Positively selected TNKS haplotype: from evolutionary advantage to the health risk in an Arabian Peninsula population

Introduction: Following the out-of-Africa diaspora, the Arabian Peninsula has experienced several waves of human migrations despite the prevailing extreme and varying environmental conditions. The potential adaptation that shaped the extant human populations of the hot and dry environment of the Arabian Peninsula have been scarcely studied.
Materials and Methods: We explored natural selection in the Arabian Peninsula region by analyzing 662,750 single nucleotide variants in 583 Kuwaiti and 96 Saudi Arabian individuals conducting multiple statistical tests, including integrated Haplotype Score (iHS), Cross Population Extended Haplotype Homozygosity (XP-EHH), Population Branch Statistics (PBS), and log-likelihood ratio scores (LLRS).
Results: Our integrative approach identified several genomic regions with strong signals of positive selection in both the populations, many of which contain loci associated with metabolic traits, asthma and blood-related phenotypes. We highlight a haplotype overlapping TNKS region in chromosome 8, associated with metabolic traits and hypertension. The TNKS haplotype exemplifies a general trend in which a more rapid metabolism rate and hypertension have been selected in the Kuwaiti population, and potentially conferred some degree of fitness advantage to the Kuwaiti ancestors for surviving in the extremely dry and hot ecological environments, while posing a considerable health risk to present-day Kuwaitis.
Conclusions: Our results suggest that past adaptive trends have further predisposed Kuwaiti populations to the health risks at the genetic level. Overall, the mechanisms through which the TNKS haplotype conferred a fitness advantage and how the same haplotype predisposes the population to metabolic diseases remain fascinating and could be explored in future research.