On our sense of smell, Neandertals, Denisovans and the peopling of America...

A reader of my blog, NeilB, (thanks Neil) has asked me about my take on a recent paper by Kara C. Hoover et al. [1] which links humans, Neandertals and Denisovans in their ability to smell a certain odor.

I had seen the paper but was (and still am) unable to access its facts as it is locked behind a paywall, so at that time I decided to let it rest for a while. A month has passed and not much has changed, but I have spent some time doing research on the subject, so today's post will address this paper and "my take on it".

Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution

There is a substance named Androstenone which is a steroid it is quite peculiar because it was the first mammalian pheromone to be discovered.

Phermomones are chemical substances that are secreted by different kinds of animals and plants, from unicellular microbes to insects to birds. These chemicals trigger different responses, and the sexual one is probably the best known.

It is found in the sweat and other excretions (i.e. urine, saliva) of animals and is an element that trigges sexual arousal or interest. Among those animals with androstenone, are male pigs.

Some people can smell it, some find the smell nasty, others agreeable and some, can not even smell it at all ("Those who cannot mell androstenone are roughly ctual androstenone non-detection in young healthy adults is between 1.8 and 5.96%" [8]).

The interesting question is why do we humans even smell a pig pheromone? or, why do some find it horrible while others dont't detect it or find it neutral? The paper by Hoover, Gokcumen, Queshy, Bruguera, Savangsuksa, Cobb and Matsumani [1] was published online on June 13, 2015 and its title is: "Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution" addresses this issue. The abstract is great and (as any good abstract, summarizes the paper clearly):

Allelic variation at 4 loci in the human olfactory receptor gene OR7D4 is associated with perceptual variation in the sex steroid-derived odorants, androstenone, and androstadienone. Androstadienone has been linked with chemosensory identification whereas androstenone makes pork from uncastrated pigs distasteful (“boar taint”).
In a sample of 2224 individuals from 43 populations, we identified 45 OR7D4 single nucleotide polymorphisms. Coalescent modeling of frequency-site-spectrum-based statistics identified significant deviation from neutrality in human OR7D4; individual populations with statistically significant deviations from neutrality include Gujarati, Beijing Han, Great Britain, Iberia, and Puerto Rico.
Analysis of molecular variation values indicated statistically significant population differentiation driven mainly by the 4 alleles associated with androstenone perception variation; however, fixation values were low suggesting that genetic structure may not have played a strong role in creating these group divisions.
We also studied OR7D4 in the genomes of extinct members of the human lineage: Altai Neandertal and Denisovan. No variants were identified in Altai but 2 were in Denisova, neither of which is shared with modern humans. A functional test of modern human and a synthesized mutant Denisova OR7D4 indicated no statistically significant difference in responses to androstenone between the 2 species. Our results suggest non-neutral evolution for an olfactory receptor gene.

Broadly what Hoover and team are postulating is that they studied the sequence of DNA that codes for OR7D4 in a sample of 2,200 persons spanning 43 populations from different parts of the world and found that this olfactory receptor gene is selected positively by evolutionary forces. Some populations have one mutation, others another and this is what influences how each population reacts to the smell of those steroids.

The pig link apparently comes from its domestication, which took place in Asia, so those who domesticated and ate pigs would have to find them appetizing, and a nice smell is a key factor in making something appealing at the table. So Asians should have the gene variant that diminishes the sensitivity to this pig steroid. While Africans (if Africa is our homeland) should have an "original" allele which finds the smell repulsive.

But since the study found that Neanderthals (who have our OR7D4 variant) and Denisovans (who had another but allowed them to smell the same as we do) both could detect the odor of androstenone, and they did not domesticate pigs, I believe that this steroid is more linked to us and our pheromones than to those of pigs. Probably pigs have the same kind of steroid that we have so we smell theirs like we can smell ours.

But Hoover (at the University of Arkansas Faibanks website) belives that the link is with the pigs as food... Below I quote her:

"The Evolution of Olfactory Receptors
Kara C. Hoover
What microevolutionary factors shaped the distribution and diversity in olfactory receptor genes in modern humans? My long-term research is to reconstruct temporal and spatial patterns of variation using genetic data from modern humans. I am particularly interested in the interplay between microevolutionary forces and diet and behavior in shaping the distribution and diversity of olfactory receptor genes during the peopling of new landscapes as humans migrated out of Africa to Eurasia. A forthcoming paper is focused on signatures of selection in OR7D4, an olfactory receptor for sex pheromone detection that is also linked to human pig meat preference. The rich archaeological and genomic record of pig domestication in Asia provides the contextual frame in which I can exploit the promise of the genomics revolution through generation of an integrative anthropological dataset. My analysis of sequence data from modern humans, Altai Neandertal, and Denisova indicates that Eurasians are more likely to have a mutated copy of the gene reducing phenotypic sensitivity to androstenone and increasing preference for pig meat...."

