Estrutura Populacional, ancestralidade e Admixture Mapping (AM)

Estrutura Populacional,
ancestralidade e Admixture
Mapping (AM)
Desenvolvimento de estratégias
metodológica para estudos de
ancestralidade
Fernanda Kehdy – PhD
LDGH – Laboratório de Diversidade Genética Humana
Email:[email protected]
Organização da apresentação
Equipe
Objetivos
 Conceitos básicos
 Perguntas científicas que podem ser respondidas
Estratégias metodológicas
Cronograma
Equipe

Dr. Eduardo Tarazona

Fernanda Kehdy (post doc, UFMG)

Wagner Magalhães (post doc, UFMG)

Moara Machado (doutoranda, UFMG)

Giordano Souza (doutorando, UFMG)

Hanaisa de Plá (IC, UFMG)

Thiago (UFBA)

Hadassa Campos (InCor)

Nubia Esteban (InCor)

Ana Cicconella (InCor)
Objetivos da Equipe
1) Inferência de ancestralidade individual da população
brasileira;
2) Determinação
brasileira;
da
estruturação
populacional
3) Inferência da ancestralidade cromossômica da
população brasileira (por exemplo para admixture
mapping);
Objetivo 1 Inferência de ancestralidade individual da população brasileira
Conceitos básicos
Marcadores Informativos de Ancestralidade (AIMs)
Polimorfismos que apresentam grande diferença de frequências
alélicas entre populações e portanto servem como marcos
podendo ser utilizados para inferir a origem geográfica de
indivíduos.
Com a utilização de AIMs é possível inferir a porcentagem individual de contribuição
de cada população parental em uma população miscigenada
Exemplos hipotéticos de bons AIMs
Frequência do AIM nas pop. parentais
Africanos
Europeus
Ameríndios
MIA africano
1,0
0,05
0,02
MIA europeu
0,00
0,90
0,05
MIA ameríndio
0,02
0,01
0,89
Aspectos importantes na seleção de MIAs
(AIMs) em estudos de miscigenação
 São específicos para cada população miscigenada;
 Devem ter frequências alélicas diferentes entre as populações
parentais;
 Não devem estar em desequilíbrio de ligação entre si;
Perguntas científicas que podem ser
respondidas com inferência da
ancestralidade individual
 Caracterização do padrão de miscigenação da população
brasileira;
 Estudos de associação entre ancestralidade e doenças ou
ancestralidade e cor da pele;
 Controle em estudos de associação (ancestralidade como fator
confundidor);
Estudos de associação entre ancestralidade e doenças
Wassel CL et al.,
Circulation:
Cardiovascular
Genetics
Kumar R et al.,
NHI Public
Access
AlarcónRiquelme’s
group, Arthritis
& Rheumatism
Sample sizes
Markers
Analysis/software
Variables
US Hispanic
AMI admixture is strongly associated with
gallbladder surgery in women, even after
adjustment for selected risk factors for
cholelithiasis. OR=2.97, CI=2.01-4.38
4,620 Hispanic
American
92 AIMs
-
Multiple covariates, including measures of adiposity, parity,
alcohol use, and education.
US
Postmenopausal diabetes, In HA women,
AMI admixture had significant associations
with diabetes risk that remained significant
after adjustment for SES and BMI (all
p < 0.0005)
In both African-American women and HA
women there was a significant positive
association between hypertension and
African admixture (P<10−4)
Adiposity and admixture. African admixture
is associated with BMI in AFA women;
Amerindian admixture is associated with
WHR but not BMI in HA women
Hispanic ethnicity was associated with
higher albumin/creatinine ratio compared
with whites, but the association varied with
the country of origin
N= 16,476
92 AIMs
STRUCTURE v2.3.3, Socioeconomic status (SES), adiposity measurements, age
SAS version 9.2, R and WHR
African-American
women (n=10 147)
and HA women
(n=4908)
11712 AFA and 5088
HA
AIMs
-
92 AIMs
STRUCTURE v2.3.3, Age, education, physical activity, parity, family income and
OpenArray® SNP
smoking
Genotyping
Analysis Software
STRUCTURE 2.1
Age, self-reported race/ethnicity, level of education, annual
household income, and smoking history, blood pressure.
Subclinical cardiovascular disease, Among
Hispanics, the highest tertile of European
ancestry was associated with a 34% higher
CAC prevalence (P=0.02) when compared
with the lowest tertile.
712 black and 705
199 genetic
Hispanic participants markers
from the Multi-Ethnic
