demography, diversity, and fitness among human …demography, diversity, and fitness among human...

SimonGravelMcGillUniversity

Demography,diversity,andfitnessamonghumanpopulations

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

Allelefrequency

time


• Geneticdriftandselectionreducevariance• Newmutationsincreasevariance,butreducefitness


• Geneticdriftandselectionreducevariance• Newmutationsincreasevariance,butreducefitness

• Thereisa“Geneticload”duetoinfluxofnewdeleteriousmutations.

Itwouldbeexpectedthattheloadwouldincreaseinasmallpopulation…

(1963)

Geneticload

Populationsize

Geneticloadislargerinsmallerpopulations

Geneticload

Populationsize

Weakselection


Geneticload

Populationsize

Weakselection

Strongselection


Geneticload

Populationsize

Weakselection

Strongselection

“Selectionmoreefficientinlargepopulations”

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

Yes!

Didbottlenecksmakeselectionlesseffective?

Yes!

Yes!

Yes!


Yes!

Yes!

Yes!

No!

No!


Yes!

Yes!

Yes!

YES!

No!

No!


Yes!

Yes!

Yes!

YES!

No+Yes!

No!

No!


A`competition’betweenselectionanddrift

Allelefrequency

time


Allelefrequency

timeDrift Selection

Fixationofnewdeleteriousallele


Drift Selection

Frequencyofdeleteriousalleles

Allelefrequency

time

Bottleneck

Drift

Bottleneck

Drift

Diversity

Bottleneck

Drift

Diversity

Selection

Bottleneck

Drift

Diversity

Selection

Frequencyoffitallele

Bottleneck

Drift

Diversity

Selection


fitness

Smallpopulation

Drift

Diversity

Selection


fitness

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


Gravel,Genetics(2016)

-0.01

2Nr s = -100-1

-0.3, -0.1

Diff

eren

ce in

load

per

Gbp


Excess OOA load

0

Diffe

renceinloadperGbp 2

1

Time



-0.01

2Nr s = -100

-30

-1

-0.3, -0.1

Diffe

renc

e in

load

per

Gbp


-10-3

Asymptotic estimateExcess OOA load

0

Diffe

renceinloadperGbp 2

1

Time



-0.01

2Nr s = -100

-30

-1

-0.3, -0.1

Diffe

renc

e in

load

per

Gbp


-10-3


Recessivevariants:fitness

0

Diffe

renceinloadperGbp 2

110

0

20

TimeTime

Bottleneck

Drift

Diversity

Selection


fitness

Bottleneck

Drift

Diversity

Selection


fitness

Homozygotes

Foundereffect



-0.01

2Nr s = -100

-30

-1

-0.3, -0.1

Diffe

renc

e in

load

per

Gbp


-10-3


0

Diffe

renceinloadperGbp

2

1

Time



-0.01

2Nr s = -100

-30

-1

-0.3, -0.1

Diffe

renc

e in

load

per

Gbp


-10-3


0

Diffe

rencein(add

itive)loadpe

rGbp

2

1

Time



-0.01

2Nr s = -100

-30

-1

-0.3, -0.1

Diffe

renc

e in

load

per

Gbp


-10-3


Recessivevariants:frequency

0

Diffe

rencein(add

itive)loadpe

rGbp

2

1

-100

0

-200

TimeTime

Bottleneck

Drift

Diversity

Selection


fitness

Homozygotes

Foundereffect

Purging

• WasselectionmoreefficientinEuropean-AmericansorinAfrican-Americans?

Whatquestionshouldwebeasking?

• WasselectionmoreefficientinEuropean-AmericansorinAfrican-Americans?

• Aretheredifferencesintheeffectofselectionforadditivevariants?– AretherevariantclassesthatareathigherfrequencyinEuropeans

Whatquestionshouldwebeasking?

Lookingatvariantsofintermediateeffects

Henn,Botigue etal,PNAS(2016)

DistanceoutofAfrica

Lookingatvariantsofintermediateeffects

Henn,Botigue etal,PNAS(2016)

• Almostcertainly!Buthardtoshow:– Longdelaybetweeneffectofdriftandselection– Thiscanconfoundclassicalstatistics(Ns,fixationrate)– Differencesonlyforasmallsubsetofvariants– Oppositeeffectfordifferentvariantclasses

• OOAbottleneckcontinuestoaffectselection

• Futureisuncertain:Admixture,changesinenvironment

DiddriftchangetheefficacyofselectioninOOApopulations?


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

1968:Neutraltheoryofevolution

TheNeutralModel

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


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=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


Rat

e of

fitn

ess

incr

ease


0.0000

0.0002

0.0004

0.0006

0.0008

0.0010

0.0012



Rat

e of

fitn

ess

incr

ease


0.0000

0.0002

0.0004

0.0006

0.0008

0.0010

0.0012


Distribution after (much)selection




Rat

e of

fitn

ess

incr

ease


0.0000

0.0002

0.0004

0.0006

0.0008

0.0010

0.0012



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




Forconstant-sizedpopulations,selectioniseffectiveif|Ns|>>1,ineffectiveif|Ns|<<1

demography, diversity, and fitness among human …demography, diversity, and fitness among human...

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