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PubMed2004

Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American.

Ethnic differences in genetic polymorphisms in UDP-glucuronosyltransferase 1A1 (UGT1A1) were investigated among African-Americans, Caucasians, and Japanese using samples obtained from 150 individuals for each population. Genotyping of -3279T>G in the phenobarbital-responsive enhancer module, TA repeats in the TATA box, 211G>A (G71R) and 686C>A (P229Q) in exon 1, and three single nucleotide polymorphisms (SNPs) (1813C> T, 1941C>G, and 2042C>G) in the 3'-untranslated region in exon 5 was performed. Eight haplotypes of block 1 (exon 1 and its 5'-flanking region) harboring the first four variations were assigned to each individual. The dominant haplotype for African-Americans was *28b (-3279G;TA(7); 211G;686C) (0.446), whereas that for the Japanese was *1a (-3279T; TA(6);211G;686C) (0.610). Frequencies of the two haplotypes *1a and *28b were comparable in Caucasians. Haplotype *6a (-3279T;TA(6); 211A;686C) was characteristic of the Japanese, whereas haplotypes *36b and *37b (-3279T;TA(5) and TA(8);211G;686C) were found mostly in African-Americans. Although the three SNPs in block 2 (exons 2-5) were in complete linkage in the Japanese, they were not completely linked in African-Americans or Caucasians. These differences in haplotype distribution patterns among the three populations suggest the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C>T (P229L), was found in an African-American. The intrinsic clearance of 7-ethyl-10-hydroxycamptothecin (SN-38) by P229L UGT1A1 expressed in COS-1 cells was about 3% of the wild type. The results of Western blotting and real-time reverse transcription-polymerase chain reaction suggest that the low glucuronidation activity of the variant was partly due to its low stability. The variation 686C>T may cause high toxicity during 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) therapy or hyperbilirubinemia in patients.

Black or African American↗
PubMed2002

Development of RGA-CAPS markers and genetic mapping of candidate genes for sugarcane mosaic virus resistance in maize.

Three previously published resistance gene analogues (RGAs), pic13, pic21 and pic19, were mapped in relation to sugarcane mosaic virus (SCMV) resistance genes ( Scmv1, Scmv2) in maize. We cloned these RGAs from six inbreds including three SCMV-resistant lines (D21, D32, FAP1360A) and three SCMV-susceptible lines (D145, D408, F7). Pairwise sequence alignments among the six inbreds revealed a frequency of one single nucleotide polymorphism (SNP) per 33 bp for the three RGAs, indicating a high degree of polymorphism and a high probability of success in converting RGAs into codominant cleaved amplified polymorphic sequence (CAPS) markers compared to other sequences. SNPs were used to develop CAPS markers for mapping of the three RGAs in relation to Scmv1 (chromosome 6) and Scmv2 (chromosome 3), and for pedigree analyses of resistant inbred lines. By genetic mapping pic21 was shown to be different from Scmv2, whereas pic19 and pic13 are still candidates for Scmv1 and Scmv2, respectively, due to genetic mapping and consistent restriction patterns of ancestral lines.

Journal Article↗
PubMed2000

Polymorphisms in the HLA-linked olfactory receptor genes in the Hutterites.

Genes in the MHC have been associated with mate choice and odor preferences in a variety of animals. Although the role of HLA genes in human mate choice has been controversial, studies in the Hutterites have demonstrated fewer than expected numbers of couples who match for an HLA haplotype, suggesting that in this population there is avoidance of mates with HLA haplotypes similar to one's own haplotype. Recently, 18 olfactory receptor (OR) genes have been mapped to the HLA region, telomeric to the HLA-F locus, providing a potential mechanism for HLA-based odor recognition and perhaps mate preferences in humans. We screened a sample of Hutterites with diverse HLA haplotypes for polymorphisms in the HLA-linked olfactory receptor gene, FAT11, by sequencing, denaturing high performance liquid chromatography, and allele-specific oligo dot-blotting. Three single nucleotide polymorphisms were detected in the single translated exon of this gene, all of which resulted in amino acid substitutions (Phe587Leu, Ala642Val, and Thr1157Ala). The FAT11 Phe587- Val642-Ala1157 allele occurred on 17 different HLA haplotypes, the Leu587-Ala642-Ala1157 allele on 15 haplotypes, the Phe587-Ala642-Ala1157 allele on 16 haplotypes, and the Phe587-Ala642-Thr1157 allele on a single haplotype. Thus, four alleles of the FAT11 gene are present in the Hutterites. This level of variation in the FAT11 gene alone may not be sufficient to contribute to the observed patterns of mate choice in the Hutterites and to individual variation in odor preferences.

