The human genome and genetic diversity

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Mechanisms of taste perception in humans

Among the five senses humans can experience – vision, olfaction, hearing, taste and touching –, taste is essential for nutrition and survival.
Because of the connection between the oral and the nasal cavities, smell is also stimulated when eating. The combination in the brain of olfactory and gustatory information generate the flavor of the food (Rolls and Baylis 1994; Small and Prescott 2005). For this reason, during a cold, flavor is considerably diminished, while tastes are still perceived. In addition, the somatosensory system – detecting sensations of temperature, pain and texture – is also involved when eating mint or chili for example. Although generally included in the broader definition of taste, these sensations are perceived by different systems. In this thesis, I will use the strict definition of taste which involves the gustatory system for the perception of sweet, bitter, umami, salty and sour.
Taste sensation is mediated by taste receptor cells (TRCs) located in taste buds, themselves organized in papillae (see figure 5). Taste buds are embedded in the stratified tongue epithelium and are open to the oral cavity via a small opening in the tongue epithelium, called taste pore. Taste buds are pseudostratified and consist in several cell types: mature polarized elongated cells of type I, II & III as well as basal cells (Roper 2006). Basal cells are nonpolarized, presumably undifferentiated, whose function is supposed to be the regulation of the turnover of taste receptor cells.
Type I cells are presumed to have a role in terminating synaptic transmission and restricting the spread of transmitters and may also transduce salt taste perception (Vandenbeuch et al. 2008). Type II cells can perceive sweet, umami and bitter, each cell expresses only receptors dedicated to one taste. Type III cells, or presynaptic cells, are characterized by clear synaptic contacts with gustatory nerve fibers and therefore are thought to be responsible for information transmission to the nervous system. Type III cells also respond to sour taste stimuli and could be the receptor cells for sour taste (Chandrashekar et al. 2006; Huang et al. 2006). It is currently accepted that each cell type is tuned to detect one taste each.
Four types of papillae can be distinguished by their shape and structure: fungiform, foliate, circumvallate and filiform (Figure 5). The latter are found all over the tongue but do not contain any taste bud and therefore are not thought to be directly involved in taste perception but to have a mechanical function. The three other type of papillae do contain taste buds: fungiform papillae are located in the anterior two-third of the dorsal surface of the tongue and contain one or two taste buds, foliate papillae are on the lateral edge of the tongue and consist in up to hundreds of taste buds, last, circumvallate papillae are found at the extreme back of the tongue and contain up to thousands of taste buds. Several nerves innervate the taste papillae. Fungiform papillae and anterior foliate papillae are innervated by the facial nerve, posterior foliate papillae and circumvallate papillae are innervated by the glossopharyngeal nerve.

The human genome and genetic diversity

The human nuclear genome is distributed among 22 pairs of autosomes, common to all humans and one pair of sex chromosomes, women carrying two copies of the X chromosome and men one copy of the X and one copy of the Y chromosome. Each nucleus contains one copy of the nuclear genome. The mitochondrial genome (~16.5kb) is found in mitochondria which exist in many copies in each cell. The Y chromosome is transmitted from father to sons while mitochondria are found in everyone but only transmitted from the mother to children.
In 2001, the International Human Genome Consortium released the major parts of the human genome (Lander et al. 2001). This has been a milestone for understanding human genetics, gene functions as well as human history. This reference human genome has been obtained from several individuals and its assembly is constantly improved. The haploid genome size is approximately 3.2 gigabases. The human genome differs at some loci among individuals and it is estimated that on average there is a SNP every 1250 base pair.
The structure of the human genome has been extensively studied but is still not completely understood. We can distinguish two types of sequences, the coding part (less than 2% of the genome, containing information for the generation of proteins) and the non-coding part. The estimated number of coding genes by the ENCODE consortium is between 20.000 to 25.000 (Birney et al. 2007). Human genes are highly variable in their structure and size but they usually consist in introns (non-coding) and exons (translated into proteins), with a promoter sequence, as well as enhancer sequences for the transcription. Out of these, only exons belong to the coding part of the genome.
The non-coding part of the genome can be divided into several categories: pseudogenes, genes for non-coding RNA, introns and untranslated regions of mRNA, regulatory regions (up to 40% of the genome (Stamatoyannopoulos 2012)), repetitive DNA sequences and mobile genetic elements (transposons and relics).
Together with the human genome project, many online tools have been developed for browsing the genome and describing gene functions. The UCSC (Kent et al. 2002) and Ensembl (Hubbard et al. 2002) genome browsers allow users to browse the genome for regions of interest. Other databases such as Gene Ontology (Ashburner et al. 2000; Gene Ontology Consortium 2015) and KEGG (Kyoto Encyclopedia of Genes and Genomes) (Kanehisa and Goto 2000) aim at classifying genes in functional sets. The PANTHER (Nikolsky and Bryant 2009) database classifies protein-coding genes into 29 functions that I display in figure 6. This classification gives an idea of the major functions and their relative importance in the genome in terms of the percentage of genes from the total number of genes in the database contained in each category. The first category is nucleic acid binding, revealing the importance of DNA handling, second comes receptors followed by transcription factors, several enzymes and signaling molecules. The “defense/immunity protein” category comes at the 11th place.

