http://epigen.grude.ufmg.br/ - PowerPoint Presentation

Slide1

http://epigen.grude.ufmg.br/

ORIGIN AND DYNAMICS OF ADMIXTURE IN BRAZIL: IMPLICATIONS FOR HEALTH

Eduardo

Tarazona

Santos

UFMG

Slide2

Iniciativa EPIGEN-Brasil: recolhendo duas tradições científicas na era genômica e do big dataHistória social do Brasil e a estrutura genética das populações

3. Do Retrato Molecular do Brasil à dinâmica da miscigenação4. Brasil e novas perspectivas da Diáspora Africana5. A miscigenação e o mapeamento de variantes não-europeias responsáveis pela susceptibilidade à doenças

Slide3

http://epigen.grude.ufmg.br/

Slide4

EPIGEN Project Board Maria Fernanda Lima-Costa (FIOCRUZ, MG),

Bambui cohort, Bernardo Lessa Horta (UFPel, RS), Pelotas cohort

Mauricio Barreto (UFBA, BA), Salvador cohort

Alexandre Costa Pereira (INCOR-USP, SP)Eduardo Tarazona Santos (UFMG, MG)

Slide5

GOALSTo study the genomic

structure of the admixed Brazilian population

Origin

and dynamics of admixture in BraziliansThe genetic

arquitecture

of

coplex

diseases

and

ancestry

-

How

genetics

,

environment

and

social

factors

interact

to

shape

susceptibility

to

complex

diseases

and

traits

Slide6

Salvador

children (1997) n=1246 18

years follow-up

Ageing cohort Bambuí (1997) n=1442 18 years follow-up

Birth-cohort

Pelotas (1982)

n=

3653

33

years

follow-up

Three most populated Brazilian regions

THE LARGEST BRAZILIAN POPULATION-BASED COHORTS

Slide7

HumanOmni2.5-8

HumanOmni5-Quad

HiSeq

2000

6222

samples

~2.3M

SNPs

265

samples

~4.3M

SNPs

30

samples

whole-genome

sequencing

10 Pelotas

10 Bambuí

10 Salvador

3649 Pelotas

1354 Bambuí

1219 Salvador

87 Pelotas

88 Bambuí

90 Salvador

Slide8

1967

2000

Sérgio D Pena

Fabrício R Santos

Slide9

Análise Tri-híbrida - ADMIXTURE (k = 3)

332 mil

SNPs

em comum

42 populações mundiais

(

HapMap

, HGDP e 1000

Genomes

)

n=1,309

n=1442

n=3,736

EUR 43%

AFR 50%

NAT 7%

EUR 77%

AFR 16%

NAT 7%

EUR 76%

AFR 16%

NAT 8%

Europeia

Africana

Nativo Americana

1 indivíduo:

Slide10

Levels of ancestry

African

European

Native American

Indiv 1

Indiv 2

Indiv 3

Indiv 4

Indiv 5

Individual ancestry

AFR

EUR

NAT

0.19

0.64

0.17

0.24

0.65

0.11

0.13

0.80

0.07

0.14

0.71

0.15

0.83

0.14

0.03

0.31

0.59

0.10

Population ancestry

average

+

+

= 1.0

Chr 1

Chr 2

Chr 3

Chromosomal ancestry

Chr ...

Infer chromosomal ancestry -> infer the ancestry of each point of each chromosome of each individual.

Slide11

Iniciativa EPIGEN-Brasil: recolhendo duas tradições científicas na era genômica e do big dataHistória social do Brasil e a estrutura genética das populações

3. Do Retrato Molecular do Brasil à dinâmica da miscigenação4. Brasil e novas perspectivas da Diáspora Africana5. A miscigenação e o mapeamento de variantes não-europeias responsáveis pela susceptibilidade à doenças

Slide12

HOW ADMIXTURE AND THEIR DISTICT SOCIO-DEMOGRAPHIC HISTORIES INFLUENCED THE GENETIC STRUCTURE OF THE EPIGEN POPULATIONS?

