Search PubMed⌕ Search

Biomedical subjects

Dennis Drayna

Publications and source records attributed to Dennis Drayna.

13 recordsLinked to original sources
PubMed2006

Variation in the human TAS1R taste receptor genes.

We have performed a comprehensive evaluation of single-nucleotide polymorphisms (SNPs) and haplotypes in the human TAS1R gene family, which encodes receptors for sweet and umami tastes. Complete DNA sequences of TAS1R1-, TAS1R2-, and TAS1R3-coding regions, obtained from 88 individuals of African, Asian, European, and Native American origin, revealed substantial coding and noncoding diversity: polymorphisms are common in these genes, and polymorphic sites and SNP frequencies vary widely in human populations. The genes TAS1R1 and TAS1R3, which encode proteins that act as a dimer to form the umami (glutamate) taste receptor, showed less variation than the TAS1R2 gene, which acts as a dimer with TAS1R3 to form the sweet taste receptor. The TAS1R3 gene, which encodes a subunit common to both the sweet and umami receptors, was the most conserved. Evolutionary genetic analysis indicates that these variants have come to their current frequencies under natural selection during population growth and support the view that the coding sequence variants affect receptor function. We propose that human populations likely vary little with respect to umami perception, which is controlled by one major form of the receptor that is optimized for detecting glutamate but may vary much more with respect to sweet perception.

DNA↗
PubMed2006

Modeling the human PTC bitter-taste receptor interactions with bitter tastants.

We employed the first principles computational method MembStruk and homology modeling techniques to predict the 3D structures of the human phenylthiocarbamide (PTC) taste receptor. This protein is a seven-transmembrane-domain G protein-coupled receptor that exists in two main forms worldwide, designated taster and nontaster, which differ from each other at three amino-acid positions. 3D models were generated with and without structural similarity comparison to bovine rhodopsin. We used computational tools (HierDock and ScanBindSite) to generate models of the receptor bound to PTC ligand to estimate binding sites and binding energies. In these models, PTC binds at a site distant from the variant amino acids, and PTC binding energy was equivalent for both the taster and nontaster forms of the protein. These models suggest that the inability of humans to taste PTC is due to a failure of G protein activation rather than decreased binding affinity of the receptor for PTC. Amino-acid substitutions in the sixth and seventh transmembrane domains of the nontaster form of the protein may produce increased steric hindrance between these two alpha-helices and reduce the motion of the sixth helix required for G protein activation.

Amino Acid Substitution↗
PubMed2005

The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.

Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis . A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types . We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) . Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals.

Animals↗
PubMed2005

Genomewide significant linkage to stuttering on chromosome 12.

Stuttering is a common and sometimes severe communication disorder, of unknown primary etiology, that exists in populations worldwide. Many types of evidence suggest a genetic contribution to stuttering; however, the complex inheritance of this disorder has hindered identification of these factors. We have employed highly inbred families to increase the power of linkage analysis of this disorder. Forty-four Pakistani families with documented or probable consanguinity, from the city of Lahore and surrounding areas, were included. Each family contained multiple cases of stuttering, which were diagnosed using the Stuttering Severity Instrument. Using the Marshfield Weber 9 marker panel, we performed a genomewide linkage scan focused on affected individuals and their parents. The analysis included 199 genotyped individuals, 144 affected and 55 unaffected. The Pedigree Relationship Statistical Test (PREST) was used to identify pedigrees that required additional specification of inbreeding. Initial nonparametric analysis gave evidence of linkage on chromosomes 1, 5, 7, and 12. Additional genotyping was performed on chromosome 12 to a 5-cM level of resolution, and 16 additional individuals were then included, bringing the number of families to 46. Analysis of the enlarged data set provided consistent evidence of linkage on chromosome 12: the S(homoz) scoring function gave a nonparametric LOD score of 4.61, and a LOD score of 3.51 was obtained using the S(all) scoring function. These results suggest that a locus on chromosome 12q may contain a gene with a large effect in this sample.

Chromosome Mapping↗
PubMed2005

Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci.

