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Localization of a Gene for Bitter-Taste Perception to Human Chromosome 5p15

1999; Elsevier BV; Volume: 64; Issue: 5 Linguagem: Inglês

10.1086/302367

1537-6605

Danielle R. Reed, Elizabeth Nanthakumar, Michael North, Callum J. Bell, Linda M. Bartoshuk, R. Arlen Price,

Multisensory perception and integration

To the Editor: Some people perceive the taste of phenylthiocarbamide and its chemical relative propylthiouracil (PROP) as intensely bitter at low concentrations, whereas others are unable to detect them, even at high concentrations. This taste blindness is an inherited trait (Snyder Snyder, 1931Snyder LH Inherited taste deficiency.Science. 1931; 74: 151-152Crossref PubMed Scopus (94) Google Scholar). Although inheritance is thought to be recessive, other possibilities have been suggested, such as multiple genes (Boyd Boyd, 1950Boyd WC Genetics and the races of man: an introduction to modern physical anthropology. Little Brown, Boston1950Google Scholar; Olson et al. Olson et al., 1989Olson JM Boehnke M Neiswanger K Roche AF Siervogel RM Alternative genetic models for the inheritance of the phenylthiocarbamide taste deficiency.Genet Epidemiol. 1989; 6: 423-434Crossref PubMed Scopus (67) Google Scholar), incomplete dominance (Johnson et al. Johnson et al., 1966Johnson FE Hertzog KP Malina RM Phenylthiocarbamide taste sensitivity and its relationship to growth variation.Am J Phys Anthrop. 1966; 24: 253-256Crossref PubMed Scopus (18) Google Scholar; Bartoshuk et al. Bartoshuk et al., 1994Bartoshuk LM Duffy VB Miller IJ PTC/PROP tasting: anatomy, psychophysics, and sex effects.Physiol Behav. 1994; 56 (Erratum [1995] Physiol Behav 58:203): 1165-1171Crossref PubMed Scopus (576) Google Scholar; Reed et al. Reed et al., 1995Reed DR Bartoshuk LM Duffy V Marino S Price RA Propylthiouracil tasting: determination of underlying threshold distributions using maximum likelihood.Chem Senses. 1995; 20: 529-533Crossref PubMed Scopus (55) Google Scholar), or multiple alleles of a single gene (Rychkov and Borodina Rychkov and Borodina, 1973Rychkov YG Borodina SR Further investigations of the genetics of hypersensitivity to phenylthiocarbamide in man (experimental, population, and familial data).Genetika. 1973; 9: 141-152Google Scholar). This trait is among the most-studied in human genetics, but the relevant gene has not been characterized. Therefore, we conducted a genomewide scan by using 98 nuclear families and 356 markers spaced at ∼10-cM intervals. Three hundred ninety-three adults and their parents participated as research subjects. The 98 families were originally recruited as part of an ongoing study of the genetics of body weight at the University of Pennsylvania's Behavioral Genetics Laboratory, and the details of family collection have been published elsewhere (Price et al. Price et al., 1998Price RA Reed DR Lee JH Obesity related phenotypes in families selected for extreme obesity and leanness.Int J Obes Relat Metab Disord. 1998; 22: 406-413Crossref PubMed Scopus (28) Google Scholar). The protocol was approved by the Committee of Studies Involving Human Beings at the University of Pennsylvania. To phenotype the subjects, filter paper was soaked in a saturated PROP solution, dried, and cut into strips. Subjects were asked to place the paper in their mouths and to rate the bitterness of taste. The scale used by the subjects to rate the taste intensity utilized descriptive words and is referred to as a "labeled-magnitude scale" (LMS; Green et al. Green et al., 1993Green BG Shaffer GS Gilmore M Derivation and evaluation of a semantic scale of oral sensation magnitude with apparent ratio properties.Chem Senses. 