Slide13

PANMIXIA RESPECT TO ANCESTRY

POSITIVE ASSORTATIVE MATING

RESPECT TO ANCESTRY

EXCESS OF HOMOZIGOSITY

(F

IT

)

INFORMATIVENESS FOR AFRICAN-EUROPEAN ANCESTRY (F

ST

)

SNP

Slide14

FST

EUROPEAN-AFRICANANCESTRYFIT

SUBPOPULATION SUBDIVISION

Smoothed

scatterplot

PELOTAS

population-based study, > 2M SNPs

ρ

FIT

-FST

=0.38

, p<10

-16

Slide15

How

population subdivision (partly ancestry-dependent) and inbreeding interact to shape population structure

PELOTAS: medium size

BAMBUI: small, isolated

SALVADOR: large city

ρ

FIT

-FST

=0.08, p<10

-16

ρ

FIT

-FST

=0.38

, p<10

-16

ρ

FIT

-FST

=0.18

, p<10

-16

F

IT =0.016

FIT =0.012FIT=-0.003

TOTAL POPULATION STRUCTUREFIS=0.010

inbreedingFIS=-0.001

FIS=-0.001

Slide16

Assortative mating by relatedness and by ancestry have modeled the genetic structure of Brazilian populations in different waysGenomic diversity show that after

five centuries of admixture, Brazilians still preferentially mate with individuals with similar ancestry (as well as its correlated morphological phenotypes and socioeconomics characteristics)How admixture and their distinct demographic histories influenced the genetic structure of these populations?

Slide17

Principal

Component

Analysis

: World

Populations

331.792

SNPs

8002

individuals

AFRICANS

EUROPE

NATIVES

JAPANESE

Slide18

World

Parental

Populations

and

Bambui

,

Pelotas

e

Salvador

331.792

SNPs

8002

individuals

AFRICANS

EUROPE

NATIVES

JAPANESE

Slide19

331.792

SNPs

8002

individuals

PCA: World

Parental

Populations

including

Salvador

AFRICANS

EUROPE

Slide20

331.792 SNPs

8002 individuals

PCA: World

Parental

Populations

including

Salvador

AFRICANS

EUROPE

SALVADOR HAS MUCH MORE AFRICAN ADMIXTURE BUT ALSO A DIFFERENT HISTORY OF ADMIXTURE

CLOSER TO PANMIXIA

OR

- AN OLDER HISTORY OF ADMIXTURE

Slide21

Modelo de democracia racial

perfeitaModelo de segregação

(África do Sul, US)

Slide22

Iniciativa EPIGEN-Brasil: recolhendo duas tradições científicas na era genômica e do big dataHistória social do Brasil e a estrutura genética das populações

3. Do Retrato Molecular do Brasil à DINÂMICA da miscigenação4. Brasil e novas perspectivas da Diáspora Africana5. A miscigenação e o mapeamento de variantes não-europeias responsáveis pela susceptibilidade à doenças

Slide23

Levels of ancestry

African

European

Native American

Indiv 1

Indiv 2

Indiv 3

Indiv 4

Indiv 5

Individual ancestry

AFR

EUR

NAT

0.19

0.64

0.17

0.24

0.65

0.11

0.13

0.80

0.07

0.14

0.71

0.15

0.83

0.14

0.03

0.31

0.59

0.10

Population ancestry

average

+

+

= 1.0

Chr 1

Chr 2

Chr 3

Chromosomal ancestry

Chr ...

Infer chromosomal ancestry -> infer the ancestry of each point of each chromosome of each individual.

Slide24

Admixture Dynamics Inference

Parental Populations

Time

Generations of admixture

Length of chromosomal segments of distinct ancestry -> number of generation since admixture

Slide25

Chr 22 ancestry Results

Individual

chromosomal

ancestry

: 20

individuals

->

PCAdmix

(10,459

SNPs

)

Salvador

Bambui

Pelotas

AFRICAN

EUROPEAN

NATIVE AMERICAN

Slide26

EUR

AFR

NAT

Tamanho do CSSA

Distribuição de CSSA

EUR

AFR

NAT

EUR

AFR

NAT

Distribution

of

admixture

tracts

and

a

dmixture

dynamics

(

cM

)

Slide27

mpop,pulso

Número de imigrantes

População (

EUR,

AFR

ou

NAT

)

Pulso de miscigenação

(1, 2 ou 3)

m

EUR,1

m

AFR,1

m

NAT,1

m

EUR,2

m

AFR,2

m

NAT,2

m

EUR,3

mAFR,3

mNAT,3

segmentos contínuos inferidos para uma única ancestralidade

A demographic

model

of three

migration pulsesThis demographic

model conciliates

statistical complexity and the real history of admixture

We

developed an

APPRIXIMATE BAYESIAN COMPUTATION framework to

infer the posterior

distribution of

the 9 parameters

Slide28

EUR

AFR

NAT

Tamanho do CSSA

% de imigrantes

6-4 gerações

12-10 gerações

18-16 gerações

Distribuição de CSSA

EUR

AFR

NAT

EUR

AFR

NAT

(90% high-posterior

density

)