Alleles↗
PubMed2003

MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years?

Elucidating how natural selection promotes local adaptation in interaction with migration, genetic drift and mutation is a central aim of evolutionary biology. While several conceptual and practical limitations are still restraining our ability to study these processes at the DNA level, genes of the major histocompatibility complex (MHC) offer several assets that make them unique candidates for this purpose. Yet, it is unclear what general conclusions can be drawn after 15 years of empirical research that documented MHC diversity in the wild. The general objective of this review is to complement earlier literature syntheses on this topic by focusing on MHC studies other than humans and mice. This review first revealed a strong taxonomic bias, whereby many more studies of MHC diversity in natural populations have dealt with mammals than all other vertebrate classes combined. Secondly, it confirmed that positive selection has a determinant role in shaping patterns of nucleotide diversity in MHC genes in all vertebrates studied. Yet, future tests of positive selection would greatly benefit from making better use of the increasing number of models potentially offering more statistical rigour and higher resolution in detecting the effect and form of selection. Thirdly, studies that compared patterns of MHC diversity within and among natural populations with neutral expectations have reported higher population differentiation at MHC than expected either under neutrality or simple models of balancing selection. Fourthly, several studies showed that MHC-dependent mate preference and kin recognition may provide selective factors maintaining polymorphism in wild outbred populations. However, they also showed that such reproductive mechanisms are complex and context-based. Fifthly, several studies provided evidence that MHC may significantly influence fitness, either by affecting reproductive success or progeny survival to pathogens infections. Overall, the evidence is compelling that the MHC currently represents the best system available in vertebrates to investigate how natural selection can promote local adaptation at the gene level despite the counteracting actions of migration and genetic drift. We conclude this review by proposing several directions where future research is needed.

Animals↗
PubMed1995

Evolution at the tip and base of the X chromosome in an African population of Drosophila melanogaster.

Hitchhiking effects of advantageous mutations have been invoked to explain reduced polymorphism in regions of low crossing-over in Drosophila. Besides reducing DNA heterozygosity, hitchhiking effects should produce strong linkage disequilibrium and a frequency spectrum skewed toward an excess of rare polymorphisms (compared to the neutral expectation). We measured DNA polymorphism in a Zimbabwe population of D. melanogaster at three loci, yellow, achaete, and suppressor of forked, located in regions of reduced crossing-over. Similar to previously published surveys of these genomic regions in other populations, we observed low levels of nucleotide variability. However, the frequency spectrum was compatible with a neutral model, and there was abundant evidence for recombination in the history of the yellow and ac genes. Thus, some aspects of the data cannot be accounted for by a simple hitchhiking model. An alternative hypothesis, background selection, might be compatible with the observed patterns of linkage disequilibrium and the frequency spectrum. However, this model cannot account for the observed reduction in nucleotide heterozygosity. Thus, there is currently no satisfactory theoretical model for the data from the tip and base of the X chromosome in D. melanogaster.

Animals↗
PubMed2006

Nonneutral evolution of organelle genes in Silene vulgaris.