More information

As that was all I could find out about Hoover's paper, I looked into other papers on the subject to see what we really know about this receptor:

A 2014 paper by Elena Ognatieva, Levitsky, Yudin, Moshkin and Kolchanov [3] tells us about the Human odorant receptor OR7D4 (the "OR" part stands for Odorant Receptor) detects the odor of two "odorous steroid", androstadiennone and androstenone. It does not detect other smells (out of 66 that were tested). It is interesting to point out that some individuals find the smell of androstenone unpleasant, while others find in quite appealing. Also some persons perceive the smell quite distinctly even in very low concentrations while others seem to be impervious to it.

The most common allele of this receptor is known as RT, then there is another quite common variante known as WM (because the substitutions are R88W and T133M).

Individuals carrying two RTs (RT/RT) find the odor of androstenone and androstadienone as unpleasant. But those carrying the WM variant either as WM/WM or WM/RT, found both steroids less unpleasant and were less sensitive to them. This had already been proven by Keller et al. [4] in 2007.

Keller et al. [4] found the following prevalence among the populations that they studied:

Out of 391 subjects, 242 were RT/RT (61.9%); 96 were RT/WM (24.6%) and 10 were WM/WM (2.6%). The remaining individuals belonged to other alleles as per detail below:

RT/P79L 26, RT/S84N 7, WM/P79L 4, RT/D52G 2, WM/S84N 2, WM/L162P 1, S84N/P79L 1.

But the prevalence had an ethnic gradient, and here we only focus on those who were either RT/RT or RT/WM:

• All subjects RT/RT: 71.6%, RT/WM: 28.4%
• African Americans RT/RT 85.9% and RT/WM 14.1%.
• Caucasian: RT/RT 63.3% and RT/WM: 36.7%

So more African Americans find the smell of pig unpleasant than Caucasians, which would buttress the "Eurasian domestication of pigs propelled the mutation to make them smell nicer theory".

They also found that some other alleles found at very low frequencies are predominant in some ethnic groups:

• rs5020280 S84N, has a 1.3% global frequency, but of those, 50% are African Americans and 10% Caucasians. None were Asians or Native Americans.
• P70L, has a 4% global prevalence and of those, 81% are Africans, none are Asians, Native Americans or Caucasians.
• D52G, with a 0.3% prevalence is exclusively found among African Americans
• L162P, with 0.1% global freqency is exclusively Caucasian.

The impact of these other alleles on the imact of the odor of the steroids is not clarified in the paper, except for S84N, whose carriers would be more sensitive to androstenone.

Another paper deals with the prevalence found in Madagascar by Razafindrazaka et al., (2015) [6], and the numbers are:

RT/RT: 64.8%; RT/WM: 32.0% and WM/WM: 3.2%, more or less similar to the values reported by Keller et al.

The paper adds that "Considering the Malagasy sample as a whole, the allele frequency of the derived form was 19% [...] The observed frequencies for both SNPs (R88W and T133M) were closer to the frequencies observed in Europe (FIN: 22%, GBR : 18%, IBS : 18%, TSI : 22%) and in Asia (CHB : 20%, CHS : 24%, JPT : 25%) than the frequencies observed in Africa (YRI : 7%, ASW : 4%, LWK : 3%).

But what about a "sexual activity in humans"? Well, there is an older paper that mentions that this odor receptor has a variant that influences the odor perception (nice or nasty) among heterosexual partners too!, (variant rs8109935) as discovered by Sookoian et al, 2001 [5].

I found this slide shown below which gives a global distribution map of the ancestral and derived form of the OR7D4 alleles. Unsruprisingly (for me), the Americas have a very low proportion of derived allele, conserving the ancestral one.

Slide 12 in [2], K. C. Hoover.

Someone who considers that America was peopled recently will say that the map shows that Paleo Indians peopled the New World before pigs were domesticated so were not subjected to evolutionary pressure to find pig smell nice. So they kept the old ancestral allele. Just like Africans, who lived in the cradle of mankind.

But that conclusion (that humans reached America before pigs were domesticated) is evidently true regardless of the smelling abilities of humans because "Pig domestication began around 9000 YBP in the Fertile Crescent and Far East" [9] and by that time people had been living in America for thousands of years.

As I see the map, the prevalence among Amerindians (exlude the Porto Ricans and Colombians, which are an admixture of Africans and Europeans) is much lower than anywhere else in the whole World. Even the Papuans... It is similar to that of Thailand, (a place where pigs were domesticated). So it is evident that pigs and their domestication don't have any relationship with our pig steroid smelling abilities.

