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Genomic studies of speciation and gene flow
Why study speciation genomics?
Why study speciation genomics?
Long-standing questions (role of geography/gene flow)
Why study speciation genomics?
How do genomes diverge?
Long-standing questions (role of geography/gene flow)
Why study speciation genomics?
Find speciation genes
How do genomes diverge?
Long-standing questions (role of geography/gene flow)
Genomic divergence during speciation
evolution.berkeley.edu
1. Speciation as a bi-product of physical isolation
2. Speciation due to selection – without isolation
Genomic divergence during speciation
evolution.berkeley.edu
1. Speciation as a bi-product of physical isolation
2. Speciation due to selection – without isolation
Genomic divergence during speciation
evolution.berkeley.edu
1. Speciation as a bi-product of physical isolation
2. Speciation due to selection – without isolation
80 100 120 140 160 180
0.0
0.4
0.8
Transect position (km)
Sd
frequ
ency
Cline theory - e.g. Barton and Gale 1993
Genomic divergence during speciation
evolution.berkeley.edu Wu 2001, JEB
1. Speciation as a bi-product of physical isolation
2. Speciation due to selection – without isolation
?
Time
Stage 1 - one or few loci under disruptive selection
Genome
FST
Gene under
selection
Feder, Egan and Nosil TiG
Stage 2 - Divergence hitchhiking
Genome
FST
Feder, Egan and Nosil TiG
Stage 2b - Inversion
Genome
FST
Feder, Egan and Nosil TiG
Inversion links co-adapted alleles
Stage 3 - Genome hitchhiking
Feder, Egan and Nosil TiG
Genome
FST
Stage 4 - Genome wide isolation
Feder, Egan and Nosil TiG
Genome
FST
Some sub-species clearly in stage 1lWing pattern “races” of Heliconius melpomene
80 100 120 140 160 180
0.0
0.4
0.8
b fre
quen
cy
19862011
n11050
80 100 120 140 160 180
0.0
0.4
0.8
D fr
eque
ncy
80 100 120 140 160 180
0.0
0.4
0.8
N fr
eque
ncy
80 100 120 140 160 180
0.0
0.4
0.8
Transect position (km)
Yb
frequ
ency
80 100 120 140 160 180
0.0
0.4
0.8
D fr
eque
ncy 1986
2011n11050
80 100 120 140 160 180
0.0
0.4
0.8
Cr
frequ
ency
80 100 120 140 160 180
0.0
0.4
0.8
Transect position (km)
Sd
frequ
ency
Heliconius erato Heliconius melpomene
Some sub-species clearly in stage 1
S. H. Martin et al. Genome Res. 23, 1817–1828 (2013). O. Seehausen et al. Nat. Rev. Genet. 15, 176–92 (2014).
lWing pattern “races” of Heliconius melpomene
B (red/orange patterns) Yb (yellow/white patterns)
Some sub-species clearly in stage 1lCarrion and hooded Crows
Poelstra, J. W. et al. Science 344, 1410–4 (2014).
FST
And here is a recent example with multiple islands
Malinsky et al., Science 350, 1493 (2015).
And here is a recent example with multiple islands
Malinsky et al., Science 350, 1493 (2015).
And here is a recent example with multiple islands
Malinsky et al., Science 350, 1493 (2015).
Other species have islands…but are they real?
Ellegren, et al. Nature 491, 756- (2012).
Anopheles gambiae and A. coluzzi Formerly M and S forms of A. gambiae
Clarkson et al. 2014 Nature Communications
Other species have islands…but are they real?
Other species have islands…but are they real?
Seehausen et al., Nature Reviews Genetics, 2014
• Fst measures relative divergence
• Peaks indicate regions of higher than expected between population divergence, given the within population divergence
• Peaks can therefore result from reduced diversity within species
• This could be due to lower Ne within species (selective sweeps, background selection)
• So peaks NOT NECESSARILY due to reduced gene flow
What do patterns of Fst really mean?
Note that sometimes sweeps within species = speciation genes
Sweeps across the species barrier can also lead to Fst peaks
Double peaks??
Nicolas Bierne, Daniel Berner and others
Anopheles M-S divergence
Relative divergence higher in low recombination regions - not significant for absolute divergence
see also: Charlesworth 1998 MBE Measures of divergence…
No evidence for higher Dxy in wing pattern loci
S. H. Martin et al. Genome Res. 23, 1817–1828 (2013). O. Seehausen et al. Nat. Rev. Genet. 15, 176–92 (2014).
lWing pattern “races” of Heliconius melpomene
B (red/orange patterns) Yb (yellow/white patterns)
No evidence for higher Dxy in wing pattern loci
S. H. Martin et al. Genome Res. 23, 1817–1828 (2013). O. Seehausen et al. Nat. Rev. Genet. 15, 176–92 (2014).
lWing pattern “races” of Heliconius melpomene
B (red/orange patterns) Yb (yellow/white patterns)
Suggestion that we use absolute measures of divergence?