Knowledge of mitochondrial gene evolution in angiosperms has taken a dramatic shift within the past decade, from universal slow rates of nucleotide change to a growing realization of high variation in rates among lineages. Additionally, evidence of paternal inheritance of plant mitochondria and recombination among mitochondrial genomes within heteroplasmic individuals has led to speculation about the potential for independent evolution of organellar genes. We report intraspecific mitochondrial and chloroplast sequence variation in a cosmopolitan sample of 42 Silene vulgaris individuals. There was remarkably high variation in two mitochondrial genes (atp1, atp9) and additional variation within a third gene (cob). Tests for patterns of nonneutral evolution were significant for atp1 and atp9, indicative of the maintenance of balanced polymorphisms. Two chloroplast genes (matK, ndhF) possessed less, but still high, variation and no divergence from neutral expectations. Phylogenetic patterns of organelle genes in both the chloroplast and mitochondria were incongruent, indicating the potential for independent evolutionary trajectories. Evidence indicated reassociation among cytoplasmic genomes and recombination between mitochondrial genes and within atp1, implying transient heteroplasmy in ancestral lineages. Although the mechanisms for long-term maintenance of mitochondrial polymorphism are currently unknown, frequency-dependent selection on linked cytoplasmic male sterility genes is a potential candidate.

Base Sequence↗
PubMed1989

DNA fingerprints of poultry.

Human minisatellite probes cross-hybridize to DNA of several species of poultry (chicken, duck, turkey and goose), and detect high levels of polymorphism. The resulting DNA fingerprints are individual specific, and allow the discrimination even between closely related birds. The pattern of poultry DNA fingerprints is different from that of humans and other animals, having a higher average proportion of large DNA fragments. Pedigree analysis revealed a low number of allelic pairs of variable DNA fragments, indicating that most of the alleles are unresolved in the DNA fingerprint or too small to be detected. The total number of detectable loci in broilers, using probe 33.6, was estimated as 62, of which 13 loci are on average scoreable and available for use. Poultry DNA fingerprints can be used for individual identification, linkage studies and as an aid in breeding programmes.

Alleles↗
PubMed2002

Genetic diversity of three Elymus species indigenous to Japan and East Asia (E. tsukushiensis, E. humidus and E. dahuricus) detected by AFLP.

With the aim of broadening the gene pool of Triticeae for crop improvement, the genetic diversity of three hexaploid Elymus species indigenous to Japan and East Asia (E. tsukushiensis, E. humidus and E. dahuricus) was evaluated using amplified fragment length polymorphism (AFLP) markers. A total of 34 accessions: five of E. tsukushiensis, 13 of E. humidus, 15 of E. dahuricus, and one tetraploid Elymus species as an outgroup, were analyzed. The AFLP analysis was conducted with 12 selective primer combinations. In all, 329 bands were scored. The average number of bands scored per accession was 135.3. Among the 34 accessions, no polymorphism was detected among 10 accessions of E. humidus and among three accessions of E. tsukushiensis. Each species showed a diagnostic band pattern. One accession of E. humidus showed a band pattern intermediate between those of E. humidus and E. tsukushiensis, suggesting the occurrence of interspecific introgression. The level of intraspecific variation was highest in E. dahuricus (1-psb = 0.17, pi = 0.010), followed by E. tsukushiensis (1-psb = 0.14, pi = 0.008) and E. humidus (1-psb = 0.03, pi = 0.002). The level of interspecific variation was higher than that of intraspecific variation in all the pairs compared. The level of divergence between E. humidus and E. tsukushiensis was relatively low, but even so it was two times higher than that of the intraspecific variation for each species. The phylogenetic tree constructed here showed clear separations of all the species. The results of this study indicate a clear divergence of E. humidus from E. tsukushiensis in spite of the morphological similarity between these two species. Based on the values of nucleotide diversity, the time of divergence between E. humidus and E. tsukushiensis was estimated to be 0.9-1.2 million years ago.

Asia↗
PubMed2002

Molecular characterization of expressed DQA and DQB genes in the California sea lion ( Zalophus californianus).

