Fine scale human genetic structure in three regions of Cameroon reveals episodic diversifying selection

Abstract

Inferences from genetic association studies rely largely on the definition and description of the underlying populations that highlight their genetic similarities and differences. The clustering of human populations into subgroups (population structure) can significantly confound disease associations. This study investigated the fine-scale genetic structure within Cameroon that may underlie disparities observed with Cameroonian ethnicities in malaria genome-wide association studies in sub-Saharan Africa. Genotype data of 1073 individuals from three regions and three ethnic groups in Cameroon were analyzed using measures of genetic proximity to ascertain fine-scale genetic structure. Model-based clustering revealed distinct ancestral proportions among the Bantu, Semi-Bantu and Foulbe ethnic groups, while haplotype-based coancestry estimation revealed possible longstanding and ongoing sympatric differentiation among individuals of the Foulbe ethnic group, and their Bantu and Semi-Bantu counterparts. A genome scan found strong selection signatures in the HLA gene region, confirming longstanding knowledge of natural selection on this genomic region in African populations following immense disease pressure. Signatures of selection were also observed in the HBB gene cluster, a genomic region known to be under strong balancing selection in sub-Saharan Africa due to its co-evolution with malaria. This study further supports the role of evolution in shaping genomes of Cameroonian populations and reveals fine-scale hierarchical structure among and within Cameroonian ethnicities that may impact genetic association studies in the country.

Figure 1

Pairwise Fst and PCA analysis of Cameroonian and world populations. (a) Clustered heatmap showing genetic distance by pairwise population F_ST (Hudson) estimation. AFR = African, EAS = East Asian, EUR = European, AMR = American and SAS = South Asian ancestry. The red color denotes closely related population, hence low F_ST while the decrease in redness to yellow represents increasing genetic distance (high F_ST). Five clusters are apparently corresponding to the five continental proxy ancestry (distinguished broadly by five colors) in the 1000 Genomes project. (b) PCA of Cameroonian populations with the 1000 Genomes populations. Cameroonian populations clustered within African populations. All plots were produced using R 3.6.1.

Figure 2

PCA of Cameroonian populations and other Africa populations. (a) Cameroonian populations with other African populations produce a clustering pattern correlated with geography where West African populations (GWD, MSL, ESN, YRI) clustered to the West, the lone east African population (LWK) clustered to the East, while Cameroonian populations clustered West-Centrally. (b) PCA for Cameroonian ethnicities only. PC1 and PC2 separate the three ethnicities, (c) PC1 and PC3 separate the Bantu and Semi-Bantu. All plots were produced using R 3.6.1.

Figure 3

Model-based clustering and Coancestry estimation. (a) Model-based clustering cross-validation (CV) error. Lowest CV error recorded at k = 3 indicating three clusters. (b) and (c) show ancestral proportions Q, for each ethnicity colored using the RGB color scheme. (d) Coancestry estimation by FineStructure. All plots were produced using R 3.6.1.

Figure 4

iHS and corresponding –log10(p-values) Manhattan plots. (a) iHS plot for the autosomes. Negative values signify selection on derived alleles while positive values are associated with selection on ancestral alleles. (b) Distribution of iHS values as observed in the populations (blue) and as expected under neutral evolution (red). Lower plot represents quantile–quantile (Q–Q) plot of iHS p-values. The plot shows that the test statistics are not inflated. The plots were generated using the R package qqman.

Figure 5

Manahattan plot of hapFLK p-values. Genome-wide significance threshold (red line), suggestive threshold (blue line). The plot was generated using qqman.