Understanding genomic divergence
No single statistic will capture the complex history of mutation, migration and selection
Patterns need to be interpreted in the specific context of the study species
Much better to use explicit tests for gene flow
Need to design sampling so the expectations in the absence of gene flow are clear and testable
Much better to use explicit tests for gene flow
Need to design sampling so the expectations in the absence of gene flow are clear and testable
The key is to identify ‘control’ populations that are not influenced by admixture
•Isolated DNA from bones 38,000 yrs old in Croatia •We diverged from Neanderthals around 270-440,000yrs ago
•Evidence for gene exchange with humans (1-4% of genome?)
Green et al., 328:710 Science 2010
Explicit tests for gene flow: Neanderthal genome
Explicit tests for gene flow: ABBA-BABA test
Explicit tests for gene flow: ABBA-BABA test
Green et al. 2010 Science 328:710-722
OBSERVE: 103612 ABBA 94029 BABA
Gene flow
Explicit tests for gene flow: ABBA-BABA test
EXPECT: 50% ABBA 50% BABA
OBSERVE: 103612 ABBA 94029 BABA
Gene flow
Green et al. 2010 Science 328:710-722
Explicit tests for gene flow: ABBA-BABA test
EXPECT: 50% ABBA 50% BABA
OBSERVE: 103612 ABBA 94029 BABA
Gene flow
Green et al. 2010 Science 328:710-722
Explicit tests for gene flow: ABBA-BABA test
Explicit tests for gene flow: ABBA-BABA test
Explicit tests for gene flow: Combining multiple signals
The genomic landscape of Neanderthal ancestry in present-day humans - Sankararaman et al. Nature 2014
1) Derived alleles at high frequency shared with Neanderthal 2) High divergence to Africa but low to Neanderthal 3) Long haplotype blocks
Explicit tests for gene flow: Combining multiple signals
Explicit tests for gene flow: Heliconius butterflies
!
Martin et al., Genome Research 2013
Explicit tests for gene flow: Heliconius butterflies
Many sources of reproductive isolation:
Female hybrids are sterile Different host plant use Different habitat preference Strong assortative mating
Explicit tests for gene flow: Heliconius butterflies
Explicit tests for gene flow: Heliconius butterflies
• Much larger proportion of genome is flowing as compared to Neanderthals
• Similarly strong effect on sex chromosome
F
Burri et al., Genome Research 2015
Sequenced 20 individuals per population at 20x coverage
An alternative is to take an explicit modelling approach
IM and IMa Jody Hey
Martin et al., Biorxiv 2015
So far models have mostly just estimated genome-wide parameters…assuming the genome is homogenous
Where we need to go next is to incorporate genome heterogeneity in selection and recombination
So far models have mostly just estimated genome-wide parameters…assuming the genome is homogenous
Where we need to go next is to incorporate genome heterogeneity in selection and recombination
High density linkage maps to map the recombination landscape
Chromosome length (Megabases)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1
00.
788
2.37
53.
163
3.95
4.73
8
6.32
5
7.91
38.
706
9.5
10.6
8611
.872
12.6
5913
.446
14.2
3415
.021
15.8
0916
.596
17.3
8418
.171
19.7
58
21.3
4622
.133
22.9
3323
.734
29.5
2530
.319
31.1
1331
.932
.688
34.2
9935
.616
46.7
73
48.3
2249
.109
50.6
96
52.2
8453
.071
54.6
59
56.2
4657
.034
57.8
21
59.4
0860
.196
60.9
83
63.3
8464
.171
64.9
5965
.746
66.5
33
71.4
5472
.248
73.0
42
74.6
29
76.2
1777
.004
77.7
92
79.3
7980
.166
80.9
6781
.767
82.5
55
85.7
8286
.569
87.3
5788
.144
88.9
3189
.719
91.3
0692
.094
92.8
81
99.6
21
102.
09
2
00.
787
1.57
5
4.80
25.