1993; 18: 683-702Crossref Scopus (463) Google Scholar). Because the LMS is continuous, it prevents the loss of information associated with categoric scales and therefore provides the type of data essential for quantitative linkage analysis. In addition, the LMS minimizes ceiling effects and is better at discriminating sensitive tasters from nontasters than the classic nine-point scale (Lucchina et al. 1998b). The scale is labeled as follows (with numeric values assigned to each level of taste intensity): barely detectable (0), weak (6), moderate (17), strong (35), very strong (54), and strongest imaginable (100). The scores from the LMS were used as phenotypes for the quantitative linkage analysis. The LMS is also a valid instrument to classify individuals as "nontasters" or "tasters." Studies scaling the suprathreshold bitterness of PROP with magnitude estimation demonstrate that psychophysical functions for nontasters and tasters diverge (Bartoshuk et al. Bartoshuk et al., 1994Bartoshuk LM Duffy VB Miller IJ PTC/PROP tasting: anatomy, psychophysics, and sex effects.Physiol Behav. 1994; 56 (Erratum [1995] Physiol Behav 58:203): 1165-1171Crossref PubMed Scopus (576) Google Scholar). The LMS produces suprathreshold functions equivalent to magnitude estimation (Green et al. Green et al., 1996Green B Dalton P Cowart B Rankin K Higgins J Evaluating the labeled magnitude scale for measuring sensations of taste and smell.Chem Senses. 1996; 21: 323-334Crossref PubMed Scopus (561) Google Scholar). Because the LMS is easier for naïve subjects to use, it is replacing magnitude estimation in studies of PROP (Snyder et al. Snyder et al., 1996Snyder D Lucchina L Duffy V Bartoshuk L Magnitude matching adds power to the labeled magnitude scale.Chem Senses. 1996; 21: 673Google Scholar; Intranuova and Powers Intranuova and Powers, 1998Intranuova L Powers A The perceived bitterness of beer and 6-n-propylthiouracil (PROP) and taste sensitivity.Ann NY Acad Sci. 1998; 855 (In: Murphy C (ed) Olfaction and taste.): 816-819Crossref PubMed Scopus (50) Google Scholar; Lucchina et al. Lucchina et al., 1998aLucchina L Curtis O Putnam P Bartoshuk L 6-n-propylthiouracil (PROP) tasters assign higher sweetness ratings to sucrose and high-intensity sweetners.Chem Senses. 1998a; 23: 560Google ScholarLucchina et al., 1998bLucchina LA Curtis OF Putnam P Drewnowski A Prutkin J Bartoshuk LM Psychophysical measurement of 6-n-propylthiouracil (PROP) taste perception..Ann NY Acad Sci. 1998b; 855 (In: Murphy C (ed) Olfaction and taste.): 816-819Crossref PubMed Google Scholar; Schwartz et al. Schwartz et al., 1998Schwartz S Janjua T Kveton J Green B Bartoshuk L Alteration in lingual somatosensation as a result of transection of the chorda tympani nerve (VII).Chem Senses. 1998; 23: 560Google Scholar; Prutkin et al., Prutkin et al., in pressPrutkin J, Fast K, Lucchina L, Bartoshuk L PROP (6-n-propylthiouracil) genetics and trigeminal innervation of fungiform papillae. Chem Senses (in press)Google Scholar). Thus, the LMS provides a convenient, reliable, and reasonable choice for a large-scale gene-mapping study. The mean rating of suprathreshold taste intensity was 31.2 ± 29.3 units, near the label "strong." As expected, the distribution of scores was kurtotic (−0.454) and skewed (.73). There was no relationship between subjects' ratings of PROP and height, weight, or body-mass index (P>.05). We genotyped microsatellite markers spaced ∼10.1 cM apart by using methods described by Lee et al. (Lee et al., 1999Lee JH Reed DR Li W-D Xu W Joo E-J Kilker RL Nanthakumar E et al.Genome scan for human obesity and linkage to markers in 20q13.Am J Hum Genet. 