Demography, diversity, and fitness among human …Demography, diversity, and fitness among human...
Transcript of Demography, diversity, and fitness among human …Demography, diversity, and fitness among human...
Goal• Understandthenumberofcommonandrarevariantsindifferentpopulations
• Understandtheimpactofselectioninrecenthumanevolution
• Understanddynamicsofhumanevolution
• Understandcausalrelationshipsbetweendemography,diversity,andselection
Fisher’stheorem
"Therateofincreaseinfitnessofanyorganismatanytimeisequaltoitsgeneticvarianceinfitnessatthattime.”(1930)
Selectionactsonvariation
Naturalselection:Therelationshipbetweenreproductivesuccessandpopulationfrequency
0.0 0.2 0.4 0.6 0.8 1.0Allele frequency
Rat
e of
fitn
ess
incr
ease
Distribution before selection
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
Average effect of selectionbefore drift
"Therateofincreaseinfitnessofanyorganismatanytimeisequaltoitsgeneticvarianceinfitnessatthattime.”(1930)
Maintainingvariation
• Geneticdriftandselectionreducevariance• Newmutationsincreasevariance,butreducefitness
Maintainingvariation
• Geneticdriftandselectionreducevariance• Newmutationsincreasevariance,butreducefitness
• Thereisa“Geneticload”duetoinfluxofnewdeleteriousmutations.
NileRiver
Red Sea
AndamanIslands
Meadowcroft19,000-12,000 years ago
Kennewick9,500 years ago
Spirit Cave9,500-9,400
years ago
Monte Verde14,800 years ago
Niah Cave40,000 years ago
Qafzeh100,000years ago
Lake Mungo45,000 years ago
Malakunanja50,000 years ago
Omo KibishOldest modern human195,000 years ago
Pestera cu Oase35,000 years ago
Yana River30,000 years ago
Zhoukoudian(Shandingdong)
11,000 years ago
Minatogawa18,000 years ago
Clovis13,500years ago
Klasies River Mouth120,000 years ago
EQUATOR
40,000-30,000years ago
20,000-15,000years ago
50,000years ago
15,000-12,000years ago
200,000 years ago
70,000-50,000 years ago
40,000years ago
AUSTRALIA
ASIA
AFRICA
EUROPE
NORTHAMERICA
SOUTHAMERICA
1
2
3
4
5
6
Migration date Generalized route
Human MigrationFossil or artifact site
40,000years ago
SOURCES: SUSAN ANTON, NEW YORK UNIVERSITY; ALISON BROOKS, GEORGE WASHINGTON UNIVERSITY; PETER FORSTER, UNIVERSITY OF CAMBRIDGE; JAMES F. O'CONNELL, UNIVERSITY OF UTAH; STEPHEN OPPENHEIMER, OXFORD UNIVERSITY; SPENCER WELLS, NATIONAL GEOGRAPHIC SOCIETY; OFER BAR-YOSEF, HARVARD UNIVERSITY
NGM MAPS
© 2006 National Geographic Society . A ll rights reserved .
HumanMigrationsOverview(Pre-1500)
MapfromNationalGeographic
DidbottlenecksincreaseloadoutsideAfrica?
