Transcript Slides

Enrichment of Immune Pathways in
Genes Under Geographically
Restricted Adaptation
in the Gullah African American
Population of South Carolina
Paula S. Ramos, Satria Sajuthi, Wei-Min Chen,
Jasmin Divers, Jyotika K. Fernandes, Gary S.
Gilkeson, Kelly J. Hunt, Diane L. Kamen, Uma
Nayak, W. Timothy Garvey, Michèle M. Sale,
Carl D. Langefeld
Disclosure Statement
The authors have no relevant financial or commercial
relationships to disclose.
Outline
• Disclaimer
• Natural selection and autoimmunity
• Gullah African-American (AA) population
• Results
• Discussion
Disclaimer
I am a human geneticist.
Disclaimer
Classical genetics
Molecular genetics
Clinical genetics
Epigenetics
Cytogenetics
Genetic counseling
Pharmacogenetics
Developmental genetics
Genetic epidemiology
Statistical genetics
Bioinformatics
Evolutionary and
population genetics
Genomics
Ethical, legal, social
and policy issues
Disclaimer
There is
NO
biological basis
for the concept of
“race”
Measuring patterns of human genetic
diversity
Characterization of the ABO blood group system by the Hirszfelds
in the early 1900s :
• Pattern of A and B blood types in World
War I soldiers showed frequency gradients
that correlated with the geographic origin
of the soldiers.
No genetic divisions among ethnic groups!
Lewontin RC. The apportionment of human diversity. Evolutionary biology 1972;
6:391-398.
•
Multiple different genetic markers (blood group
systems and serum protein markers).
•
More than 100 populations sampled across
seven socially constructed “racial” groups
(Caucasians, Africans, East Asians, South Asians,
Amerindians, Oceanians, and Australians).
•
Vast majority of human genetic diversity (∼85%) is caused by individual
differences that are shared across “all” populations and races.
•
Despite substantial genetic variation within the human population, such
variation has accumulated over time; most of this variation appeared
before the expansion of Homo sapiens out of Africa and the resulting
isolation of populations within continents.
Genetic variation is extensive and largely
shared across populations.
The considerable genetic differences we see
between individuals has very little to do with socalled “racial” boundaries.
Rather, it is merely the variation that was present
in the original human population that seeded all
the current human populations.
The same genetic variants are found in most
populations, although their frequencies may
differ substantially.
Lewontin’s findings…
•
At the time of publication were controversial, but consensus
gradually emerged that genetic differences among populations are
modest.
•
The observation that patterns in human genetic variation were
largely gradual according to geographic boundaries and not
subject to sudden population-specific changes that followed
preconceived racial notions removed the biological argument for
race - or it should have!
Aim
Identify autoimmune risk alleles with evidence of
population
differentiation
that
may
result
from
geographically restricted, subtle selective pressure.
Autoimmune diseases
affect at least 5-8% of the
population!
In the US there are:
• 22 million people with an
autoimmune disease
• 20 million with cancer
Natural selection drives adaptation
Skin color
Malaria and sickle cell anemia
Lactose intolerance
Genetic variation
Reproductive/selective
advantage
Increased allele
frequency in
population
The Sea Islands Gullah population
• Higher (~89%) global African ancestry than what is typically
reported for AA (~80%)
(Huang Y. et al, ICHG/ASHG 2011)
• Higher African ancestry composition from Far West Africa
(Bryc K. et al, ASHG 2012)
Methods
•
We had genotype data on:
- 277 healthy Gullahs
- 400 Sierra Leoneans (SL)
- 203 Yoruba from Nigeria (YRI) HapMap3
•
Computed the Weir and Cockerham’s (1984) FST between Gullah
and SL, and Gullah and YRI.
•
A total of 582,100 autosomal SNPs met standard GWAS quality
control.
•
Gene regions with at least one variant within the top 0.01% of
highest FST between populations were prioritized.
Selected loci with multiple SNPs within the top 0.01% of
highest FST between Gullah and YRI
SNP
Chr
rs6881896
5
Position
(kb)
55,508
rs160935
5
rs152345
Gene region
Fst
ANKRD55
0.088
55,518
ANKRD55
0.073
5
55,595
ANKRD55
0.064
rs6457710
6
33,029
HLA
0.101
rs7744381
6
33,082
HLA
0.094
rs6930960
6
33,851
HLA
0.085
rs7767496
6
33,852
HLA
0.096
rs7797671
7
80,041
CD36
0.088
rs1334518
7
80,226
CD36
0.117
rs4728191
7
80,270
CD36
0.120
rs1358339
7
80,359
CD36
0.093
rs4507728
8
10,851
XKR6
0.083
rs4320511
8
10,871
XKR6
0.081
rs6601550
8
10,888
XKR6
0.104
•
A total of 16 gene regions
in the Gullah vs. SL and 27
in the Gullah vs. YRI met
the top FST criteria.
•
The HLA and ANKRD55 are
associated with multiple
autoimmune diseases,
XKR6 with lupus.
•
The HLA and CD36 regions
have previously been
shown to be under
selection that happened
pre-admixture in AfricanAmericans.
Enriched biological functions and
pathways among loci with highest FST
Gullah vs SL
Gullah vs YRI
•
Cellular Function and
Maintenance (P=6.1E-04)
•
Cancer functions (P=4.1E-04)
•
Antigen presentation
(P=4.93E-04) and allograft
rejection signaling pathways
(P=8.30E-04)
•
CCR3 signaling in eosinophils
pathway (P=4.82E-04)
Discussion
• These data reveal several regions consistent with evidence for
selection in the Gullah. However, we cannot rule out that
other population genetic factors (e.g. founder effects)
contribute to these patterns in some genomic regions.
• The paucity of genes in the top distribution of the FST that are
also associated with an autoimmune disease might be due to
the lack of genetic association studies (GWAS) in AfricanAmericans (AA).
• The enrichment of immune pathways suggests that
autoimmune risk alleles might be present in the Gullah, as well
as other AA.
• Given the increased prevalence of several complex traits in
AA and the homogeneity of the Gullah, identification of these
regions in the Gullah has the potential to elucidate complex
disease risks in AA.
Goal
The goal of this research is to understand the
etiology of ethnic disparities in autoimmune
disease prevalence and severity.
Acknowledgements
All the study participants.
NIH grants K01 AR067280
NIH grant P60 AR062755
WFU Center for Public Health Genomics
South Carolina Clinical & Translational Research (SCTR) Institute (NIH
Grants UL1 RR029882 and UL1 TR000062)