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Bitter taste receptors (TAS2Rs) are noted for their role in perception, and mounting evidence suggests that they mediate responses to compounds entering airways, gut, and other tissues. The importance of these roles suggests that TAS2Rs have been under pressure from natural selection. To determine the extent of variation in TAS2Rs on a global scale and its implications for human evolution and behavior, we analyzed patterns of diversity in the complete 25 gene repertoire of human TAS2Rs in â¼2,500 subjects representing worldwide populations. Across the TAS2R family as a whole, we observed 721 single nucleotide polymorphisms (SNPs) including 494 nonsynonymous SNPs along with 40 indels and gained and lost start and stop codons. In addition, computational predictions identified 169 variants particularly likely to affect receptor function, making them candidate sources of phenotypic variation. Diversity levels ranged widely among loci, with the number of segregating sites ranging from 17 to 41 with a mean of 32 among genes and per nucleotide heterozygosity (π) ranging from 0.02% to 0.36% with a mean of 0.12%. F ST ranged from 0.01 to 0.26 with a mean of 0.13, pointing to modest differentiation among populations. Comparisons of observed π and F ST values with their genome wide distributions revealed that most fell between the 5th and 95th percentiles and were thus consistent with expectations. Further, tests for natural selection using Tajima's D statistic revealed only two loci departing from expectations given D's genome wide distribution. These patterns are consistent with an overall relaxation of selective pressure on TAS2Rs in the course of recent human evolution.
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CD36 and GNAT3 mediate taste responses, with CD36 acting as a lipid detector and GNAT3 acting as the α subunit of gustducin, a G protein governing sweet, savory, and bitter transduction. Strikingly, the genes encoding CD36 and GNAT3 are genomically superimposed, with CD36 completely encompassing GNAT3. To characterize genetic variation across the CD36-GNAT3 region, its implications for phenotypic diversity, and its recent evolution, we analyzed from ~2,500 worldwide subjects sequenced by the 1000 Genomes Project (1000GP). CD36-GNAT3 harbored extensive diversity including 8,688 single-nucleotide polymorphisms (SNPs), 414 indels, and other complex variants. Sliding window analyses revealed that nucleotide diversity and population differentiation across CD36-GNAT3 were consistent with genome-wide trends in the 1000GP (π = 0.10%, P = 0.64; FST = 9.0%, P = 0.57). In addition, functional predictions using SIFT and PolyPhen-2 identified 60 variants likely to alter protein function, and they were in weak linkage disequilibrium (r2 < 0.17), suggesting their effects are largely independent. However, the frequencies of predicted functional variants were low (P¯ = 0.0013), indicating their contributions to phenotypic variance on population scales are limited. Tests using Tajima's D statistic revealed that pressures from natural selection have been relaxed across most of CD36-GNAT3 during its recent history (0.39 < P < 0.67). However, CD36 exons showed signs of local adaptation consistent with prior reports (P < 0.035). Thus, CD36 and GNAT3 harbor numerous variants predicted to affect taste sensitivity, but most are rare and phenotypic variance on a population level is likely mediated by a small number of sites.
Assuntos
Seleção Genética , Paladar , Antígenos CD36 , Proteínas Heterotriméricas de Ligação ao GTP , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Bitter taste perception plays vital roles in animal behavior and fitness. By signaling the presence of toxins in foods, particularly noxious defense compounds found in plants, it enables animals to avoid exposure. In vertebrates, bitter perception is initiated by TAS2Rs, a family of G protein-coupled receptors expressed on the surface of taste buds. There, oriented toward the interior of the mouth, they monitor the contents of foods, drinks and other substances as they are ingested. When bitter compounds are encountered, TAS2Rs respond by triggering neural pathways leading to sensation. The importance of this role placed TAS2Rs under selective pressures in the course of their evolution, leaving signatures in patterns of gene gain and loss, sequence polymorphism, and population structure consistent with vertebrates' diverse feeding ecologies. The protective value of bitter taste is reduced in modern humans because contemporary food supplies are safe and abundant. However, this is not always the case. Some crops, particularly in the developing world, retain surprisingly high toxicity and bitterness remains an important measure of safety. Bitter perception also shapes health through its influence on preference driven behaviors such as diet choice, alcohol intake and tobacco use. Further, allelic variation in TAS2Rs is extensive, leading to individual differences in taste sensitivity that drive these behaviors, shaping susceptibility to disease. Thus, bitter taste perception occupies a critical intersection between ancient evolutionary processes and modern human health.