Bitter taste perception in humans is mediated by receptors encoded by 25 genes that together comprise the TAS2R (or T2R) gene family. The ability to identify the ligand(s) for each of these receptors is dependent on understanding allelic variation in TAS2R genes, which may have a significant effect on ligand recognition. To investigate the extent of coding variation among TAS2R alleles, we performed a comprehensive evaluation of sequence and haplotype variation in the human bitter taste receptor gene repertoire. We found that these genes exhibit substantial coding sequence diversity. In a worldwide population sample of 55 individuals, we found an average of 4.2 variant amino acid positions per gene. In aggregate, the 24 genes analyzed here, along with the phenylthiocarbamide (PTC) receptor gene analyzed previously, specify 151 different protein coding haplotypes. Analyses of the ratio of synonymous and nonsynonymous nucleotide substitutions using the Ka/Ks ratio revealed an excess of amino acid substitutions relative to most other genes examined to date (Ka/Ks = 0.94). In addition, comparisons with more than 1,500 other genes revealed that levels of diversity in the TAS2R genes were significantly greater than expected (pi = 0.11%; p < 0.01), as were levels of differentiation among continental populations (FST = 0.22; p < 0.05). These diversity patterns indicate that unusually high levels of allelic variation are found within TAS2R loci and that human populations differ appreciably with respect to TAS2R allele frequencies. Diversity in the TAS2R genes may be accounted for by natural selection, which may have favored alleles responsive to toxic, bitter compounds found in plants. These findings are consistent with the view that different alleles of the TAS2R genes encode receptors that recognize different ligands, and suggest that the haplotypes we have identified will be important in studies of receptor-ligand recognition.

Alleles↗
PubMed2005

Founder mutations.

Explore the source record for details and available documents.

Anemia, Iron-Deficiency↗
PubMed2005

Human taste genetics.

Humans show substantial differences in taste sensitivity to many different substances. Some of this variation is known to be genetic in origin, and many other inter-individual differences are likely to be partially or wholly determined by genetic mechanisms. Recent advances in the understanding of taste at the molecular level have provided candidate genes that can be evaluated for contributions to phenotypic differences in taste abilities. This approach has provided an understanding of variation in the ability to taste phenylthiocarbamide (PTC), and has resolved long-standing controversies about the genetics of this classic human genetic trait. Significant coding sequence variation exists in taste receptor genes, which suggests that PTC tasting may indicate more general taste sensory variation. However, many aspects of taste perception remain poorly characterized. Better understanding of the molecular components of salty and sour tastes is still needed, as is a more complete picture of second messenger and downstream signaling mechanisms for all taste modalities. More general studies of linkage and association between genetic markers and taste phenotypes may reveal genes encoding proteins that were previously unsuspected to be involved in this sensory process.

Evolution, Molecular↗
PubMed2004

Natural selection and molecular evolution in PTC, a bitter-taste receptor gene.

The ability to taste phenylthiocarbamide (PTC) is a classic phenotype that has long been known to vary in human populations. This phenotype is of genetic, epidemiologic, and evolutionary interest because the ability to taste PTC is correlated with the ability to taste other bitter substances, many of which are toxic. Thus, variation in PTC perception may reflect variation in dietary preferences throughout human history and could correlate with susceptibility to diet-related diseases in modern populations. To test R. A. Fisher's long-standing hypothesis that variability in PTC perception has been maintained by balancing natural selection, we examined patterns of DNA sequence variation in the recently identified PTC gene, which accounts for up to 85% of phenotypic variance in the trait. We analyzed the entire coding region of PTC (1,002 bp) in a sample of 330 chromosomes collected from African (n=62), Asian (n=138), European (n=110), and North American (n=20) populations by use of new statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two intermediate-frequency haplotypes corresponding to "taster" and "nontaster" phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low (FST=0.056) in comparison with estimates based on other genes. In addition, Tajima's D and Fu and Li's D and F statistics demonstrated a significant deviation from neutrality because of an excess of intermediate-frequency variants when human population growth was taken into account (P<.01). These results combine to suggest that balancing natural selection has acted to maintain "taster" and "nontaster" alleles at the PTC locus in humans.