Study of
Atherosclerosis
African Americans
African ancestry was inversely related to
forced expiratory volume in 1 second
(FEV(1)) and forced vital capacity in the
CARDIA cohort
Latin Americans
Amerindian ancestry is associated with an
increased number of risk alleles for SLE
(Lupus)
777 participants selfidentified as African
American; 813
participants in HABC
and and 579
participants in the
CHS
804 Mestizo lupus
patients and 667
Mestizo healthy
controls
2012
2012
Phenotype/association
2010
2012
2012
US Hispanic
HA self-identified postmenopausal women.
Hispanics and White
participants.
Mexican, Central
Americans, Dominicans
and Puerto Ricans
Hispanic participants
from the Multi-Ethnic
Study of Atherosclerosis
2009
Kosoy R et al.,
Journal of
Human
Hypertension
Nassir R et al.,
International
Journal of
Obesity
Peralta CA et
al., Circulation:
Cardiovascular
Genetics
Population
2010
First author,
Year
Journal
Nassir R et al.,
The American
Journal of
Gastroenterolo
gy
Qi L et al.,
Diabetologia
2010
20848568
20647190
20031644
20445135
2148739
9
2161402
1
22322919
22415198
PMID
1417 Hispanic versus 171 AIMS
white participants
104, 107 and 24
AIMs. Total of 235
AIMs.
Age, body mass index, years since menopause and a
measurement of socioeconomic status
STRUCTURE version Age, gender, ethnicity, smoking, alcohol use,
2.2
education, and annual household income, Waist
circumference, systolic
and diastolic blood pressures, triglycerides, high-density
lipoprotein
cholesterol, low-density lipoprotein cholesterol, fasting
glucose, and
C-reactive protein
Linear regression, Percent African ancestry, age, lifetime pack-years of smoking,
Admixture
body-mass index (BMI), height, square of the height, and
software program, study site
Structure
347 admixture
STRUCTURE 2.3.1, Proportion of Amerindian ancestry
informative marker PLINK 1.0.7, Linear
Regression, Breslo
w-Day test,
StatsDirect
software, version
2.4.6, HelixTree,
version 7.2.3,
Desenvolvida por Hanaisa Sant’Anna e Thaís Muniz
Objetivo 2 Determinação da estruturação populacional brasileira
Conceitos básicos
 Análise dos componentes principais (PCA)
Agrupamento da variabilidade genética em um número mínimo de
componentes que expliquem ao máximo essa variabilidade.
Verificar a relação de proximidade genética entre indivíduos
Perguntas científicas que podem ser
respondidas com determinação da
estruturação populacional
 Quantificação da proximidade genética entre indivíduos da
população brasileira e demais populações parentais;
 Entendimento da história demográfica e evolucionária da
população brasileira e das suas populações ancestrais;
 Controle em estudos de associação (estruturação como fator
confundidor);
Objetivo 3 Inferência da ancestralidade cromossômica da população brasileira
Conceitos básicos
Mapeamento por miscigenação
(quando a miscigenação pode ajudar a encontrar genes responsáveis por doenças complexas)
Formação de população miscigenada
PP1
PP2 maior incidência da doença
População miscigenada utilizada
para estudos caso-controle
Determinação da origem ancestral de fragmentos
cromossômicos em todos os cromossomos da
população miscigenada.
Mapeamento por miscigenação
(quando a miscigenação pode ajudar a encontrar genes
responsáveis por doenças)
Procura-se as região cromossômica nos
casos que apresentam estatisticamente
maior ancestralidade da PP2
Região onde provavelmente existe
algum gene responsável pela
doença
Estudos de associação entre ancestralidade e doenças
Wassel CL et al.,
Circulation:
Cardiovascular
Genetics
Kumar R et al.,
NHI Public
Access
AlarcónRiquelme’s
group, Arthritis
& Rheumatism
Sample sizes
Markers
Analysis/software
Variables
US Hispanic
AMI admixture is strongly associated with
gallbladder surgery in women, even after
adjustment for selected risk factors for
cholelithiasis. OR=2.97, CI=2.01-4.38
4,620 Hispanic
American
92 AIMs
-
Multiple covariates, including measures of adiposity, parity,
alcohol use, and education.
US
Postmenopausal diabetes, In HA women,
AMI admixture had significant associations
with diabetes risk that remained significant