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In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies.
Assuntos
Negro ou Afro-Americano/genética , Fumar Cigarros/genética , Haplótipos/genética , Mentol , Receptores Acoplados a Proteínas G/genética , Adulto , Estudos de Coortes , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Nicotiana/efeitos adversosRESUMO
The traditional description of "the scientific method" as a stepwise, linear process of hypothesis testing through experimentation is a myth. Although the teaching and learning of the scientific method have been a curriculum and assessment goal, the notion of the 'scientific method' itself has been identified as being problematic. Many researchers have recognised there is no single scientific method. However, there does not seem to be any useful guidelines for how best to deal with the nature of scientific methods in school science, including in high-stakes summative assessment. The article presents the use of a framework to illustrate the diversity of scientific methods that goes beyond the traditional limitations of a scientific method, to provide a more comprehensive and inclusive account, including non-manipulative parameter measurements. The framework not only clarifies the definition of scientific methods but also is adapted as an analytical framework to trace how scientific methods are framed in high-stakes chemistry examination papers from three examination boards in England. Such analyses can potentially point to what is emphasised in chemistry lessons, given how instrumental high-stakes testing is for driving teaching and learning. Results from an empirical investigation of examination questions are presented, highlighting an imbalance in the representation of methods in chemistry tests.
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Ability to perceive the bitter compound phenylthiocarbamide (PTC) is inherited via a dominant "taster" allele of the TAS2R38 gene, whereas inability is inherited via a recessive "non-taster" allele. This raises a question: Is the non-taster allele functionless, or does it mediate perception of compounds other than PTC? New evidence supports speculation that it is indeed functional. Associations between TAS2R38 mutations and bitter sensitivity to the tropical berry Antidesma bunius are the inverse of those PTC, suggesting that the non-taster allele enables perception to compounds in the fruit.
Assuntos
Feniltioureia , Paladar , Frutas , Haplótipos , Receptores Acoplados a Proteínas G/genética , Percepção GustatóriaRESUMO
Common TAS2R38 taste receptor gene variants specify the ability to taste phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP) and structurally related compounds. Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Accordingly, it has been suggested that non-taster individuals may be more likely to smoke because of their inability to taste bitter compounds present in tobacco smoke, but results to date have been conflicting. We studied three cohorts: 237 European-Americans from the state of Georgia, 1,353 European-Americans and 2,363 African-Americans from the Dallas Heart Study (DHS), and 4,973 African-Americans from the Dallas Biobank. Tobacco use data was collected and TAS2R38 polymorphisms were genotyped for all participants, and PTC taste sensitivity was assessed in the Georgia population. In the Georgia group, PTC tasters were less common among those who smoke: 71.5% of smokers were PTC tasters while 82.5% of non-smokers were PTC tasters (P = 0.03). The frequency of the TAS2R38 PAV taster haplotype showed a trend toward being lower in smokers (38.4%) than in non-smokers (43.1%), although this was not statistically significant (P = 0.31). In the DHS European-Americans, the taster haplotype was less common in smokers (37.0% vs. 44.0% in non-smokers, P = 0.003), and conversely the frequency of the non-taster haplotype was more common in smokers (58.7% vs. 51.5% in non-smokers, P = 0.002). No difference in the frequency of these haplotypes was observed in African Americans in either the Dallas Heart Study or the Dallas Biobank. We conclude that TAS2R38 haplotypes are associated with smoking status in European-Americans but not in African-American populations. PTC taster status may play a role in protecting individuals from cigarette smoking in specific populations.