Distribution

of

admixture

tracts

and

a

dmixture dynamics inferences

SXVI

SXVIII

SXIX

Slide29

EUR

AFR

NAT

Tamanho do CSSA

% de imigrantes

6-4 gerações

12-10 gerações

18-16 gerações

Distribuição de CSSA

EUR

AFR

NAT

EUR

AFR

NAT

(90% high-posterior

density

)

Distribution

of

admixture

tracts

and

a

dmixture dynamicsNative

Americans

SXVI

SXVIII

SXIX

Slide30

EUR

AFR

NAT

Tamanho do CSSA

% de imigrantes

6-4 gerações

12-10 gerações

18-16 gerações

Distribuição de CSSA

EUR

AFR

NAT

EUR

AFR

NAT

(90% high-posterior

density

)

Distribution

of

admixture

tracts

and

a

dmixture dynamicsAfricans

SXVI

SXVIII

SXIX

Slide31

EUR

AFR

NAT

Tamanho do CSSA

% de imigrantes

6-4 gerações

12-10 gerações

18-16 gerações

Distribuição de CSSA

EUR

AFR

NAT

EUR

AFR

NAT

(90% high-posterior

density

)

Distribution

of

admixture

tracts

and

a

dmixture dynamicsEuropean

SXVI

SXVIII

SXIX

Slide32

Diversidade da ancestralidade

Européia

no sul e sudeste do Brasil é maior em relação a

Salvador (restrita a Península Ibérica)

PCA – Análises de Componentes Principais

Pelotas

Bambuí

Salvador

North

Europe

Ibéricos

Slide33

Iniciativa EPIGEN-Brasil: recolhendo duas tradições científicas na era genômica e do big dataHistória social do Brasil e a estrutura genética das populações

3. Do Retrato Molecular do Brasil à dinâmica da miscigenação4. Brasil e novas perspectivas da Diáspora Africana5. A miscigenação e o mapeamento de variantes não-europeias responsáveis pela susceptibilidade à doenças

Slide34

WHAT IS THE PATTERN OF SUBCONTINENTAL ANCESTRY IN DIFFERENT BRAZILIAN POPULATIONS?

Principal Component Analysis (eigenstrat) and model-based unsupervised ADMIXTURE analysis (Alexander et al. 2010)

Slide35

Admixture Analysis, K = 7

Europe

Middle

East

AFRICANS

ASW

Natives

JPT

MEX

PUR

CLM

K = 7

WHAT DO BRAZILIANS TELL US ABOUT AFRICAN DIVERSITY?

Brazil

: ~4 000 000

African

slaves

(

longer

slave

trade)

US: ~560 000

African

slaves

WEST

EAST

Slide36

2

5%

36%

44%

Cluster associado a Oeste África/

Bantus

Cluster associado a Leste/

Bantus

Dois

novos clusters subcontinentais

Africanos

Consistente com o fato de que os escravos

Bantus

de Moçambique desembaraçavam preferencialmente no porto do Rio de Janeiro.

Pela primeira vez

Substruturação

Africana nos Brasileiros aumenta o entendimento da

Diáspora Africana

Slide37

Disease / Trait

N.SNPsSNP list (38)

F

ST1Crohn's disease

3

rs7702331

rs7517847

rs6556412

0.0750

0.0603

0.0599

Inflammatory bowel disease

3

rs477515

rs2382817

rs7517847

0.1261

0.0683

0.0603

Multiple sclerosis

2

rs12466022

rs533259

0.0688

0.0688

Obesity related

2

rs7964120

rs7784447

0.1322

0.0957

Emphysema-related traits

Epstein-Barr virus immune response

Liver enzyme levels

Schizophrenia

Myopia (pathological)