Enrichment analysis applied to genetic data

Today, human genetic studies can produce large amounts of data that can be complex to make sense of. For example, the number of candidate loci identified in genome scans or association studies is typically large and difficult to assess. Moreover, the large amount of genetic variants in the data, generate considerable multiple testing issues.
The motivation behind enrichment analysis is to test whether it is possible to see patterns in high dimensional data. For example, scans of selection or association can be interpreted in a functional way (Huang et al. 2009). The basic idea is to test whether a gene or a set of genes contains a greater fraction of extreme values than expected by chance. A set of genes is usually a list of genes put together because of their involvement in a functional or metabolic pathway. Another advantage of enrichment analysis is to give more weight to not very strong signals. For example, p-values at 0.01 are not significant in a genome-wide scan considering millions of variants, but they can reflect small effects that are scattered over a whole set of genes. In that case, their distribution among gene-sets becomes informative.
Many databases have been developed to group the knowledge about genes. UCSC genome browser, Ensembl and PANTHER have already been mentioned. The Gene Ontology database (Gene Ontology Consortium 2015) and the KEGG encyclopedia (Kanehisa and Goto 2000) can be used as gene-set databases for enrichment analysis. The reason for this is that they group genes together with regard to their function or involvement in biological processes.

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Psycho-physiological tests for taste perception

Psycho-physiological tests are non-invasive ways to study the response of a person to stimuli in order to better understand cognitive processes such as taste perception.
There are different concepts in taste perception: “taste sensation” is a taste stimuli, “taste acuity” (or taste sensitivity) is the ability of a person to detect a taste, “taste intensity” is how intense a person judges a taste sensation, and “hedonic sensation” is how a person experiences (liking/disliking) a taste sensation.
Because the overall taste experience is actually a combination of gustatory, olfactory and visual stimuli, the study of taste perception in its strict sense is usually reduced to the dissolution of non-odorant and invisible compounds in water. In this thesis, taste acuity was studied, as it is believed to be the least influenced by judgement and potentially closest to reflecting the determinism of taste perception. Taste acuity is evaluated using measurement of a taste threshold: the minimum concentration at which a taste is perceived. To do this, tests are developed in which a participant is asked to taste solutions of single compounds dissolved in water with increasing concentration (staircase method).
In this thesis, a field-adapted test was performed as follows:
• Participants are informed that they might encounter tastes like water, salty, sour, sweet, bitter and umami (described as savory, meaty, or bouillon taste).
• Participants are semi-blindly (the tester knows the order) given to taste solutions with increasing concentrations of a pure compound dissolved in water. After tasting each solution, they express the taste they perceived and are asked to rinse their mouth with the water used for the test.
• Once participants clearly determine the actual taste of the solution for two consecutive concentration, the threshold is set as the least concentrated of the two.
This test is adapted to field conditions, mainly for time constraints. There are some caveats to this method. The first is that the test is not repeated although answers to the test of a same person might vary when the same test is duplicated. The second is the water used for the dissolutions. For taste psycho-physiological tests, the usage of the least mineral-rich water is recommended in order not to influence the answer of the participants. Under field conditions, the access to ideal water is often not possible. In these cases, we used filtered-water from local sources (in small villages with little access to shops) or bottles (in cities), for all individuals of the same sample group. Although the water we used might have a higher mineral content than the recommended waters, they usually have the neutrality of the every-day water consumption.