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Variação Genética , Receptores Acoplados a Proteínas G/genética , Fumar/genética , Percepção Gustatória/genética , Adulto , Negro ou Afro-Americano/genética , Estudos de Coortes , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioureia/farmacologia , Percepção Gustatória/efeitos dos fármacos , Produtos do Tabaco , População Branca/genética , Adulto JovemRESUMO
Bitter taste receptor genes (TAS2Rs) harbor extensive diversity, which is broadly distributed across human populations and strongly associated with taste response phenotypes. The majority of TAS2R variation is composed of single-nucleotide polymorphisms. However, 2 closely positioned loci at 12p13, TAS2R43 and -45, harbor high-frequency deletion (Δ) alleles in which genomic segments are absent, resulting in copy number variation (CNV). To resolve their chromosomal structure and organization, we generated maps using long-range contig alignments and local sequencing across the TAS2R43-45 region. These revealed that the deletion alleles (43Δ and 45Δ) are 37.8 and 32.2kb in length, respectively and span the complete coding region of each gene (~1kb) along with extensive up- and downstream flanking sequence, producing separate CNVs at the 2 loci. Comparisons with a chimpanzee genome, which contained intact homologs of TAS2R43, -45, and nearby TAS2Rs, indicated that the deletions evolved recently, through unequal recombination in a cluster of closely related loci. Population genetic analyses in 946 subjects from 52 worldwide populations revealed that copy number ranged from 0 to 2 at both TAS2R43 and TAS2R45, with 43Δ and 45Δ occurring at high global frequencies (0.33 and 0.18). Estimated recombination rates between the loci were low (ρ = 2.7×10(-4); r = 6.6×10(-9)) and linkage disequilibrium was high (D' = 1.0), consistent with their adjacent genomic positioning and recent origin. Geographic variation pointed to an African origin for the deletions. However, no signatures of natural selection were found in population structure or integrated haplotype scores spanning the region, suggesting that patterns of diversity at TAS2R43 and -45 are primarily due to genetic drift.
Assuntos
Variações do Número de Cópias de DNA/genética , Genética Populacional , Receptores Acoplados a Proteínas G/genética , Alelos , Sequência de Aminoácidos , Humanos , Alinhamento de Sequência , Paladar/genética , Percepção Gustatória/genéticaRESUMO
The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.
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Evolução Molecular , Receptores Acoplados a Proteínas G/genética , Seleção Genética/genética , Paladar/genética , Bases de Dados Genéticas , Variação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Feniltioureia/química , Propiltiouracila/químicaRESUMO
The ability to taste bitterness evolved to safeguard most animals, including humans, against potentially toxic substances, thereby leading to food rejection. Nonetheless, bitter perception is subject to individual variations due to the presence of genetic functional polymorphisms in bitter taste receptor (TAS2R) genes, such as the long-known association between genetic polymorphisms in TAS2R38 and bitter taste perception of phenylthiocarbamide. Yet, due to overlaps in specificities across receptors, such associations with a single TAS2R locus are uncommon. Therefore, to investigate more complex associations, we examined taste responses to six structurally diverse compounds (absinthin, amarogentin, cascarillin, grosheimin, quassin, and quinine) in a sample of the Caucasian population. By sequencing all bitter receptor loci, inferring long-range haplotypes, mapping their effects on phenotype variation, and characterizing functionally causal allelic variants, we deciphered at the molecular level how a subjects' genotype for the whole-family of TAS2R genes shapes variation in bitter taste perception. Within each haplotype block implicated in phenotypic variation, we provided evidence for at least one locus harboring functional polymorphic alleles, e.g. one locus for sensitivity to amarogentin, one of the most bitter natural compounds known, and two loci for sensitivity to grosheimin, one of the bitter compounds of artichoke. Our analyses revealed also, besides simple associations, complex associations of bitterness sensitivity across TAS2R loci. Indeed, even if several putative loci harbored both high- and low-sensitivity alleles, phenotypic variation depended on linkage between these alleles. When sensitive alleles for bitter compounds were maintained in the same linkage phase, genetically driven perceptual differences were obvious, e.g. for grosheimin. On the contrary, when sensitive alleles were in opposite phase, only weak genotype-phenotype associations were seen, e.g. for absinthin, the bitter principle of the beverage absinth. These findings illustrate the extent to which genetic influences on taste are complex, yet arise from both receptor activation patterns and linkage structure among receptor genes.
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Estudos de Associação Genética , Receptores Acoplados a Proteínas G/genética , Percepção Gustatória/genética , Alelos , Animais , Genótipo , Haplótipos , Humanos , Iridoides/química , Feniltioureia/química , Polimorfismo de Nucleotídeo Único , Quassinas/química , Quinina/química , Sesquiterpenos/química , Sesquiterpenos de Guaiano/química , Papilas Gustativas/metabolismo , População BrancaRESUMO
Mutations in odorant receptor genes predict olfactory perception of common compounds in foods and flowers. Through recombination they can generate extensive combinatorial variation in sensory ability among individuals.