589
6.37
7
7.96
4
9.55
2
11.1
39
12.7
2613
.514
14.3
01
20.9
78
23.3
7824
.166
27.3
93
29.7
9330
.581
31.3
6832
.156
32.9
43
34.5
335
.318
36.9
0537
.693
38.4
8639
.28
40.8
6841
.655
42.4
4243
.23
44.8
1745
.617
46.4
1647
.203
47.9
9148
.778
51.1
7951
.967
52.7
5553
.542
54.3
29
55.9
2456
.705
57.4
92
60.7
19
62.3
1363
.094
63.8
88
65.5
0266
.282
67.0
767
.857
69.4
45
71.0
32
72.6
273
.407
74.9
94
3
00.
787
1.57
5
3.97
54.
763
5.55
6.33
7
10.4
0511
.19
13.5
8914
.376
15.9
6416
.751
19.2
1220
.02
20.8
07
23.2
08
24.7
9525
.583
27.9
8328
.774
29.5
6430
.352
31.1
3931
.927
32.7
1433
.502
35.0
89
36.6
77
38.2
6639
.056
40.6
4341
.426
43.0
09
44.6
0645
.384
46.9
7147
.759
49.3
46
50.9
3451
.721
54.1
2154
.909
55.7
0956
.509
58.0
97
62.3
863
.019
63.8
19
65.4
2
68.6
46
71.0
4771
.834
74.2
35
75.8
2676
.61
78.1
98
80.5
98
82.2
1282
.999
84.1
8585
.371
86.9
5887
.746
90.9
7391
.773
92.5
73
94.1
6194
.948
4
00.
787
1.57
52.
362
3.15
5.55
6.33
87.
125
7.91
28.
79.
494
10.2
8711
.075
11.8
6212
.65
13.4
37
15.8
37
18.2
38
19.8
2520
.619
21.4
13
22.9
42
25.4
7226
.265
27.0
6627
.86
28.6
4729
.435
30.2
22
31.8
4332
.61
35.8
536
.637
43.3
14
44.9
01
46.4
8947
.276
48.0
64
50.4
6451
.248
52.8
3953
.626
55.2
1456
.001
56.7
89
58.3
6
62.5
3763
.337
64.1
38
65.7
2566
.519
67.3
1368
.168
.887
69.6
7570
.462
72.0
5372
.843
75.2
77
76.8
64
78.4
5279
.239
80.8
27
82.4
14
84.0
02
85.5
8986
.376
87.1
49
88.7
7789
.564
5
0
1.58
8
3.98
84.
775
7.17
6
11.2
4312
.031
12.8
1813
.605
15.1
9315
.98
19.2
0719
.995
21.5
82
24.8
0925
.626
.387
27.9
7728
.785
30.3
7231
.159
31.9
4732
.747
33.5
4834
.335
35.1
22
38.3
49
48.7
01
51.1
0251
.889
52.6
7653
.464
54.2
5155
.039
55.8
26
59.8
9360
.681
61.4
6862
.256
63.8
43
65.4
3
67.8
7868
.657
70.2
5571
.033
71.8
2472
.616
73.4
03
75.8
0476
.591
77.3
7978
.166
78.9
5479
.741
82.1
4282
.93
83.7
1784
.505
85.2
9286
.08
86.8
67
6
0
1.58
7
3.17
5
4.76
25.
556.
337
7.92
5
9.51
2
11.1
1911
.912
13.5
15.0
87
16.6
75
18.2
6219
.05
19.8
3720
.624
21.4
12
24.6
3925
.419
27.0
39
29.4
4
31.0
27
32.6
15
34.2
0234
.989
35.7
7736
.564
38.1
5538
.933
40.5
2741
.315
42.1
02
44.5
0345
.29
47.4
7
51.9
67
54.3
6755
.154
57.5
958
.381
65.9
5866
.746
67.5
3368
.321
69.1
0869
.895
70.6
83
72.2
773
.058
73.8
4574
.632
77.0
33
78.6
2
86.1
9886
.972
88.5
46
90.6
8191
.727
92.5
14
94.9
1295
.705
96.4
9697
.285
101.
354
106.
276
108.
677
111.
078
111.
866
112.
653
113.
44
115.
028
115.
815
116.
603
117.
403
118.
203
118.
991
7
0
2.4
3.18
8
5.58
86.
376
7.16
3
8.75
1
10.3
38
13.2
1313
.984
15.1
8815
.976
16.7
63
18.3
519
.147
19.9
44
21.5
3222
.319
23.1
0723
.894
25.4
8126
.269
28.6
69
30.2
5731
.044
35.9
6636
.754
38.3
41
41.5
6842
.342
44.7
5745
.544
47.1
32
48.7
2649
.507
52.7
3353
.52
54.3
08
56.7
08
59.1
0959
.896
60.6
8461
.471
62.2
5863
.046
63.8
464
.633
65.4
2166
.208
68.6
0969
.396
73.4
6374
.251
75.0
3875
.826
77.4
13
79.0
0779
.788
80.5
76
84.6
4385
.43
86.2
18
87.8
05
91.8
7292
.66
93.4
4794
.235
97.4
62
99.0
49
100.