To date, there are no published MHC sequences from the California sea lion (Zalophus californianus), a thriving species that, by feeding high on the marine food web, could be a sentinel for disturbances in marine and coastal ecosystems. In this study, degenerate primers and RACE technology were used to amplify near-full-length (MhcZaca- DQB) and full-length (MhcZaca- DQA) expressed class II MHC gene products from the peripheral blood mononuclear cells of two California sea lions in rehabilitation. Five unique Zaca- DQA sequences and eight unique Zaca- DQB sequences, all encoding functional proteins, were identified in the two animals, indicating the presence of multiple DQ- loci in this species. An additional three Zaca- DQB sequences containing features compatible with pseudogenes or null alleles were also identified. Despite the identification of multiple DQA and DQB sequences, the degree of heterogeneity between them was extremely low. To confirm the limited degree of Zaca-DQ nucleotide variation between individuals, we used denaturing gradient gel electrophoresis to examine putative peptide binding region sequences from the peripheral blood leukocyte-derived RNAs of 19 wild-caught California sea lions from physically distinct populations. The pattern of Zaca-DQ sequence migration was identical between individuals and independent of geographical region. This apparent Zaca-DQ sequence identity between sea lions was confirmed by direct sequencing of individual bands. In combination, these findings raise important questions regarding immunogenetic diversity within this thriving species, and should prompt further research into the existence of a highly polymorphic sea lion class II MHC molecule with sequence features that support traditional peptide binding functions.

Alleles↗
PubMed2006

Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I.

Two animal models of trait anxiety, HAB/LAB rats and mice, are described, representing inborn extremes in anxiety-related behavior. The comprehensive phenotypical characterization included basal behavioral features, stress-coping strategies and neuroendocrine responses upon stressor exposure with HAB animals being hyper-anxious, preferring passive coping, emitting more stressor-induced ultrasonic vocalization calls and showing typical peculiarities of the hypothalamic-pituitary-adrenocortical axis and line-specific patterns of Fos expression in the brain indicative of differential neuronal activation. In most cases, unselected Wistar rats and CD1 mice, respectively, displayed intermediate behaviors. In both HAB/LAB rats and mice, the behavioral phenotype has been found to be significantly correlated with the expression of the neuropeptide arginine vasopressin (AVP) at the level of the hypothalamic paraventricular nucleus (PVN). Additional receptor antagonist approaches in HABs confirmed that intra-PVN release of AVP is likely to contribute to hyper-anxiety and depression-like behavior. As shown exemplarily in HAB rats and LAB mice, single nucleotide polymorphisms (SNPs) in regulatory structures of the AVP gene underlie AVP-mediated phenotypic phenomena; in HAB rats, a SNP in the promoter of the AVP gene leads to reduced binding of the transcriptional repressor CBF-A, thus causing AVP overexpression and overrelease. Conversely, in LAB mice, a SNP in the AVP gene seems to cause an amino acid exchange in the signal peptide, presumably leading to a deficit in bioavailable AVP likely to underlie the total hypo-anxiety of LAB mice in combination with signs of central diabetes insipidus. Another feature of LAB mice is overexpression of glyoxalase-I. The functional characterization of this enzyme will determine its involvement in anxiety-related behavior beyond that of a reliable biomarker. The further identification of quantitative trait loci, candidate genes (and their products) and SNPs will not only help to explain inter-individual variation in emotional behavior, but will also reveal novel targets for anxiolytic and antidepressive interventions.

Animals↗
PubMed1992

Reduced levels of DNA polymorphism and fixed between-population differences in the centromeric region of Drosophila ananassae.

We have estimated DNA sequence variation within and between two populations of Drosophila ananassae, using six-cutter restriction site variation at vermilion (v) and furrowed (fw). These two gene regions are located close to the centromere on the left and right X chromosome arms, respectively. In the fw region, no DNA polymorphism was detected within each population. In the v region, average heterozygosity per nucleotide was very low in both populations (pi = 0.0005 in the Burma population, and 0.0009 in the India population). These estimates are significantly lower than those from loci in more distal gene regions. The distribution of DNA polymorphisms between both populations was also striking. At fw, three fixed differences between the Burma and India populations were detected (two restriction site differences and one insertion/deletion of approximately 2 kb). At v, each DNA polymorphism in high frequency in the total sample was nearly fixed in one or the other population, although none of them reached complete fixation. The observed pattern of reduced variation within populations and fixed differences between populations appears to correlate with recombination rate. We conclude that recent hitchhiking associated with directional selection is the best explanation for this pattern. The data indicate that different selective sweeps have occurred in the two populations. The possible role of genetic hitchhiking in rapid population differentiation in gene regions of restricted recombination is discussed.