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Preferências Alimentares , Variação Genética , Norisoprenoides/metabolismo , Odorantes/análise , Receptores Odorantes/genética , Olfato , Feminino , Humanos , MasculinoRESUMO
Mutational polymorphism in the TAS2R38 bitter taste receptor is a key determinant of threshold taste detection of isolated compounds, such as phenylthiocarbamide (PTC) and propylthiouracil (PROP), as well as complex orosensation-mediated traits such as diet choice and smoking habits. These relationships are accounted for, in part, by 2 common alleles differing in functionality, TAS2R38-PAV and TAS2R38-AVI. However, TAS2R38 harbors extensive additional polymorphism whose functional significance remains unknown. To examine this variation, we ascertained genetic diversity in 56 Caucasian subjects via whole-gene sequencing, analyzed allele-specific responses to 5 TAS2R38 agonists (PTC, PROP, goitrin, methimazole, and sinigrin) using in vitro assays, and assessed genotypic associations with threshold detection phenotypes. Sequencing identified 3 single-nucleotide substitutions encoding 3 amino acid changes (C145G/P49A, C785T/A262V, and A886G/I296V), which combined to form 6 haplotypes in our sample. In vitro assays revealed a continuous range of response across alleles, and associations with threshold were significant for all single nucleotide polymorphisms (P < 0.002) and PAV/AVI haplotypes (P < 0.001). Haplotypes other than PAV and AVI did not exhibit phenotypic associations in our sample, possibly as a result of their low frequencies. However, prior studies have indicated that these alleles are common in some global regions, suggesting that alleles rare in our sample may be phenotypically relevant in other populations.
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Variação Genética/genética , Fenótipo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Percepção Gustatória/genética , Adulto , Alelos , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas G/agonistasRESUMO
BACKGROUND: Balkan Endemic Nephropathy (BEN) is late-onset kidney disease thought to arise from chronic exposure to aristolochic acid, a phytotoxin that contaminates wheat supplies in rural areas of Eastern Europe. It has recently been demonstrated that humans are capable of perceiving aristolochic acid at concentrations below 40 nM as the result of high-affinity interactions with the TAS2R43 bitter taste receptor. Further, TAS2R43 harbors high-frequency loss-of-function mutations resulting in 50-fold variability in perception. This suggests that genetic variation in TAS2R43 might affect susceptibility to BEN, with individuals carrying functional forms of the receptor being protected by an ability to detect tainted foods. METHODS: To determine whether genetic variation in TAS2R43 predicts BEN susceptibility, we examined genotype-phenotype associations in a case-control study. A cohort of 88 affected and 99 control subjects from western Bulgaria were genotyped with respect to two key missense variants and a polymorphic whole-gene deletion of TAS2R43 (W35S, H212R, and wt/Δ), which are known to affect taste sensitivity to aristolochic acid. Tests for association between haplotypes and BEN status were then performed. RESULTS: Three major TAS2R43 haplotypes observed in previous studies (TAS2R43-W35/H212, -S35/R212 and -Δ) were present at high frequencies (0.17, 0.36, and 0.47 respectively) in our sample, and a significant association between genotype and BEN status was present (P = 0.020; odds ratio 1.18). However, contrary to expectation, BEN was positively associated with TAS2R43-W35/H212, a highly responsive allele previously shown to confer elevated bitter sensitivity to aristolochic acid, which should drive aversion but might also affect absorption, altering toxin activation. CONCLUSIONS: Our findings are at strong odds with the prediction that carriers of functional alleles of TAS2R43 are protected from BEN by an ability to detect and avoid aristolochic acid exposure. Evidence for a positive association between high-sensitivity alleles and BEN status suggests instead that possession of toxin-responsive receptor variants may paradoxically increase vulnerability, possibly by shifting attractive responses associated with low-intensity bitter sensations. The broad-spectrum tuning of the ~25-member TAS2R family as a whole toward xenobiotics points to a potentially far-reaching relevance of bitter responses to exposure-related disease in both individuals and populations.
