Abcb4 gene in their natural state. How can they do it?
create KO gene
try to fix/treat
Natural KO
find nature’s cure!
We have now collected • Million genomic loci by Fifty mammals• Thousands of scored mammalian traits
And we are playing MATCH and TEST.
Reverse Genetics:Pick interesting loci, mutate and try to figure out phenotype/s
Reverse Genomics:Compute independent loss for ALL genomic loci, match to traits
phenotype genotype
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Reverse Genomics
Reverse Genomics of Enhancers
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Back of an Envelope Wish
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Poster Child Example
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