Alzheimer's disease

F-cell distribution

Amyotrophic lateral sclerosis

Menopause

Eosinophil counts

Obsessive-compulsive disorder

HIV related

Sphingolipid levels

IgE

levels in asthmatics

Economic and political preferences

Bladder cancer

Duodenal ulcer

Nasopharyngeal carcinoma

Non-alcoholic fatty liver disease histology

Prostate cancer

Resp.to irinotecan/platinum-based chemo. lung cancer

Sudden cardiac arrest

Type 1 diabetes

Bipolar disorder

Response to gemcitabine in pancreatic cancer

Mean platelet volume

Pancreatic cancer

Breast size

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

rs641525rs477515rs4547811rs1635rs4142248rs610932rs7565301

rs2819332rs11889862rs4143832rs9652236rs1020064rs1000778rs10404342rs210648rs2294008rs2294008rs6774494rs887304rs4242382rs344924rs5762311rs1004446rs7250872

rs1901440rs12526480rs10088262rs71047450.14690.12610.11080.08620.08250.08220.07380.07260.07250.07190.07170.0716

0.0689

0.06730.06670.06600.06600.06600.06580.06520.06470.06370.06340.06260.06250.06250.06200.0612

GWAS hits for SNPs differentiated between Blue (West Africa, non-Bantu-associated) and mustard (East Africa/Bantu associated) ADMIXTURE clusters

Slide38

AFRICAN ANCESTRY:BRAZILIANS HAVE THE SIGNATURE OF GENOMIC VARIATION FROM DIFFERENT AFRICAN REGIONS, INCLUDING SOUTH-CENTRAL AND EASTERN AFRICASALVADOR (NE), THE MOST AFRICAN BRAZILIAN CITY, SIMILAR TO AFRICAN-AMERICAN

SE AND SOUTHERN BRAZILIANS, MORE EUROPEAN, BUT HOST DIVERSITY FROM ANGOLA, MOZAMBIQUETHES DIFFERENCES IN ORIGIN MAY DETERMINE DIFFERENCES IN VARIANTES RESPONSIBLE FOR SUSCEPTIBILITY TO DISEASESWHAT IS THE PATTERN OF SUBCONTINENTAL ANCESTRY IN DIFFERENT BRAZILIAN POPULATIONS?

Slide39

CONCLUSIONSAncestry-positive assortative mating permeated Brazilian historyWe traced European ancestry in the Southeast/South to a wider

European/Middle Eastern region with respect to the Northeast,where ancestry seems restricted to Iberia.By developing an ABC framework, we infer more recent European

immigration to the Southeast/South than to the Northeast.The low Native-American ancestry (6–8%) was

mostly introduced in different regions of Brazil soon after theEuropean Conquest. We broadened our understanding of the African diaspora, byrevealing that Brazilians display two within-Africa ancestry components:one associated with non-Bantu/western Africans (more

evident in the Northeast and African Americans) and one associated

with Bantu/eastern Africans (more present in the

Southeast/

South

).

Slide40

EPIGEN GENOMIC ANALYSIS GROUP

MAIRA RODRIGUES(BIOINFORMATICS)

WAGNER MAGALHÃESHAPLOTYPES/INPUTATION)

FERNANDA KEHDY(POPULATION STRUCTURE)

ALEXANDRE COSTA PEREIRA

UFMG

Slide41

Iniciativa EPIGEN-Brasil: recolhendo duas tradições científicas na era genômica e do big data

História social do Brasil e a estrutura genética das populações3. Do Retrato Molecular do Brasil à dinâmica da miscigenação

4. Brasil e novas perspectivas da Diáspora Africana5. A miscigenação e o mapeamento de variantes não-europeias responsáveis pela susceptibilidade à doenças

Marilia ScliarPROJETO EM DESENVOLVIMENTO

Slide42

Classical GWAS, CADSchunkert et al. 2010

>90% participants in GWAS are Europeans or US whites living in Europe/US

Slide43

Advantages:

statistical power (less

individuals needed

) probability to

find

new

variants

ADMIXTURE MAPPING

GWAS

test

association

between

phenotype

and

the

genotype

of

each

markerAdmixture Mappingtest association

between phenotype and local

ancestry (the ancestry of

each marker)

A method to identify phenotype-related genetic variants that differ in frequency across parental populations

Hypothesis: differences in disease rates between populations are due in part to frequency differences in disease–causing genetic variants

Slide44

Levels of ancestry

African

European

Native American

Indiv 1

Indiv 2

Indiv 3

Indiv 4

Indiv 5

Individual ancestry

AFR

EUR

NAT

0.19

0.64

0.17

0.24

0.65

0.11

0.13

0.80

0.07

0.14

0.71

0.15

0.83

0.14

0.03

0.31

0.59

0.10

Population ancestry

average

+

+

= 1.0

Chr 1

Chr 2

Chr 3

Chromosomal ancestry

Chr ...

Infer chromosomal ancestry -> infer the ancestry of each point of each chromosome of each individual.

