Genetic and functional odorant receptor variation in the Homo lineage

Abstract

Humans, Neanderthals, and Denisovans independently adapted to a wide range of geographic environments and their associated food odors. Using ancient DNA sequences, we explored the in vitro function of thirty odorant receptor genes in the genus Homo. Our extinct relatives had highly conserved olfactory receptor sequence, but humans did not. Variations in odorant receptor protein sequence and structure may have produced variation in odor detection and perception. Variants led to minimal changes in specificity but had more influence on functional sensitivity. The few Neanderthal variants disturbed function, whereas Denisovan variants increased sensitivity to sweet and sulfur odors. Geographic adaptations may have produced greater functional variation in our lineage, increasing our olfactory repertoire and expanding our adaptive capacity. Our survey of olfactory genes and odorant receptors suggests that our genus has a shared repertoire with possible local ecological adaptations.

Keywords: Anthropology; Archeology; Evolutionary biology; Molecular biology.

Graphical abstract

Figure 1

Percent OR variation The percentage of variation was calculated by taking the total variant count per gene divided by total basepairs per gene for each population. We used raw counts for ancient populations and raw counts for the consensus sequence of each gene for each of 26 groups in 1000 Genomes. We used the consensus sequence for each of the 1000 Genomes groups rather than total raw counts because the sample sizes are divergent. By using the consensus raw count, we compare percentage variation of one gene to another gene.

Figure 2

Regression results for dose responses (A) Comparison of human (xaxis) and Neanderthal (yaxis) OR responses to odorants in vitro, (B) Comparison of human (xaxis) and Denisovan (yaxis) OR responses to odorants in vitro. (C) Boxplots of in vitro OR responses for all samples showing median, box boundaries (first and third quartiles), and two whiskers (upper whisker extends to the largest value no further than 1.5 inter-quartile range from the third quartile; lower whisker extends to the smallest value at most 1.5 inter-quartile range of first quartile, outliers identified with red asterisk), (D) OR response by lineage and gene. Each OR is represented by a different color and each point represents the natural log of the response to an odorant. Dotted lines correspond to the linear regression for the entire set of ORs responses for a given lineage. The corresponding equation and R2 values are shown on the regression plot. Raw and analyzed data are in DataS1.

Figure 3

Homology model of the human consensus odorant receptor The transmembrane domains are represented in tubes and numbered from 1 to 7. The location of each of the variants is pointed on the human consensus OR homology model by a colored ring. For each variant, dotted lines connect the variant location to a panel showing the ORs dose-response to odorants that were significantly activating ORs in screening. The xaxis of panels represents the logarithmic transformation of the odorant concentration (M) and the yaxis the normalized luminescence (Luciferase (L) normalized by Renilla (R) luminescence, see STAR Methods) generated by the OR activation in luciferase assay. The empty vector pCI is added as a negative control. Error bars are SEM (standard error of the mean) of n = 4 replicates. The Homo lineage origin of the OR variant is color coded in the OR homology model and the dose-responses as modern human = orange, Denisova = blue, Neanderthal Vindija = light purple, Neanderthal Chagyrskaya = dark purple. Statistical significance of OR response between of the human and Homo lineage versions is assessed by Extra sum-of-square F test on the dose-response and shown as ∗∗∗p<0.001, ∗∗0.001

Figure 4

Comparison of OR activity index for human and extinct lineages Color coding is from low (purple) to high (mustard). Odor qualities are from Good Scents Company.