YRI
CEU
CHBJPT
NA7300
NAF14474
NB1861
NEU01032NAS0550
TAF148kya
TB51kya
TEuAs23kya
mAfBmAfEumAfAs
mEuAs
(Africa)
(Europe)
(Asia)
Time
A`competition’betweenselectionanddrift
Allelefrequency
timeDrift Selection
Fixationofnewdeleteriousallele
A`competition’betweenselectionanddrift
Drift Selection
Frequencyofdeleteriousalleles
Allelefrequency
time
Theamountofdeleteriousvariation
YRI
CEU
CHBJPT
NA7300
NAF14474
NB1861
NEU01032NAS0550
TAF148kya
TB51kya
TEuAs23kya
mAfBmAfEumAfAs
mEuAs
Time
2Nr s = -100
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
Excess OOA load
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)0
Diffe
renceinloadperGbp 2
1
Time
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100-1
-0.3, -0.1
Diff
eren
ce in
load
per
Gbp
Time since split (generations)
Excess OOA load
0
Diffe
renceinloadperGbp 2
1
Time
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100
-30
-1
-0.3, -0.1
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
-10-3
Asymptotic estimateExcess OOA load
0
Diffe
renceinloadperGbp 2
1
Time
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100
-30
-1
-0.3, -0.1
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
-10-3
Asymptotic estimateExcess OOA load
Recessivevariants:fitness
0
Diffe
renceinloadperGbp 2
110
0
20
TimeTime
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100
-30
-1
-0.3, -0.1
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
-10-3
Asymptotic estimateExcess OOA load
0
Diffe
renceinloadperGbp
2
1
Time
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100
-30
-1
-0.3, -0.1
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
-10-3
Asymptotic estimateExcess OOA load
0
Diffe
rencein(add
itive)loadpe
rGbp
2
1
Time
ExcessloadinOut-of-Africapopulations
Gravel,Genetics(2016)
-0.01
2Nr s = -100
-30
-1
-0.3, -0.1
Diffe
renc
e in
load
per
Gbp
Time since split (generations)
-10-3
Asymptotic estimateExcess OOA load
Recessivevariants:frequency
0
Diffe
rencein(add
itive)loadpe
rGbp
2
1
-100
0
-200
TimeTime
• WasselectionmoreefficientinEuropean-AmericansorinAfrican-Americans?
• Aretheredifferencesintheeffectofselectionforadditivevariants?– AretherevariantclassesthatareathigherfrequencyinEuropeans
Whatquestionshouldwebeasking?
• Almostcertainly!Buthardtoshow:– Longdelaybetweeneffectofdriftandselection– Thiscanconfoundclassicalstatistics(Ns,fixationrate)– Differencesonlyforasmallsubsetofvariants– Oppositeeffectfordifferentvariantclasses
• OOAbottleneckcontinuestoaffectselection
• Futureisuncertain:Admixture,changesinenvironment
DiddriftchangetheefficacyofselectioninOOApopulations?
Gravel,Genetics(2016)
Admixturetotherescue
LWK
MXL
PUR
YRIASW
CLMAmericas
Africa
FINGBRCEUTSI
JPT
CHBCHS
Asia Europe
Mor
ton
effica
cy (r
elat
ive
to LW
K)
h
A)
FINGBRCEUTSI
JPT
CHBCHS
Asia Europe
LWK
MXL
PUR
YRIASW
CLMAmericas
Africa
FIT
effica
cy (r
elat
ive
to LW
K)h
B)
ASW average of ancestral populations
PURCLMMXL
C)
Mor
ton
effica
cy (r
elat
ive
to LW
K)
h
Motivation
• Testourmodelofgeneticdiversity–Mutation– Selection– Demography
• Improveourunderstandingofdiseasearchitecture
• Improvethestatisticalpowerofassociationtests
Currentdriftdoesnotaffectaverageallelefrequencies
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0
Currentdriftdoesnotaffectaverageallelefrequencies
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0t=1, N=∞
Currentdriftdoesnotaffectaverageallelefrequencies
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0t=1, N=∞
0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.600
5
10
15
20
Allele frequency
probabilitydensity
t=0t=1, N=∞
t=1, N=500
Accumulateddrifthampersselection
0.0 0.2 0.4 0.6 0.8 1.0Allele frequency
Rat
e of
fitn
ess
incr
ease
Distribution before selection
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
Average effect of selectionbefore drift
0.0 0.2 0.4 0.6 0.8 1.0Allele frequency
Rat
e of
fitn
ess
incr
ease
Distribution before selection
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
Average effect of selectionbefore drift
Distribution after (much)selection
Accumulateddrifthampersselection
Accumulateddrifthampersselection
0.0 0.2 0.4 0.6 0.8 1.0Allele frequency
Rat
e of
fitn
ess
incr
ease
Distribution before selection
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
Average effect of selectionbefore drift
0.0 0.2 0.4 0.6 0.8 1.0Allele frequency
Rat
e of
fitn
ess
incr
ease
Distribution before drift
*
Average effect of selectionafter drift
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
Average effect of selectionbefore drift
Accumulateddrifthampersselection