The map shows that Amerindians did not get their allele from East Asians, theirs predates the mutation it is the ancestral one. Not shared by Denisovans, but surely by Neanderthals or even more ancient ancestors like H. erectus.

It is an ancestral trait, dating back to the primates:

Olfactory Receptor Genes in Primates, fig. 2 in [7]

The figure above, from Zhuang (2007) [7] is acompanied by the following text:

"The putative hominine ancestor (node γ in Fig. 2), which had the same sequence as the ancestor of human, bonobo and chimpanzee (node δ in Fig. 2) , showed a reduction in both sensitivity and efficacy compared with the putative Great Ape ancestor (Fig. 1B). In contrast, the bonobo and chimpanzee ancestor (node ε) showed greater response than the ancestor of human, bonobo, and chimpanzee (node δ)... OR7D4 shows a signature for positive selection in the primate lineage"

They add: "although there is no evidence for a behavioral role of these odorants in a primate species other than human. As an OR for sex-steroid derived compounds, OR7D4 is not likely to be involved in food detection or toxicity avoidance. If functional evolution of OR7D4 is adaptive, it is tempting to speculate that sensitivity to androstenone and androstadienone, which is at least partly determined by OR7D4 in humans, could play a role in the reproductive fitness in some primate species. Nonetheless, it is also likely that functional ORs for androstenone other than OR7D4 exist in primate species."

This is more or less in line with my thoughts: OR7D4 played a role in reproduction among our ancestors, Neanderthal and Denisovans and older ones too, Homo erectus for instance, and also among modern humans. The pig link is a coincidence. Selection acts upon this receptor and others too. The ancestral allele has survived because it plays a key role in our reproductive success.

The red segments in the map above all over Eurasia and Siberia (putative home of Amerindians) indicates a recent mutation once the original wave of hominins spread into the New World. The island in Thailand (once part of the range of Homo Erectus) and the high frequencies of the ancestral variant there, in America and Sub Saharan Africa support a very old dispersal into America. By the way, S.E.Asia is one of the places where Y-Hg. C is found, and also in the New World, which I suggested may indicate an ancient peopling of America.

Sources
[1] Kara C. Hoover et al., (2015) Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution, Chem. Senses (2015) doi: 10.1093/chemse/bjv030 First published online: June 13, 2015.
[2] Murdock Site Visit, 5 September 2014 Evolution of Human Olfaction, Kara C Hoover, Anthropology.
[3] Elena V. Ignatieva, Victor G. Levitsky, Nikolay S. Yudin, Mikhail P. Moshkin and Nikolay A. Kolchanov, (2014). Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset , Front Psychol. 2014; 5: 247. Published online 2014 Mar 24. doi: 10.3389/fpsyg.2014.00247 PMCID: PMC3970011
[4] Keller A, Zhuang H, Chi Q, Vosshall LB, Matsunami H., (2007), Genetic variation in a human odorant receptor alters odour perception. Nature. 2007 Sep 27; 449(7161):468-72.
[5] Sookoian S, Burgueño A, Gianotti TF, Marillet G, Pirola CJ, Odor perception between heterosexual partners: its association with depression, anxiety, and genetic variation in odorant receptor OR7D4, Biol Psychol. 2011 Mar; 86(3):153-7.
[6] Razafindrazaka, Harilanto; Monnereau, Aurore; Razafindrazaka, Dina; Tonasso, Laure; Schiavinato, Stephanie; Rakotoarisoa, JeanAimé; Radimilahy, Chantal; Letellier, Thierry; and Pierron, Denis, (2015) Genetic Admixture and Flavor Preferences: Androstenone Sensitivity in Malagasy Populations. Human Biology Open Access Pre-Prints. Paper 71.
[7] Hanyi Zhuang, Ming-Shan Chien and Hiroaki Matsunami, (2009). Dynamic functional evolution of an odorant receptor for sex-steroid- derived odors in primates, PNAS vol. 106 no. 50, 21247–21251, doi: 10.1073/pnas.0808378106
[8] Elizabeth A. Bremner, Joel D. Mainland, Rehan M. Khan and Noam Sobel, (2003), The Prevalence of Androstenone Anosmia Chem. Senses (2003) 28 (5): 423-432. doi: 10.1093/chemse/28.5.423
[9] S E Ramos-Onsins, W Burgos-Paz, A Manunza and M Amills, (2014). Mining the pig genome to investigate the domestication process. Heredity 113, 471-484 (December 2014) | doi:10.1038/hdy.2014.68
[10]Lunde K, Egelandsdal B, Skuterud E, Mainland JD, Lea T, Hersleth M, Matsunami H (2012) Genetic variation of an odorant receptor OR7D4 and sensory perception of cooked meat containing androstenone PLoS One. 2012; 7(5):e35259.

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