Animals↗
PubMed2002

Single-strand conformation polymorphism (SSCP) assays for major histocompatibility complex B genotyping in chickens.

We have developed a DNA-based method for defining MHC B system genotypes in chickens. Genotyping by this method requires neither prior determination of allele-specific differences in nucleotide sequence nor the preparation of haplotype-specific alloantisera. Allelic differences at chicken B-F (class I) and B-L (class II) loci are detected in PCR single-strand conformation polymorphism (SSCP) assays. PCR primer pairs were designed to hybridize specifically with conserved sequences surrounding hypervariable regions within the two class I and two class I loci of the B-complex and used to generate DNA fragments that are heat- and formamide-denatured and then analyzed on nondenaturing polyacrylamide gels. PCR primer pairs were tested for the capacity to produce SSCP patterns allowing the seven B haplotypes in the MHC B congenic lines, and seven B haplotypes known to be segregating in two commercial broiler breeder lines to be distinguished. Primer pairs were further evaluated for their capacity to reveal the segregation of B haplotypes in a fully pedigreed family and in a closed population. Concordance was found between SSCP patterns and previously assigned MHC types. B-F and B-L SSCP patterns segregated in linkage as expected for these closely linked loci. We conclude that this method is valuable for defining MHC B haplotypes and for detecting potential recombinant haplotypes especially when used in combination with B-G (class IV) typing by restriction fragment pattern.

Animals↗
PubMedDate not supplied

Amino acid comparison of infectious bursal disease viruses placed in the same or different molecular groups by RT/PCR-RFLP.

Infectious bursal disease virus (IBDV) strains have been identified and placed into molecular groups by a reverse transcriptase (RT)/polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay. The predicted amino acid sequences corresponding to the region of the genome examined by RFLP were determined and compared for 14 IBDV strains from different molecular groups and 11 IBDV strains that were identified in molecular group 6. Among the viruses within molecular group 6, 13 amino acid positions had mutations, and among the viruses in different molecular groups, 27 amino acid positions had mutations. In addition to having more mutations, viruses compared from different molecular groups also had mutations at key positions that were previously reported to be important for the formation of neutralizing epitopes. Three of these IBDV strains with unique RFLP patterns were used to challenge 1-wk-old broiler chickens with maternal immunity to IBDV. One of these viruses, T1, broke through this maternal immunity as evidenced by detection of the virus by RT/PCR-RFLP and production of an active virus neutralizing antibody response to classic and variant IBDV strains. Unique amino acid mutations in the T1 virus that may have contributed to its ability to break through this maternal immunity were observed at amino acids 318 and 322. The results indicate that RFLP profiles and nucleotide sequences can be used to predict the relative similarities and differences among IBDV strains, but determining the actual antigenic differences among viruses requires testing in vivo.

Amino Acid Sequence↗
PubMed2004

Hotspot mutations of BRAF gene are not associated with pediatric solid neoplasms.

