the dynamics of nuclear gene order in the eukaryotes
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The dynamics of nuclear gene order in the
eukaryotes
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Genome archaeology in the angiosperms
Todd VisionDepartment of Biology
University of North Carolina at Chapel Hill
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Comparative maps Spaghetti Diagram Crop Circle
Livingstone et al 1999 Genetics 152:1183Gale & Devos 1998 PNAS 95:1972
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Arabidopsis as a hub for plant comparative maps
genome sizes in angiosperms
145262
367 367 372 415 439 473 560 622
907
0
250
500
750
1000
mega
base
s
data from Arumuganathan & Earle (1991)Plant Mol Biol Rep 9:208-218
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Tomato-Arabidopsis synteny
Bancroft (2001) TIG 17, 89 after Ku et al (2000) PNAS 97, 9121
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Outline
• Ancient genome duplication– How can we reconstruct genomic history?
• Computational challenges
• Role of different classes of gene duplication in genome evolution
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Outline
• Ancient genome duplication– How can we reconstruct genomic history?
• Computational challenges
• Role of different classes of gene duplication in genome evolution
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Mayer et al. (2001) Genome Res. 11, 1167
Rice-Arabidopsis synteny
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Paleotetraploidy?
The Arabidopsis Genome Initiative. 2000. Nature 408:796
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Genomic dot-plot
gene 1 2 3 4 5 6 7 8 1 1 0 0 0 1 0 0 0 2 0 1 0 0 0 1 0 0 3 0 0 1 0 0 0 1 0 4 0 0 0 1 0 0 0 1 5 1 0 0 0 1 0 0 0 6 0 1 0 0 0 1 0 0 7 0 0 1 0 0 0 1 0 8 0 0 0 1 0 0 0 1
1 2 3 4
5 6 7 8Chromosome copy 1Chromosome copy 2
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Duplication vs. multiplication
Multiple duplications generate abundant overlaps among homeologous regions
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Vision et al. (2000) Science 290:2114-7.
Segmental paralogy in Arabidopsis
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A B DC E F
Many duplicated segments but few duplication events
0
2
4
6
8
10
12
0 .1 .2 .3 .4 .5 .6 .7 .8 .9
amino acid substitution
freq
uenc
y of
blo
cks
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Blanc, Hokamp, Wolfe (2003) Genome Res. 13, 137-144.
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Arabidopsis
tomatoAngiosperm Phylogeny Website. Version 2 August 2001. http://www.mobot.org/MOBOT/research/APweb/.
rice
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Block 37 after
Asterid-Rosidsplit
Block 57before
monocot-dicot divergence
Raes, Vandepoele, Saeys, Simillion, Van de Peer (2003) J. Struct. Func. Genomics 3, 117-129
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Divergence of homeologs
• Homeologs from age class C and older share less than a third of their genes
– Gene loss
– Or subsequent gene movement?
• There is no evidence for uneven proportions of duplicated genes between homeologs
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Redundant gene function: SHATTERPROOF
Martin Yanofsky
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Implications for comparative maps
• Networks of synteny
• Goodbye to pairwise comparisons
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Outline
• Ancient genome duplication– How can we reconstruct genomic history?
• Computational challenges
• Role of different classes of gene duplication in genome evolution
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Ghosts and Muggles
Simillion, Vandepoele, Van Montagu, Zabeau, Van de Peer (2002) PNAS 99, 13627
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Interspecies comparison can reveal Ghosts
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Things needful
• Identification of highly diverged Muggles
• A systematic way to identify Ghosts
• Centralization of mapped and sequenced DNA markers from multiple species
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FISH(Fast Identification of Segmental
Homology)• Identifies candidate segmental homologies
– Dynamic programming
• Statistically evaluates candidates– Null model of transpositional duplication
• No permutations required
• Approaches limits to sensitivity
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FISH under null model
k observed number
standard error
upper bound
lower bound
2 45.8 0.06 47.6 40.1
3 2.28 0.02 2.39 1.78
4 0.113 0.003 0.120 0.079
5 0.006 0.001 0.006 0.004
6 0.0003 0.0002 0.0003 0.0002
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eAssembler
• Reconstructs ancestral gene order by joining duplicated blocks with overlapping gene content
• Uses ‘breakpoint median’ as objective function
• Similar to algorithms used in sequence assembly
Blanc, Hokamp, Wolfe (2003) Genome Res. 13, 137-144.
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PHYTOMEintegrating plant genome maps,
sequences and phylogenies
From www.plantgdb.org
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Outline
• Ancient genome duplication– How can we reconstruct genomic history?
• Computational challenges
• Role of different classes of gene duplication in genome evolution
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Gene duplications in a chromosomal context
• Turnover within gene families can be high– Rate of duplication= 0.002/gene*MY– Half-life=23MY
• Three modes of duplication– Tandem– Transpositional– Segmental
• How does the mode of origin affect the molecular and functional divergence of duplicate genes?
