Genomic Analysis of Obesity Gene Risk Variations: Understanding the Thrifty‐Genotype Hypothesis on an Evolutionary Time‐Scale

James Neel introduced the idea of a thrifty genotype in 1962, wherein a genotype bestows an enhanced ability to maintain macronutrient stores during times of famine. Since then, there has been great controversy whether or not his hypothesis holds true. This work attempts to shed some light on the situation by taking a genomic view of 375 common obesity gene risk variants and their evolutionary history. When these variants are separated into groups based on their designation of ancestral or derived, evidence of selective pressures become clear. Frequencies of these variants vary from population to population. When compared to geographic location of these populations and the timeframe of the selective pressures responsible for variant selection, we see that there are two distinct selective pressures that shaped modern human genotypes. Early in Homo sapiens development, a reliance upon endurance hunting selected for gene variants that allowed humans to run for great distances in the heat of day to hunt for prey. We term these ancestral variants the ‘early’ thrifty genotype. Later in human development after global migration, humans became dependent upon agriculture for sustenance. Dependence upon agriculture selected for thrifty variants in time of famine. These fit the classic thrifty gene hypothesis as introduced by Neel. We call these derived variants the ‘late’ thrifty genotype. We then investigate the evolutionary history of a specific obesity gene, Niemann‐Pick C1 (NPC1). Clarification of the evolutionary processes responsible for the thrifty genotype can put to rest any controversies surrounding the topic, and thus spur progress into understanding potential new treatments and therapies that could be developed to combat obesity on a global scale. Support or Funding Information This work is done with help from generous donations from private anonymous donors.Mean frequency of 169 ancestral SNPs associated with obesity among various populations sorted from high to low. Box represents plus and minus one standard deviation. Upper and lower whisker represents range. Means without a common letter differ significantly.Mean frequency of 206 derived SNPs associated with obesity among various populations. Box represents plus and minus one standard deviation. Upper and lower whisker represents range. Means without a common letter differ significantly. Populations are kept in the same order as in Figure 1 for clarity of comparison.NPC1 risk variant frequency among multiple ethnic groups. Cohorts are organized by descending average risk allele frequency. Data gathered from NCBI and local collaborative cohorts. Missing bars denote unavailable data.(A) Select regions of NPC1 protein sequence alignment showing amino acid variants (H215R, M642I, and I858V) encoded by single nucleotide polymorphisms in the gene. Variant locations are marked by dashed lines. (B) Phylogenic tree of NPC1 protein based on sequence alignment.