1. The Genome Diversity in Africa Project
Manjinder Sandhu
Wellcome Trust Sanger Institute

2. Why study genetic variation in Africa?
Genetic and linguistic diversity
Has been subjected to various environmental selection forces over time and in different regions
High disease burden- genetic determinants of disease poorly understood
Few large scale genomic studies in the region

3. Complexities in the study of genomics in Africa
Population structure and differentiation
Gene flow from Europe/Asian/middle eastern populations
Gene flow within Africa
Differences in LD structure between populations
Allelic differentiation between populations due to local adaptation

4. Key questions
How do we best capture common and rare from African populations?
What designs are best for large-scale genomic studies in Africa- how can these be optimised in terms of cost efficiency?
How much of variation in African populations is private?
Can data from different parts of Africa be combined?
Can Africa specific reference panels improve imputation into African populations?
How should such reference panels be curated in light of the variation between populations?
Do we need an Africa specific chip to capture the variation across Africa?

5. African Genome Variation Project
Aim: to study genetic variation in Africa to inform large scale studies in African genomics
Study of 16 ethno-linguistic groups across SSA from populations relevant to medical genomics
100 individuals with dense (2.5M) genotype data in each
Largest diversity panel from Africa so far

6. Genome Diversity in Africa Project
APCDR – 14 centres in 10 countries across Africa
H3A Africa
Wellcome Trust Sanger Institute
MRC, Uganda
Trypanogen

7. Aims and objectives
To characterise genetic variation in populations across Africa
To study population structure and differentiation between populations with the objective of informing large-scale studies in African genomics
Extend our understanding of our human origins, population history
Global resource to help design, implement and interpret genomic studies in Africa and globally
To develop capacity for analysis and storage of data in Africa

8. Scientific objectives and cross-cutting activities of the GDAP

9. Sampling to date
4x sequencing of 3 populations completed (320 samples)
2100 more in the pipeline
Collections ongoing in East Africa
GDAP
1000 G

10. Data processing and output
Illumina Hiseq 4x
Read mapping (BWA)
Bam improvement (sample level)
Populations r2
Concordance
Baganda
0.96
0.99
Ethiopia
0.95
Zulu
Variant calling (Unified Genotyper)
VQSR filtering
Genotype refinement (Beagle with 1000 G reference)

11. Functional mutations enriched among rare MAF

12. Population structure
Moderate differentiation between Ethiopians and other populations
Very little differentiation between Zulu and Baganda
Fst differentiation
Baganda
Zulu
Ethiopia
0.008
0.028
0.035

13. Preliminary results: sharing of variants
Zulu
Ethiopia
18.7 M
N=100
0.5 M
17 M
N=120
2.5 M
13.3%
1.6 M
9.4%
14 M
1.7 M
0.9 M
Pop
Novel variants
Zulu 9%
Baganda 7%
Ethiopia
15%
2.4 M
12.6%
Baganda
19 M
N=100

14. Generating a new reference panel for imputation
Several questions about how best to process data:
Single population calling vs multiple population calling
Can these approaches be combined?
Best algorithms for genotype refinement
Will this panel improve imputation compared to the 1000 Genomes Project panel?

15. Assessing the utility of extremely low coverage designs
What coverage is ideal for large scale genomic studies in Africa
How well can we capture common genetic variation with 2x, 1x and 0.5x coverage data in Africa
Can we improve capture with better reference panel
Trade off of sample size and accuracy

16. Next steps
Large-scale sequencing effort- expand collections to central, West Africa and North Africa
Characterise variation in populations representative of most regions in Africa, including HG populations
Develop a large reference panel for imputation
Develop a chip array specific to Africa

17. Acknowledgements WTSI South Africa Deepti Gurdasani Tommy Carstensen
Elizabeth Young
Cristina Pomilla
Eleftheria Zeggini
MRC Uganda
Anatoli Kamali
Janet Seeley
Pontiano Kaleebu
Oxford
Jonathan Marchini
Ayesha Motala
Fraser Pirie
Brenna Henn
Eileen Hoal
Ethiopia (WTSI)
Chris Tyler Smith
Luca Pagani
Sanger pipeline teams
All participants