Detecting local adaptation in Humans (Paper II, III and IV)

Human populations have peopled and adapted to almost all terrestrial environments. The understanding of the genetic basis of local adaptation in human populations is a key topic in human population genetics. Although local adaptation is intensively studied, it is still poorly understood. This is probably due to methodological reasons, since most of the methods aim at detecting hard sweeps, but also to the so far uneven sampling of human populations around the world.
In paper II, we specifically looked for regions in the HapMap III data where a specific population show a signal of high frequency private haplotype using MFPH, and where other statistics do not show a strong signal (table 4). Interestingly, on chromosome 3 we found a region potentially selected in Maasai between 50.6Mb and 51.3 Mb previously shown to be linked to height (Jarvis et al. 2012). Also potentially selected in Maasai, the region containing the gene IMPG2 coding for an interphotoreceptor proteoglycan that has been associated with retinopathy (Simo-Servat et al. 2013) and potentially have been selected in Maasai in response to a high solar exposure probably damaging to the eyes.

Taste perception and lifestyle (Paper IV)

Taste is important for dietary choices, as it helps to select beneficial foods and avoid harmful ones. Lifestyle and environment have a strong impact on the availability of different foods and for this reason, taste might have been under various selection pressures in human populations. In paper IV, I present the results of taste sensitivity phenotypes together with genotype data from four populations differing in lifestyle and environmental diversity from Cameroon and Uzbekistan. I contrasted Baka hunter-gatherers and Nzime farmers living in the Cameroonian rainforest as well as nomad-herders of Kazak origin (referred to as Kazaks) and farmers of the Tajik-speaking area of Uzbekistan (referred to as Tajiks).
I performed various association studies on taste phenotypes and confirmed previous knowledge about taste determinism of sensitivity to bitter-tasting compounds 6-n-propylthiouracil (PROP) and Quinine. We confirmed the association between haplotypes of the SNPs rs10246939 (Ile296Val), rs1726866 (Val262Ala) and rs713598 (Ala49Pro) in the TAS2R38 gene with variation in PROP perception. The signal was stronger in Uzbekistan than in Cameroon, and this is probably due to a higher genetic diversity in Cameroonian populations (Campbell et al. 2011; Robino et al. 2014). In both areas, the PAV (Pro-Ala-Val) haplotype is dominant and confers hypersensitivity to PROP. We also detected associations between several TAS2R genes previously shown to be associated with sensitivity to Quinine and also in vitro responsive to Quinine stimuli (Meyerhof et al. 2010; Reed et al. 2010).
Our results also suggest links between Gene Ontology terms (GO-term) and taste perception that were not previously reported (see table 5). GO-terms for rhombomere and kidney development appear to be associated with Fructose tasting. These GO-terms either contain genes previously shown to be involved in taste perception and food intake, or are linked with the development of the facial nerve necessary for the transport of taste stimuli to the brain. Moreover, the GO-term “stereocilium” is associated with the overall sensitivity (calculated across all taste phenotypes). Stereocilium is a microvilli structure potentially similar to the membrane structure of taste receptor cells. Apart from previously identified genes involved in bitter tasting, the GO-term “olfactory receptor activity” is associated with Quinine perception. Although no previous link has been made between olfactory receptors and bitter taste perception, some of these receptors are expressed in the oral cavity and could be responsive to taste stimuli as well. GO-terms related to the neurotransmitter norepinephrine are associated with salt perception. Finally, GO-terms related to localization to mitochondrion are associated with sucrose tasting.

Table of contents :

Origins of Homo sapiens
Out of Africa
Population structure in Africa
Peopling of Central Asia
Lifestyle transitions in Human history
Adaptation in modern Humans
Taste and diet
Mechanisms of taste perception in humans
Background and methods
Genetic variation
Evolutionary forces and equilibrium models
The human genome and genetic diversity
Detecting local adaptation in populations
Inferring human demography
Association studies
Enrichment analysis applied to genetic data
Psycho-physiological tests for taste perception
Research Aims
Results and discussion
Origins of modern humans (Paper I)
Methods for detecting local adaptation (Paper II)
Detecting local adaptation in Humans (Paper II, III and IV)
Taste perception and lifestyle (Paper IV)
Conclusions and future prospects
Svensk sammanfattning
Résumé en Français
Origines de l’Homme Moderne
Peuplement du globe et structure de population
Etude de l’adaptation locale
Goût et mode de vie
Conclusions générales


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