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Nefropatia dos Bálcãs/genética , Receptores Acoplados a Proteínas G/genética , Idoso , Alelos , Ácidos Aristolóquicos/química , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Deleção de Genes , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Paladar/genéticaRESUMO
There are four tests--the likelihood ratio (LR) test, Wald's test, the score test and the exact test--commonly employed in genetic association studies. On comparison of the four tests, we found that Wald's test, popular in genome-wide screens due to its low computational demands, exhibited a paradoxical behaviour in that the test statistic decreased as the effect size of the variant increased, resulting in a loss of power. The LR test always achieved the most significant P-values, followed by the exact test. We further examined the results in a real data set composed of high- and low-cholesterol subjects from the Dallas Heart Study (DHS). We also compared the single-variant LR test with two multi-variant analysis approaches--the burden test and the C-alpha test--in analysing the sequencing data by simulation. Our results call for caution in using Wald's test in genome-wide case-control association studies and suggest that the LR test is a better alternative in spite of its computational demands.
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Estudos de Associação Genética/métodos , Doenças Raras/genética , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos de Validação como AssuntoRESUMO
Bitter taste perception is initiated by TAS2R receptors, which respond to agonists by triggering depolarization of taste bud cells. Mutations in TAS2Rs are known to affect taste phenotypes by altering receptor function. Evidence that TAS2Rs overlap in ligand specificity suggests that they may also contribute joint effects. To explore this aspect of gustation, we examined bitter perception of saccharin and acesulfame K, widely used artificial sweeteners with aversive aftertastes. Both substances are agonists of TAS2R31 and -43, which belong to a five-member subfamily (TAS2R30-46) responsive to a diverse constellation of compounds. We analyzed sequence variation and linkage structure in the â¼140 kb genomic region encoding TAS2R30-46, taste responses to the two sweeteners in subjects, and functional characteristics of receptor alleles. Whole-gene sequences from TAS2R30-46 in 60 Caucasian subjects revealed extensive diversity including 34 missense mutations, two nonsense mutations and high-frequency copy-number variants. Thirty markers, including non-synonymous variants in all five genes, were associated (P< 0.001) with responses to saccharin and acesulfame K. However, linkage disequilibrium (LD) in the region was high (D', r(2) > 0.95). Haplotype analyses revealed that most associations were spurious, arising from LD with variants in TAS2R31. In vitro assays confirmed the functional importance of four TAS2R31 mutations, which had independent effects on receptor response. The existence of high LD spanning functionally distinct TAS2R loci predicts that bitter taste responses to many compounds will be strongly correlated even when they are mediated by different genes. Integrative approaches combining phenotypic, genetic and functional analysis will be essential in dissecting these complex relationships.
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Receptores Acoplados a Proteínas G/genética , Sacarina/farmacologia , Edulcorantes/farmacologia , Percepção Gustatória/genética , Paladar/genética , Adulto , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Percepção Gustatória/efeitos dos fármacos , Adulto JovemRESUMO
Bitter taste receptors (TAS2Rs) enable animals to detect and avoid toxins in the environment, including noxious defense compounds produced by plants. This suggests that TAS2Rs are under complex pressures from natural selection. To investigate these pressures, we examined signatures of selection in the primate TAS2R38 gene. Whole-gene (1,002 bp) sequences from 40 species representing all major primate taxa uncovered extensive variation. Nucleotide substitutions occurred at 448 positions, resulting in 201 amino acid changes. Two single-nucleotide deletions, one three-nucleotide in-frame deletion, and one premature stop codon were also observed. The rate of non-synonymous substitution (ω = dN/dS), was high in TAS2R38 (ω = 0.60) compared to other genes, but significantly lower than expected under neutrality (P = 4.0 × 10(-9)), indicating that purifying selection has maintained the basic structure of the receptor. However, differences were present among receptor subregions. Non-synonymous rates were significantly lower than expected in transmembrane domains (ω = 0.55, P = 1.18 × 10(-12)) and internal loops (ω = 0.51, P = 7.04 × 10(-5)), but not external loops (ω = 1.16, P = 0.53), and evidence of positive selection was found in external loop 2, which exhibited a high rate (ω = 2.53) consistent with rapid shifts in ligand targeting. These patterns point to a history of rapid yet constrained change in bitter taste responses in the course of primate evolution.