Slide45

LOCAL ANCESTRY - PCADMIX

Chromosome

22

Individuals

African

European

Native American

Predominance

of European ancestry

and sparse segments of African and Native American ancestries

Slide46

a

b

c

d

e

F

a

b

c

d

e

f

a

b

c

d

e

f

a

b

C

d

e

f

a

b

c

d

e

f

a

B

c

d

e

f

A

B

C

D

E

f

A

B

C

D

e

F

A

B

C

D

E

F

A

B

C

D

E

F

A

B

C

D

E

F

A

B

C

D

E

F

A

B

C

D

E

F

A

B

C

D

E

f

a

b

c

d

e

F

a

b

c

d

e

f

a

b

c

d

e

f

a

b

c

D

E

F

50%

50%

PP1

PP2

Admixed population

Crossing-over

a

bcDEF

A

B

C

def

ABCDE

f

A

B

C

D

e

f

A

B

C

D

E

F

a

b

c

d

e

f

A

B

c

d

e

f

a

B

C

D

E

f

a

b

C

d

e

F

a

b

C

D

e

f

a

b

c

d

e

f

A

b

C

d

e

F

Disease

associated

variant

Crossing-over

Slide47

a

b

c

D

E

F

A

B

C

d

e

f

A

B

C

D

E

f

A

B

C

D

e

f

A

B

C

D

E

F

a

b

c

d

e

f

A

B

c

d

e

f

a

B

C

D

E

f

a

b

C

d

e

F

a

b

C

D

e

f

a

b

c

d

e

f

A

b

C

d

e

F

a

b

C

d

e

F

A

B

c

d

e

f

a

B

C

D

E

f

a

b

C

D

e

f

A

b

C

d

e

F

A

B

C

D

E

F

Casos

A

B

C

D

E

F

A

b

c

d

e

F

A

B

c

d

e

f

a

B

C

D

E

f

a

B

c

D

e

f

A

b

C

d

e

F

a

b

c

D

E

f

Controles

A

B

C

D

E

F

Amostragem para estudo casos-controles

Crossing-over

Local

ancestry

Slide48

Slide49

BMI =

weight (kg) / height

(m

2)

overweight

: BMI >=

25

kg/m

2

obesity

: BMI >=

30

kg/m

2

Prevalence of obesity

:

African Americans

European Americans

BODY MASS INDEX - OBESITY

Slide50

Linear regressionTransformation of

BMI to 1/BMI (cm2/kg)

P

ELOTAS

IS BMI ASSOCIATED WITH ANCESTRY AFTER ADJUSTMENT FOR COVARIATES?

YES!

1 /BMI

Coef

.

Std

.

Err

.

P>|t|

[95% Conf.

Interval

]

Male

-7.077

2.330

0.002

-11.645

-2.508

European

20.995

6.131

0.001

8.975

33.016

Income

1.1-3

-6.972

3.117

0.025

-13.064

-0.882

3.1-6

-11.464

3.821

0.003

-18.955

-3.973

6.1-10

-7.334

5.692

0.198

-18.495

3.826

10+

-2.846

5.997

0.635

-14.603

8.912



0

428.022

4.969

0.000

418.279

437.765

Slide51

ADMIXTURE MAPPING OF BMI

Quantitative

variable: Linear regression

adjusting

for

covaritaes

(sex,

income

,

and

European

ancestry

)

Additive

model

: 0, 1

or

2

alleles

of

African

ancestry

NOT PUBLISHED RESULTS, NOT AVAILABLE

Slide52

HumanOmni2.5-8

HumanOmni5-Quad

HiSeq

2000

6222

samples

~2.3M

SNPs

265

samples

~4.3M

SNPs

30

samples

whole-genome

sequencing

10 Pelotas

10 Bambuí

10 Salvador

3649 Pelotas

1354 Bambuí

1219 Salvador

87 Pelotas

88 Bambuí

90 Salvador

Slide53

Slide54

EPIGEN - REFERENCEEPIGEN 5M - (530 haplotypes)EPIGEN GENOMES – (60 Haplotypes)EPIGEN 5M + GENOMES – (590 Haplotypes)

With this strategy we are able to create a reference panel that is genetically similar to the study samples and can increase the imputation accuracy.Two Stage Approach

: Where a subset of individuals is selected for NGS or denser genotyping arrays.

Slide55

LABORATORY OF HUMAN GENETIC DIVERSITY, UFMG

Bionfo

UFMG