Alleles↗
PubMed2004

Results of a genome-wide linkage scan for stuttering.

We performed a linkage study of stuttering using 392 markers distributed across the genome in a series of 68 families identified in the general outbred population of North America and Europe. Standardized diagnosis was performed using recorded samples of both conversation and reading, in which stuttering dysfluencies were scored as percentage of dysfluent words and syllables. Analysis was first performed using non-parametric methods implemented in GENEHUNTER, where we obtained maximum statistical support for markers of chromosome 18, with a maximum NPL (Sall) of 1.51 at D18S976. The single largest pedigree within our sample (pedigree 0006) alone gave an NPL of 4.72 at D18S976. For fine mapping, we analyzed 18 markers on chromosome 18 across all families using ALLEGRO. Overall NPL (Srobdom) scores >5 were obtained with markers on 18p, and Z(lr) scores >/=2.5 on 18p and proximal 18q. Furthermore, pedigree 0006 alone gave an NPL (Srobdom) of 5.35. Overall our results suggest chromosome 18 may harbor a predisposing locus for this disorder, and additional genes may exist.

Chromosome Mapping↗
PubMed2003

Mutant dynactin in motor neuron disease.

Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower motor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.

Amino Acid Motifs↗
PubMed2003

Genetic analysis of a complex trait in the Utah Genetic Reference Project: a major locus for PTC taste ability on chromosome 7q and a secondary locus on chromosome 16p.

The ability to taste phenylthiocarbamide (PTC) shows complex inheritance in humans. We obtained a quantitative measure of PTC tasting ability in 267 members of 26 large three-generation families that were part of a set of CEPH families that had been used for genetic mapping. Significant bimodality was found for the distribution of age and gender adjusted scores (P<0.001), with estimated means of 3.16 (SD=1.80) and 9.26 (SD=1.54). Using the extensive genotyping available in these families from the genetic mapping efforts, we performed a genome scan by using 1324 markers with an average spacing of 4 cM. Analyses were first carried out with a recessive genetic model that has traditionally been assumed for the trait, and a threshold score of 8.0 delineating tasters from non-tasters. In this qualitative analysis, the maximum genome-wide lod score was 4.74 at 246 cM on chromosome 7; 17 families showed segregation of the dichotomous PTC phenotype. No other lod scores were significant; the next highest score was on chromosome 10 (lod=1.64 at 85 cM), followed by chromosome 3 (lod=1.29 at 267 cM). Because PTC taste ability exhibited substantial quantitative variation, the quantitative trait was also analyzed by using a variance components approach in SOLAR. The maximum quantitative genome-wide lod score was 8.85 at 246 cM on chromosome 7. Evidence for other possible quantitative loci was found on chromosomes 1 (lod=2.31 at 344 cM) and 16 (lod=2.01 at 14 cM). A subsequent two-locus whole-genome scan conditional on the chromosome 7 quantitative trait locus identified the chromosome 16 locus (two-locus lod=3.33 at 14 cM).

Adolescent↗
PubMed2003

Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.

The ability to taste the substance phenylthiocarbamide (PTC) has been widely used for genetic and anthropological studies, but genetic studies have produced conflicting results and demonstrated complex inheritance for this trait. We have identified a small region on chromosome 7q that shows strong linkage disequilibrium between single-nucleotide polymorphism (SNP) markers and PTC taste sensitivity in unrelated subjects. This region contains a single gene that encodes a member of the TAS2R bitter taste receptor family. We identified three coding SNPs giving rise to five haplotypes in this gene worldwide. These haplotypes completely explain the bimodal distribution of PTC taste sensitivity, thus accounting for the inheritance of the classically defined taste insensitivity and for 55 to 85% of the variance in PTC sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrates that this gene has a direct influence on PTC taste sensitivity and that sequence variants at different sites interact with each other within the encoded gene product.

Alleles↗