1999; 64: 1063-1070Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). All half-siblings were eliminated prior to analysis. Computation of descriptive statistics and correlation coefficients were conducted with SPSS (6.1.1.). Quantitative trait loci analysis was conducted with the computer program MAPMAKER/SIBS version 2.0 (Kruglyak and Lander Kruglyak and Lander, 1995Kruglyak L Lander E Complete multipoint sib-pair analysis of qualitative and quantitative traits.Am J Hum Genet. 1995; 54: 439-454Google Scholar). For analysis of transmission disequilibrium, the quantitative data were dichotomized into taster and nontaster categories, with all tasters reporting that suprathreshold concentrations of PROP tasted "strong," "extremely strong," or "strongest imaginable" (n=180; 45.8%). Nontasters rated PROP as "barely detectable" or "weak" (n=115; 29.3%). Subjects giving intermediate responses were excluded from analysis (n=98; 25%). These cut-off values are conservative. Transmission of alleles from heterozygous parents to nontaster offspring was computed with TDTLIKE version 2.1 (Terwilliger Terwilliger, 1995Terwilliger J A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci.Am J Hum Genet. 1995; 56: 777-787PubMed Google Scholar), which corrects for multiple-allele testing. The telomeric portion of 5p gave the strongest evidence for linkage (t-score = 3.28, P=.0005; fig. 1), with the peak score near D5S2505. The linkage peak spanned ∼10 cM, from D5S406 to D5S2081, and was the only region of the genome that had a t score ⩾ 3.0. No candidate genes are apparent in 5p15. Markers from the telomeric portion of chromosome 5 were then examined for transmission disequilibrium. There was significant distortion in transmission of alleles from heterozygous parents to nontaster children for markers from the linked region, with D5S2505 being the most significant (D5S406, P=.031; D5S2505, P=.007, D5S635, P=.017; D5S807, P=.034; D5S2081, P=.012). These results are consistent with the hypothesis that a gene that confers the ability to taste PROP lies on the telomeric region of human chromosome 5p. In addition to chromosome 5, there was a suggestion of linkage on chromosome 7, ∼35–40 cM centromeric to the KELL locus, with a maximum t-score of 2.34 (P=.008) near D7S1789 and D7S796. Initial linkage studies suggested a locus was near KELL on chromosome 7 (Chautard-Freire-Maia Chautard-Freire-Maia, 1974Chautard-Freire-Maia EA Linkage relationships between 22 autosomal markers.Ann Hum Genet. 1974; 38: 191-198Crossref PubMed Scopus (20) Google Scholar; Conneally et al. Conneally et al., 1976Conneally PM Dumont-Driscoll M Huntzinger RS Nance WE Jackson CE Linkage relations of the loci for Kell and phenylthiocarbamide taste sensitivity.Hum Hered. 1976; 26: 267-271Crossref PubMed Scopus (32) Google Scholar), but later reports were unable to replicate this finding (Spence et al. Spence et al., 1984Spence MA Falk CT Neiswanger K Field LL Marazita ML Allen Jr, FH Siervogel RM et al.Estimating the recombination frequency for the PTC-Kell linkage.Hum Genet. 1984; 67: 183-186Crossref PubMed Scopus (11) Google Scholar). The results of the current study suggest that a region on chromosome 7 may also influence the taster phenotype. The present work was supported by National Institutes of Health (NIH) grant R03DC03509 (to D.R.R).; NIH grants R01DK44073, R01DK48095, and funds from Axys Pharmaceuticals and Glaxo-Wellcome (to R.A.P.); and NIH grants 5M01RR00125-350922, 5R01DC00283, and 5R21DC03003 to (L.M.B.). We acknowledge the generous cooperation of participating families. We thank Robin L. Kilker, Wei-Dong Li, Andrew C. Krakowski, Guang Ming Yuan, Christa L. Alberry Mayr, Elizabeth Joe, Kruti Quazi, Karynn Henry, Paula Kwon, Samantha J. Weisberg, Balasahib G. Shinde, Robert Brian Chin, Cassandra George, Nicole Baker, and Adam S. Crystal for technical assistance and Joseph H. Lee for statistical advice.