636
103.
037
103.
824
104.
612
105.
399
106.
248
106.
313
8
0
1.6
2.38
83.
175
3.96
2
6.36
37.
157.
938
9.54
510
.282
17.9
2518
.713
19.5
21.0
88
22.6
75
24.2
62
25.8
5
28.2
5
30.6
5131
.445
32.2
3833
.026
33.8
13
35.4
0136
.188
36.9
7537
.763
38.5
539
.338
40.1
2540
.912
44.2
0744
.98
46.5
6847
.355
49.0
24
51.5
1252
.313
53.1
13
54.7
55.4
8856
.275
57.0
6957
.863
61.0
9
63.4
9
65.0
78
66.6
65
68.2
49
70.6
5371
.441
72.2
2873
.016
73.8
0374
.59
75.3
7876
.165
77.7
53
80.1
53
81.7
41
9
0
3.39
1
4.97
85.
766
6.55
3
8.14
1
12.2
0812
.995
15.3
9616
.183
17.7
7118
.558
19.3
45
20.9
3321
.619
25.8
95
27.4
8228
.27
29.0
7229
.865
33.9
4134
.73
36.3
1737
.105
37.8
56
40.3
3141
.119
41.9
0642
.694
44.3
1145
.122
47.5
2248
.309
50.7
151
.497
53.8
9854
.685
56.2
7357
.06
57.8
48
62.7
763
.558
64.3
46
65.9
33
67.5
21
69.1
08
71.5
0972
.302
73.0
9673
.883
80.5
6
82.1
4782
.935
83.7
22
85.3
1
86.8
9787
.685
88.4
72
10
0
1.6
2.38
83.
175
3.96
24.
75
6.33
7
7.92
58.
712
9.5
10.2
8711
.074
11.8
6212
.649
13.4
3714
.224
15.0
1215
.799
16.5
86
18.9
87
20.5
7821
.362
22.9
4923
.737
25.3
2426
.112
27.6
9928
.486
29.2
74
30.8
6131
.649
33.2
36
34.8
2435
.611
37.2
24
39.3
9640
.461
42.0
7842
.836
43.6
3
45.2
3646
.024
46.8
1147
.599
48.3
8649
.174
50.7
6151
.548
52.3
3653
.123
54.7
1155
.498
56.2
9657
.094
58.6
82
60.2
6961
.056
65.1
2465
.911
66.7
0867
.499
68.2
8669
.074
69.8
6170
.648
71.4
3672
.223
73.8
1174
.753
78.6
5579
.443
81.0
381
.818
84.2
1885
.006
88.2
32
89.8
290
.607
91.3
9592
.182
The effect of background selection on introgression in humans
Harris and Nielson Biorxiv 2015
The effect of background selection on introgression in humans
Harris and Nielson Biorxiv 2015
Admixture is less in gene rich regions supporting this model…..
Population and speciation genomics: Conclusions
• Great power to detect subtle signals of selection and gene flow
• Can make more general observations about genes and regions involved in adaptation
• BUT genomic processes complicate the picture
• Best approaches combine multiple signals to infer process
• Eventually we need to combine background selection, recombination, positive selection
And finally a shameless plug….
And finally a shameless plug….
Adaptive introgression
Photo credit Andrei Sourakov
Photo credit Andrei Sourakov
Photo credit Andrei Sourakov
Photo credit Andrei Sourakov
43 s
peci
es 77 s
peci
es
Fritz Müller
–G-test:G=7.25,d.f.=1,p=0.007
Expected number
0
15
30
No.
Mod
els
Atta
cked
H. melpomene H. cydno F1 hybrid
Merrill et al., Proc. Roy. Soc 2012
102 204 76
Several major loci control Heliconius patterns
Several major loci control Heliconius patterns
Several major loci control Heliconius patterns
Several major loci control Heliconius patterns
Several major loci control Heliconius patterns
Several major loci control Heliconius patterns
Reed et al., 2011 Science
E
Richard Wallbank
Cross-species sharing
Heliconius Genome Consortium Nature 2012
Cross-species sharing
Heliconius Genome Consortium Nature 2012
Cross-species sharing
Heliconius Genome Consortium Nature 2012
Phylogenies across B/D
ML tree based on
50,000 bp
Heliconius Genome Consortium Nature 2012
Phylogenies across B/D
ML tree based on
50,000 bp
Heliconius Genome Consortium Nature 2012
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Phylogenies across B/D
ML tree based on
50,000 bp
Okay, so introgression causes mimicry
Okay, so introgression causes mimicry
But mimicry is weird, right?
