Patterns of Ancestry, Signatures of Natural Selection, and Genetic Association with Stature in Western African Pygmies

Abstract

African Pygmy groups show a distinctive pattern of phenotypic variation, including short stature, which is thought to reflect past adaptation to a tropical environment. Here, we analyze Illumina 1M SNP array data in three Western Pygmy populations from Cameroon and three neighboring Bantu-speaking agricultural populations with whom they have admixed. We infer genome-wide ancestry, scan for signals of positive selection, and perform targeted genetic association with measured height variation. We identify multiple regions throughout the genome that may have played a role in adaptive evolution, many of which contain loci with roles in growth hormone, insulin, and insulin-like growth factor signaling pathways, as well as immunity and neuroendocrine signaling involved in reproduction and metabolism. The most striking results are found on chromosome 3, which harbors a cluster of selection and association signals between approximately 45 and 60 Mb. This region also includes the positional candidate genes DOCK3, which is known to be associated with height variation in Europeans, and CISH, a negative regulator of cytokine signaling known to inhibit growth hormone-stimulated STAT5 signaling. Finally, pathway analysis for genes near the strongest signals of association with height indicates enrichment for loci involved in insulin and insulin-like growth factor signaling.

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

“…This confirms the suggestive associations found by a recent genome-wide study. 22 Interestingly, the SNPs identified here in the GHR and IGF1 genes have not been shown to be associated with height in large-scale genome-wide association studies. 57 Indeed, their frequency is low in the European population (CEU) from HapMap 56 (GHR rs4642376: 10.17%, rs1912107: 10.0%, rs2972419: 11.67% and IGF1 rs11831436: 5.83%).…”

“…[18][19][20][21] A recent genome-wide study has identified regions in the genome that might be involved in the difference in stature observed between pygmies from Cameroon and their non-pygmy neighbors, although this signal was not significant. 22 Some of these regions contain genes linked to the GH-IGF1 signaling pathway.…”

The impact of agricultural emergence on the genetic history of African rainforest hunter-gatherers and agriculturalists

“…Ultimately, 295 individuals were retained for subsequent analyses, including 216 unrelated individuals, 21 complete trios and 8 duos, totalling 266 unrelated samples. This data set was analysed in conjunction with genome-wide data from 11 additional African populations 26,29 , including 4 Western RHG populations (Baka, Bakola and Bezan of Cameroon, and Biaka of Central African Republic-CAR), 1 Eastern RHG population (Mbuti of the Democratic Republic of Congo) and 6 AGR relevant populations ( Fig. 1a; Supplementary Table 1).…”

“…We merged our genotyping data for 930,134 SNPs in 295 individuals with data for 221 additional samples, retrieved from previous studies 26,29 Table 1; dbGaP study accession: phs000449.v2.p1). We restricted the three data sets to the SNPs that were genotyped in all, yielding a total of 363,088 polymorphic SNPs in 516 individuals.…”

“…Recent genome-wide studies based on single nucleotide polymorphism (SNP) array data or whole-genome sequences have documented the somewhat genetic isolation of RHG and identified candidate genes involved in their relatively small stature as well as other adaptive traits 22,[26][27][28] . However, these reports were based on a single or small number of RHG populations, or focused on a limited geographic area (that is, West-Central Africa), despite the fact that they occupy a vast territory extending west-to-east in the equatorial rainforest from the Congo Basin to Lake Victoria.…”