after adjustment for SES and BMI (all
p < 0.0005)
In both African-American women and HA
women there was a significant positive
association between hypertension and
African admixture (P<10−4)
Adiposity and admixture. African admixture
is associated with BMI in AFA women;
Amerindian admixture is associated with
WHR but not BMI in HA women
Hispanic ethnicity was associated with
higher albumin/creatinine ratio compared
with whites, but the association varied with
the country of origin
N= 16,476
92 AIMs
STRUCTURE v2.3.3, Socioeconomic status (SES), adiposity measurements, age
SAS version 9.2, R and WHR
African-American
women (n=10 147)
and HA women
(n=4908)
11712 AFA and 5088
HA
AIMs
-
92 AIMs
STRUCTURE v2.3.3, Age, education, physical activity, parity, family income and
OpenArray® SNP
smoking
Genotyping
Analysis Software
STRUCTURE 2.1
Age, self-reported race/ethnicity, level of education, annual
household income, and smoking history, blood pressure.
Subclinical cardiovascular disease, Among
Hispanics, the highest tertile of European
ancestry was associated with a 34% higher
CAC prevalence (P=0.02) when compared
with the lowest tertile.
712 black and 705
199 genetic
Hispanic participants markers
from the Multi-Ethnic
Study of
Atherosclerosis
African Americans
African ancestry was inversely related to
forced expiratory volume in 1 second
(FEV(1)) and forced vital capacity in the
CARDIA cohort
Latin Americans
Amerindian ancestry is associated with an
increased number of risk alleles for SLE
(Lupus)
777 participants selfidentified as African
American; 813
participants in HABC
and and 579
participants in the
CHS
804 Mestizo lupus
patients and 667
Mestizo healthy
controls
2012
2012
Phenotype/association
2010
2012
2012
US Hispanic
HA self-identified postmenopausal women.
Hispanics and White
participants.
Mexican, Central
Americans, Dominicans
and Puerto Ricans
Hispanic participants
from the Multi-Ethnic
Study of Atherosclerosis
2009
Kosoy R et al.,
Journal of
Human
Hypertension
Nassir R et al.,
International
Journal of
Obesity
Peralta CA et
al., Circulation:
Cardiovascular
Genetics
Population
2010
First author,
Year
Journal
Nassir R et al.,
The American
Journal of
Gastroenterolo
gy
Qi L et al.,
Diabetologia
2010
20848568
20647190
20031644
20445135
2148739
9
2161402
1
22322919
22415198
PMID
1417 Hispanic versus 171 AIMS
white participants
104, 107 and 24
AIMs. Total of 235
AIMs.
Age, body mass index, years since menopause and a
measurement of socioeconomic status
STRUCTURE version Age, gender, ethnicity, smoking, alcohol use,
2.2
education, and annual household income, Waist
circumference, systolic
and diastolic blood pressures, triglycerides, high-density
lipoprotein
cholesterol, low-density lipoprotein cholesterol, fasting
glucose, and
C-reactive protein
Linear regression, Percent African ancestry, age, lifetime pack-years of smoking,
Admixture
body-mass index (BMI), height, square of the height, and
software program, study site
Structure
347 admixture
STRUCTURE 2.3.1, Proportion of Amerindian ancestry
informative marker PLINK 1.0.7, Linear
Regression, Breslo
w-Day test,
StatsDirect
software, version
2.4.6, HelixTree,
version 7.2.3,
Desenvolvida por Hanaisa Sant’Anna e Thaís Muniz
Perguntas científicas que podem ser
respondidas com inferência da
ancestralidade cromossômica
 Admixture mapping;
 Inferência da dinâmica de miscigenação através dos tamanhos
de fragmentos cromossômicos;
 Análise de Seleção Natural recente;
 Melhoramento do mapa de recombinação;
 Análise de ancestralidade em alta resolução através se “genomas
virtuais”;
Files básicos para
análises
Estratégias
Metodológicas
Ancestralidade
cromossômica
Seleção de AIMs
Ancestralidade individual
Análise de PCA
Estratégias Metodológicas
Arquivos base para as análises
Estratégias
Metodológicas
Seleção de AIMs
Estratégias
Metodológicas
Ancestralidade individual
Exemplo de resultado de ancestralidade individual
Família
78
89
102
87
121
132
112
144
164
154
219
230
233
236
246
352
262
321
268
252
392
396
404
408
375
366
362
372
380
368
1
2
3
4
5
6
7
8
9
10
ID indiv
HGDP00448
HGDP00449