BRAF (v-raf murine sarcoma viral oncogene homolog B1) activating mutations in a high proportion of melanomas and in a small fraction of other cancers have been recently reported. All the presented mutations of BRAF are located in exons 11 and 15, and the hotspot mutation at codon 599 accounts for 87% of BRAF mutations. Because the mutational status is unclear in pediatric solid neoplasms, we screened BRAF mutations comprehensively in our tumor series presented in childhood. Two pairs of primers were designed to amplify exons 11 and exon 15, respectively, and 181 tumor samples (65 neuroblastomas, 23 Wilms tumors, 19 hepatoblastomas, 16 teratomas, 17 rhabdomyosarcomas, 13 ganglioneuromas, etc.) were investigated by PCR-SSCP method. On agarose gel electrophoresis, amplified PCR fragments showed no size-altered changes in exons 11 and 15, and SSCP analysis revealed uniform band patterns in both exons. Subsequent direct sequencing of selected 10 samples confirmed only normal sequences without any nucleotide substitutions. The current study represents the first genetic analysis of the BRAF gene in pediatric solid tumors. Our data suggest that mutations of BRAF gene as a mechanism of tumorigenesis is unlikely to be associated with most childhood neoplasms.

Child↗
PubMed2006

Striatal dopamine transporter binding in Parkinson's disease associated with the LRRK2 Gly2019Ser mutation.

We measured striatal dopamine transporter binding using [(123)I]ioflupane and SPECT in patients with Parkinson's disease associated with the LRRK2 (PARK8) Gly2019Ser gene mutation (LRRK2-PD) and in gene-negative patients with idiopathic Parkinson's disease (IPD) of comparable disease duration and severity. The LRRK2-PD group consisted of a total of 10 patients (3 sporadic) with mean age 62 +/- 14 years, disease duration 9 +/- 3 years, and UPDRS III motor score 21.60 +/- 6.65. The control IPD group consisted of 15 patients with mean age 59 +/- 9 years, disease duration 9 +/- 5 years, and UPDRS III motor score 23.80 +/- 8.69. [(123)I]ioflupane-specific uptake ratios were calculated for caudate nucleus and putamen using the occipital cortex as reference region. We found no differences between the LRRK2-PD group and IPD in all items studied. In particular, putamen and caudate uptake values as well as side asymmetry indexes and putamen/caudate ratios all revealed comparable between-group values. We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD.

Amino Acid Substitution↗
PubMed1999

The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q.

Neuregulin-2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, neuregulin-2 induces the growth and differentiation of epithelial, neuronal, glial and other types of cells. In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns. By using radiation hybrid mapping panels, the human NRG2 gene was mapped to the D5S658-D5S402 region within 5q23-q33, close to an autosomal recessive form of demyelinating Charcot-Marie-Tooth (CMT) disease. The NRG2 gene was found to be on two yeast artificial chromosomes overlapping the candidate interval and was, thus, considered a good positional candidate for this form of CMT. When the entire neuregulin-2 coding sequence and splice junctions were explored, however, no mutation was identified in one CMT family linked to 5q23-q33. In addition, three intronic single nucleotide polymorphisms were identified in the NRG2 gene. Genotyping in two families localized the NRG2 gene outside of the revised candidate interval between D5S402-D5S210 and excluded NRG2 as the gene responsible for this form of CMT disease.

Adult↗
PubMed2000

Evidence for directional selection acting on pheromone-binding proteins in the genus Choristoneura.

Patterns of nucleotide variation consistent with the action of natural selection have been discovered at a number of different gene loci. Here, pheromone-binding proteins (PBPs) are examined to determine if selection has acted to fix amino acid changes in PBPs in lineages in which pheromone changes have occurred. PBPs from five different species of moths in the genus Choristoneura were sequenced, along with the PBP of Argyrotaenia velutinana, which serves as an outgroup. Three independent major pheromone changes are represented within this group of five Choristoneura species. Two different lineages show evidence for selection based on polymorphism and divergence comparisons and comparisons of rates of replacement evolution to silent and noncoding evolution. Along one of these lineages, leading to Choristoneura fumiferana, there has been a change to an aldehyde pheromone from an acetate pheromone. The second branch does not appear to be associated with a major pheromone change. Other branches in the tree show a trend toward greater replacement fixation than expected under neutrality. This trend could reflect undetected selective events within this group of PBPs. Selection appears to have acted to fix amino acid changes in the PBP of moths from the genus Choristoneura, but it is not clear that this selection is due to pheromone changes between species.

Amino Acid Sequence↗