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Evolução Molecular , Primatas/genética , Receptores Acoplados a Proteínas G/genética , Seleção Genética , Paladar/genética , Substituição de Aminoácidos , Animais , Humanos , Filogenia , Estrutura Terciária de Proteína/genética , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, yet it is still unclear how population bottlenecks, admixture, or positive selection contribute to its genetic structure. Here we analyzed a large AJ cohort and found higher linkage disequilibrium (LD) and identity-by-descent relative to Europeans, as expected for an isolate. However, paradoxically we also found higher genetic diversity, a sign of an older or more admixed population but not of a long-term isolate. Recent reports have reaffirmed that the AJ population has a common Middle Eastern origin with other Jewish Diaspora populations, but also suggest that the AJ population, compared with other Jews, has had the most European admixture. Our analysis indeed revealed higher European admixture than predicted from previous Y-chromosome analyses. Moreover, we also show that admixture directly correlates with high LD, suggesting that admixture has increased both genetic diversity and LD in the AJ population. Additionally, we applied extended haplotype tests to determine whether positive selection can account for the level of AJ-prevalent diseases. We identified genomic regions under selection that account for lactose and alcohol tolerance, and although we found evidence for positive selection at some AJ-prevalent disease loci, the higher incidence of the majority of these diseases is likely the result of genetic drift following a bottleneck. Thus, the AJ population shows evidence of past founding events; however, admixture and selection have also strongly influenced its current genetic makeup.
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Genética Populacional , Judeus/genética , Seleção Genética , Cromossomos Humanos , Variação Genética , Humanos , Desequilíbrio de LigaçãoRESUMO
The perceived bitterness of cruciferous vegetables such as broccoli varies from person to person, but the functional underpinnings of this variation are not known. Some evidence suggests that it arises, in part, from variation in ability to perceive goitrin (5-vinyloxazolidine-2-thione), a potent antithyroid compound found naturally in crucifers. Individuals vary in ability to perceive synthetic compounds similar to goitrin, such as 6-propyl-2-thiouracil (PROP) and phenylthiocarbamide (PTC), as the result of mutations in the TAS2R38 gene, which encodes a bitter taste receptor. This suggests that taste responses to goitrin itself may be mediated by TAS2R38. To test this hypothesis, we examined the relationships between genetic variation in TAS2R38, functional variation in the encoded receptor, and threshold taste responses to goitrin, PROP, and PTC in 50 subjects. We found that threshold responses to goitrin were associated with responses to both PROP (P = 8.9 x 10(-4); r(s) = 0.46) and PTC (P = 7.5 x 10(-4); r(s) = 0.46). However, functional assays revealed that goitrin elicits a weaker response from the sensitive (PAV) allele of TAS2R38 (EC(50) = 65.0 µM) than do either PROP (EC(50) = 2.1 µM) or PTC (EC(50) = 1.1 µM) and no response at all from the insensitive (AVI) allele. Furthermore, goitrin responses were significantly associated with mutations in TAS2R38 (P = 9.3 × 10(-3)), but the same mutations accounted for a smaller proportion of variance in goitrin response (r(2) = 0.16) than for PROP (r(2) = 0.50) and PTC (r(2) = 0.57). These findings suggest that mutations in TAS2R38 play a role in shaping goitrin perception, but the majority of variance must be explained by other factors.
Assuntos
Oxazolidinonas/farmacologia , Paladar/fisiologia , Alelos , Genótipo , Humanos , Fenótipo , Feniltioureia/farmacologia , Polimorfismo de Nucleotídeo Único , Propiltiouracila/farmacologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Limiar Gustativo/fisiologiaRESUMO
Previous studies have found that at most human loci, ancestral alleles are "African," in the sense that they reach their highest frequency there. Conventional wisdom holds that this reflects a recent African origin of modern humans. This paper challenges that view by showing that the empirical pattern (of elevated allele frequencies within Africa) is not as pervasive as has been thought. We confirm this African bias in a set of mainly protein-coding loci, but find a smaller bias in Alu insertion polymorphisms, and an even smaller bias in noncoding loci. Thus, the strong bias that was originally observed must reflect some factor that varies among data sets--something other than population history. This factor may be the per-locus mutation rate: the African bias is most pronounced in loci where this rate is high. The distribution of ancestral alleles among populations has been studied using 2 methods. One of these involves comparing the fractions of loci that reach maximal frequency in each population. The other compares the average frequencies of ancestral alleles. The first of these methods reflects history in a manner that depends on the mutation rate. When that rate is high, ancestral alleles at most loci reach their highest frequency in the ancestral population. When that rate is low, the reverse is true. The other method--comparing averages--is unresponsive. Average ancestral allele frequencies are affected neither by mutation rate nor by the history of population size and migration. In the absence of selection and ascertainment bias, they should be the same everywhere. This is true of one data set, but not of 2 others. This also suggests the action of some factor, such as selection or ascertainment bias, that varies among data sets.