Novelty can arise through introgression and recombination
Heliconius heurippa
NNBB
Mavarez et al., Nature 2006
Camilo Salazar
Novelty can arise through introgression and recombination
Heliconius cydno cordula
Heliconius melpomene melpomene
NNbb
nnBB
Heliconius heurippa
NNBB
Mavarez et al., Nature 2006
Camilo Salazar
optix100kb
Wallbank et al., PLoS Biology 2016
Red
optix100kb
Wallbank et al., PLoS Biology 2016
RedBlue
optix100kb
Wallbank et al., PLoS Biology 2016
RedBlue
optix100kb
Wallbank et al., PLoS Biology 2016
Wallbank et al., PLoS Biology 2016
Wallbank et al., PLoS Biology 2016
Generate dated trees using this node as a reference point
Wallbank et al., PLoS Biology 2016
H. cydno
H. pachinus
H. heurippa
H. tristeroH. timareta
H. melpomene
H. elevatus
H. pardalinus
H. luciana
H. athis
H. hecale
H. ethilla
H. nattereri
H. besckei
H. ismenius
H. numata
Million Years Ago4 3 2 1 0
AB C D E
Wallbank et al., PLoS Biology 2016
What about behaviour?
What about behaviour?
H. melpomene X H. cydno
bb Bb
-10
010
2030
Genotype
Num
ber o
f app
roac
hes
Diff
eren
ce b
etw
een
appr
oach
es to
cyd
no a
nd
mel
ponm
ene
Richard Merrill
Mate preference segregates withforewing colour in backcross hybrids
Rel
ativ
e pr
obab
ility
of c
ourti
ngH
. mel
pom
ene
fem
ales
Merrill et al. Proc Roy Soc B, 2011
Mate preference segregates withforewing colour in backcross hybrids
Rel
ativ
e pr
obab
ility
of c
ourti
ngH
. mel
pom
ene
fem
ales
Merrill et al. Proc Roy Soc B, 2011
H. melpomene measured preference
H. cydnomeasured preference
Large effect: 35% of thedifference betweenparental species
G = 58.64, P << 0.001
Heliconius cydno cordula
Heliconius melpomene melpomene
NNbb
nnBBHeliconius heurippa
NNBB
Mavarez et al., Nature 2006
cordula heurippa melpomene
010
2030
40
Num
ber o
f app
roac
hes
Melo et al., Evolution 2009
Now working on QTL maps of species differences in behaviour:
01234
LOD
sco
re
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 X
01234
LOD
sco
re
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 X
01234
Chromosome
LOD
sco
re
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 X
Lamichhaney et al., Nature 2015
Lamichhaney et al., Nature 2015
Pointy
Blunt
ALX1 associated with beak shape
Most of these studies use phenotype associations to identify introgressed loci
But can we identify them a priori using the ABBA-BABA method?
Explicit tests for gene flow: ABBA-BABA test
Explicit tests for gene flow: ABBA-BABA test
Green et al. 2010 Science 328:710-722
D is quite dependent on the number of informative sites (the denominator)
Martin et al., MBE 2014
D is quite dependent on the number of informative sites (the denominator)
D is not at all good at detecting outlier windows
Martin et al., MBE 2014
D is quite dependent on the number of informative sites (the denominator)
D is not at all good at detecting outlier windows
Martin et al., MBE 2014
D is quite dependent on the number of informative sites (the denominator)
D is not at all good at detecting outlier windows
Martin et al., MBE 2014
Where s is numerator from the D equation f is the fraction of introgression compared to maximum possible
Martin’s F
Martin et al., MBE 2014
Martin’s F
But Martin’s F is quite good at finding the introgression outliers
Martin et al., MBE 2014
• Smith and Kronforst argued that introgression could be inferred where ABBA-BABA outliers showed lower Dxy compared to genome-wide average
• Be wary of window based D statistics
• F is better than D…
• Sampling design is very important!
Implications for tree-thinking
Archaea
Eukarya
Bacteria
The tree of life is reticulatedThe tree of life is reticulated
Implications for tree-thinking
Mallet, Hahn and Besansky BioEssays 2015 Hahn and Nakhleh Evolution 2015
Okay, so what have we learnt and where do we go from here?