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Gene family turnover
Lynch and Conery (2000) Science 290, 1151
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Importance of tandem and transpositional duplications
~10% of genes are in tandem arrays
85% of dispersed duplications are not in blocks
• Duplicates on the same chromosome are 20% more common than expected by chance
• Duplicates on the same chromosome are 86% as distant as would be expected by chance
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Aux/IAA and ARF sister families
• Importance in Arabidopsis
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Diversification of the Aux/IAA gene family
David Remington and Jason Reed
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Diversification of ARF gene family
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Chromosome 2-4 complex:242 duplicated gene pairs
2600
3000
3400
3800
4200
1200 1600 2000 2400 2800
chromosome 2 (5.6 Mb)
chro
mos
ome
4 (4
.6 M
b)
45
52
49
54
56
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Substitutions in coding sequences
• silent substitutions (Ks) only alter the codon, not the resulting amino acid
• replacement substitutions (Ka) alter the amino acid
• Ka and Ks are standardized by the numbers of synonymous and nonsynonymous sites
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Ratio of Ka to Ks
Ka/Ks < 1 selective constraint
Ka/Ks = 1 pure neutrality
Ka/Ks > 1positive selection
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How have these ancient segmental duplicates diverged?
1. What is the variation in Ka and Ks among simultaneously duplicated pairs?
2. Do the Ka/Ks ratios suggest positive selection?
3. Do the members of each duplicated pair evolve at the same rate?
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0
10
20
30
40
50
60
70
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Ka
frequency
0
20
40
60
80
100
120
0 1 2 3 4 5
Ks
frequency
coefficient of variation = 0.67
coefficient of variation = 0.53
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Relationship between Ka and Ks
Ka/Ks =1
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5
Ks
Ka
r2=0.558, p<0.001
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Relative rate test
O (outgroup) A B
d1 d2 d3
compare the fit of a model in which d2 = d3with one in which they are allowed to vary
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Relative rate tests
• 105 gene pairs could be evaluated against an outgroup
• >30 showed significantly unequal rates of evolution• no evident chromosomal or regional biases
Distance measure Significant pairs
protein 15
Ka 29
Ks 9
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Are paralogs different than orthologs?
• Homologous genes are either– Paralogs that diverged through duplication
– Orthologs that diverged though speciation
• Paralogs must coexist in the same genome – do they diverge differently as a result?
• Comparison to 212 Arabidopsis-Brassica orthologs by Tiffin and Hahn (2002) JME 54, 746.– For all pairs, Ka/Ks < 1
– Ka/Ks unimodal around 0.14 (as opposed to 0.20)
– CVKs/CVKa is appx. 2
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Conclusions
• A network of synteny due to duplication and gene loss makes deep comparative mapping difficult
• But phylogenetically-informed methods should allow us to go much deeper than at present
• Only by going deep will we be able to understand the varied roles of different kinds of duplication events in the diversification of gene families
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Acknowledgements• Arabidopsis genome evolution
– Daniel Brown– Steven Tanksley
• Comparative mapping– Peter Calabrese– Sugata Chakravarty– Luke Huan
• Evolution of duplicated genes– Liqing Zhang– Brandon Gaut– David Remington– Jason Reed
• Support– USDA– NSF
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Conservation of gene orientation
parallel
convergent
divergent
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Formulating the problem in terms of graph traversal
• nodes are matches• edges are unidirectional• edges have associated distances
The putative duplicated blocks consist of the paths through the graph that traverse edges with short distances
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Statistical framework• Null model of duplications
– Single-gene duplication/random transposition
– Leads to uniformly distributed dots
• Null distribution for– The edge distance between nearest neighbors
– The number of serially connected short edges
• Observed edge distances and path lengths analytically compared to null expectation
• Can be approximated by a permutation test
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Only a fraction of the genes are (still?) duplicated
Chr2 segment1183 genes
Chr4 segment1168 genes
326duplicates
(~28%)
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271 (83%) pairwise duplications
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Tandem substitutions
• correlation between Ka and Ks disappears when tandem substitutions are excluded
• could be due to– doublet mutations– compensatory substitutions
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At2g18750
AT4g31000
49.5 calmodulin-binding protein 49.62 beta-expansin
AT4g28250At2g20750
49.63 NADH-ubiquinone oxireductase
At2g20800
AT4g28220
56.1 unknown transmembrane
At2g23810
AT4g30430
tobacco1698547
0.13
0.16
0.37
rice8118436
Hemerocallis3551953
p<0.0001
p<0.05
p<0.0001
p<0.01
0.300.10
0.22
0.14
0.160.29
0.220.120.70
potato5734586