HGDP00450
HGDP00451
HGDP00454
HGDP00455
HGDP00456
HGDP00457
HGDP00458
HGDP00459
HGDP00511
HGDP00512
HGDP00513
HGDP00514
HGDP00515
HGDP00516
HGDP00517
HGDP00518
HGDP00519
HGDP00520
HGDP00870
HGDP00871
HGDP00872
HGDP00873
HGDP00874
HGDP00875
HGDP00876
HGDP00877
HGDP00878
HGDP01037
NA19663
NA19664
NA19665
NA19722
NA19723
NA19649
NA19669
NA19656
NA19657
NA19658
População
Biaka_Pygmies
Mbuti_Pygmies
Mbuti_Pygmies
Biaka_Pygmies
Biaka_Pygmies
Biaka_Pygmies
Mbuti_Pygmies
Biaka_Pygmies
Biaka_Pygmies
Biaka_Pygmies
French
French
French
French
French
French
French
French
French
French
Maya
Maya
Maya
Maya
Maya
Maya
Maya
Maya
Maya
Pima
Mexican
Mexican
Mexican
Mexican
Mexican
Mexican
Mexican
Mexican
Mexican
Mexican
País
Central_African_Republic
Democratic_Republic_of_Congo
Democratic_Republic_of_Congo
Central_African_Republic
Central_African_Republic
Central_African_Republic
Democratic_Republic_of_Congo
Central_African_Republic
Central_African_Republic
Central_African_Republic
France
France
France
France
France
France
France
France
France
France
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Mexico
Anc. Europeia
0.00000
0.01440
0.00000
0.02742
0.00000
0.00000
0.00000
0.00000
0.00000
0.00000
0.89015
0.94489
0.89516
0.98608
0.92256
0.90613
0.90857
0.82602
0.89572
0.96659
0.08458
0.29908
0.08228
0.00000
0.00000
0.08786
0.22401
0.08643
0.26904
0.00000
0.35961
0.27488
0.29450
0.34241
0.32425
0.71419
0.59387
0.41379
0.36565
0.54990
Anc. Africana
1.00000
0.96983
1.00000
0.94737
1.00000
1.00000
1.00000
1.00000
1.00000
1.00000
0.03506
0.01640
0.04555
0.01392
0.07152
0.08290
0.05819
0.07622
0.07636
0.03341
0.00000
0.00000
0.02559
0.00000
0.00000
0.02792
0.01500
0.00000
0.00000
0.00000
0.26999
0.20813
0.12220
0.07913
0.15423
0.11368
0.10494
0.27930
0.03553
0.07532
Anc. Amerindia
0.00000
0.01577
0.00000
0.02521
0.00000
0.00000
0.00000
0.00000
0.00000
0.00000
0.07479
0.03870
0.05928
0.00000
0.00592
0.01097
0.03324
0.09776
0.02793
0.00000
0.91543
0.70092
0.89214
1.00000
1.00000
0.88422
0.76100
0.91357
0.73096
1.00000
0.37040
0.51699
0.58331
0.57847
0.52152
0.17213
0.30119
0.30692
0.59882
0.37478
Estratégias
Metodológicas
PCA
Estratégias
Metodológicas
Ancestralidade cromossômica
Cronograma
 Fev/2013: inferência da miscigenação individual
 Abr/2013: inferência da ancestralidade cromossômica
Referências Bibliográficas
Winkler CA, Nelson GW, Smith MW. Admixture mapping comes of age. Annu Rev
Genomics Hum Genet. 2010 Sep 22;11:65-89.
Galanter JM, Fernandez-Lopez JC, Gignoux CR, Barnholtz-Sloan J, Fernandez-Rozadilla
C, Via M, Hidalgo-Miranda A, Contreras AV, Figueroa LU, Raska P, Jimenez-Sanchez G,
Zolezzi IS, Torres M, Ponte CR, Ruiz Y, Salas A, Nguyen E, Eng C, Borjas L, Zabala W,
Barreto G, González FR, Ibarra A, Taboada P, Porras L, Moreno F, Bigham A, Gutierrez G,
Brutsaert T, León-Velarde F, Moore LG, Vargas E, Cruz M, Escobedo J, Rodriguez-Santana
J, Rodriguez-Cintrón W, Chapela R, Ford JG, Bustamante C, Seminara D, Shriver M, Ziv E,
Burchard EG, Haile R, Parra E, Carracedo A; LACE Consortium. Development of a panel of
genome-wide ancestry informative markers to study admixture throughout the Americas.
PLoS Genet. 2012;8(3):e1002554.
Tang H, Choudhry S, Mei R, Morgan M, Rodriguez-Cintron W, Burchard EG, Risch NJ.
Recent genetic selection in the ancestral admixture of Puerto Ricans. Am J Hum Genet.
2007 Sep;81(3):626-33.
Referências Bibliográficas
Johnson NA, Coram MA, Shriver MD, Romieu I, Barsh GS, London SJ, Tang H.
Ancestral components of admixed genomes in a Mexican cohort. PLoS Genet.
2011 Dec;7(12):e1002410. doi: 10.1371/journal.pgen.1002410.
Verdu P, Rosenberg NA. A general mechanistic model for admixture histories of
hybrid populations. Genetics. 2011 Dec;189(4):1413-26. Epub 2011 Oct 3.
Wegmann D, Kessner DE, Veeramah KR, Mathias RA, Nicolae DL, Yanek LR,
Sun YV, Torgerson DG, Rafaels N, Mosley T, Becker LC, Ruczinski I, Beaty TH,
Kardia SL, Meyers DA, Barnes KC, Becker DM, Freimer NB, Novembre J.
Recombination rates in admixed individuals identified by ancestry-based
inference. Nat Genet. 2011 Jul 20;43(9):847-53. doi: 10.1038/ng.894.