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PubMed1997

Evolution of human immunodeficiency virus type 1 in perinatally infected infants with rapid and slow progression to disease.

We addressed the relationship between the origin and evolution of human immunodeficiency virus type 1 (HIV-1) variants and disease outcome in perinatally infected infants by studying the V3 regions of viral variants in samples obtained from five transmitting mothers at delivery and obtained sequentially over the first year of life from their infected infants, two of whom (rapid progressors) rapidly progressed to having AIDS. Phylogenetic analyses disclosed that the V3 sequences from each mother-infant pair clustered together and were clearly distinct from those of the other pairs. Within each pair, the child's sequences formed a monophyletic group, indicating that a single variant initiated the infection in both rapid and slow progressors. Plasma HIV-1 RNA levels increased in all five infants during their first months of life and then declined within the first semester of life only in the three slow progressors. V3 variability increased over time in all infants, but no differences in the pattern of V3 evolution in terms of potential viral phenotype were observed. The numbers of synonymous and nonsynonymous substitutions varied during the first semester of life regardless of viral load, CD4+-cell count, and disease progression. Conversely, during the second semester of life the rate of nonsynonymous substitutions was higher than that of synonymous substitutions in the slow progressors but not in the rapid progressors, thus suggesting a stronger host selective pressure in the former. In view of the proposal that V3 genetic evolution is driven mainly by host immune constraints, these findings suggest that while the immune response to V3 might contribute to regulating viral levels after the first semester of life, it is unlikely to play a determinant role in the initial viral decline soon after birth.

Amino Acid Sequence↗
PubMed1998

Evolution of envelope sequences from the genital tract and peripheral blood of women infected with clade A human immunodeficiency virus type 1.

The development of viral diversity during the course of human immunodeficiency virus type 1 (HIV-1) infection may significantly influence viral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infected with a single virus variant of subtype B HIV-1. In this study, we evaluated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripheral blood and cervical secretions of three women with genetically heterogeneous viral populations near seroconversion. At the first sample following seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of ds as sequences from blood or mucosa evolved. Mutations affected each of the three variable regions of the envelope gene differently; insertions and deletions dominated changes in V1, substitutions involving charged amino acids occurred in V2, and sequential replacement of amino acids over time at a small subset of positions distinguished V3. The relationship among envelope nucleotide sequences obtained from peripheral blood mononuclear cells, plasma, and cervical secretions was evaluated for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (phylogenetic tissue compartmentalization). At time points after seroconversion in two individuals, there was also greater genetic identity among sequences from the same tissue compartment than among sequences from different tissue compartments (phenetic tissue compartmentalization). Over time, temporal phylogenetic and phenetic structure was detectable in mucosal and plasma viral samples from all three women, suggesting a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of that population.

Amino Acid Sequence↗
PubMed2005

Evolution of nef variants in gut associated lymphoid tissue of rhesus macaques during primary simian immunodeficiency virus infection.

We utilized the simian immunodeficiency virus model of AIDS to examine evolution of nef gene in gut-associated lymphoid tissue (GALT) during primary and early asymptomatic stages of infection. Macaques were infected with a cloned virus, SIVmac239/nef-stop harboring a premature stop codon in the nef gene. Restoration of the nef open reading frame occurred in GALT early at 3 days post-infection. Analysis of nef sequences by phylogenetic tools showed that evolution of nef was neutral thereafter, as evidenced by the ratio of synonymous to nonsynonymous substitutions, a star pattern in unrooted trees and distribution of amino acid replacements fitting a simple Poisson process. Two regions encoding for a nuclear localization signal and a CTL epitope were conserved. Thus, GALT was a site for strong positive selection of functional nef during initial stages of infection. However, evolution of the nef gene thereafter was neutral during early asymptomatic stage of infection.

Amino Acid Substitution↗
PubMed1999

Cutaneous T cell lymphoma in children.

Cutaneous T cell lymphoma (CTCL) is a term used to describe a heterogeneous group of lymphoproliferative disorders that involve the skin. Mycosis fungoides and Sézary syndrome are two forms of CTCL that arise in adults and are uncommon in children. Dermatologists frequently employ the term CTCL as a synonym for mycosis fungoides and Sézary syndrome. There has been increased recognition that the mycosis fungoides and Sézary syndrome forms of CTCL may arise in children and adolescents. Moreover, younger adults with these types of CTCL report onset of symptoms during adolescence. The literature regarding CTCL in childhood is limited. The purpose of this article is the review the literature regarding CTCL arising in children. The clinical presentation including morphologic variants, diagnosis, prognosis, and management are summarized.

Child↗
PubMed2006

Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies.

Arsenic contaminates ground water worldwide. Methylation is an important reaction in the biotransformation of arsenic. We set out to study the pharmacogenetics of human arsenic methyltransferase (AS3MT, previously CYT19). After cloning the human AS3MT cDNA, we annotated the human gene and resequenced its 5'-flanking region, exons, and splice junctions using 60 DNA samples from African-American (AA) and 60 samples from Caucasian-American (CA) subjects. We observed 26 single nucleotide polymorphisms (SNPs), including 3 non-synonymous cSNPs, as well as a variable number of tandem repeats in exon 1 within an area encoding the cDNA 5'-untranslated region. The nonsynonymous cSNPs included T860C (M287T) with frequencies of 10.8 and 10% in AA and CA subjects, respectively, as well as C517T (A173W) in one AA and C917T (T306I) in one CA sample. Haplotype analysis showed that Ile(306) was linked to Thr(287), so this double variant allozyme was also studied functionally. After expression in COS-1 cells and correction for transfection efficiency, the Trp(173) allozyme displayed 31%, Thr(287) 350%, Ile(306) 4.8%, and Thr(287)/Ile(306) 6.2% of the activity of the wild type (WT) allozyme, with 20, 190, 4.4, and 7.9% of the level of WT immunoreactive protein, respectively. Apparent K(m) values for S-adenosyl-l-methionine were 4.6, 3.1, and 11 mum for WT, Trp(173), and Thr(287) allozymes, with K(m) values for sodium arsenite with the same allozymes of 11.8, 8.9, and 4.5mum. The Ile(306) and Thr(287)/Ile(306) allozymes expressed too little activity for inclusion in the substrate kinetic studies. Expression of reporter gene constructs for the 5'-flanking region and the variable number of tandem repeats in the 5'-untranslated region demonstrated cell line-dependent variation in reporter gene expression, with shorter repeats associated with increased transcription in HepG2 cells. These results raise the possibility that inherited variation in AS3MT may contribute to variation in arsenic metabolism and, perhaps, arsenic-dependent carcinogenesis in humans.

5' Untranslated Regions↗
PubMed2002

A longitudinal analysis of T-cell epitope-coding regions of hepatitis C virus after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV)-related liver failure is the single leading indication for orthotopic liver transplantation (OLT) worldwide. The mechanisms that underlie the observed differences in natural history of HCV recurrence remain poorly understood. We have previously demonstrated that differential T-cell responses correlate with histologic severity after OLT. We hypothesized that amino acid substitutions within critical T-cell epitopes could lead to increased severity of HCV disease. METHODS: We determined the peptide sequences from sequential serum-derived viral RNA by reverse transcription and direct polymerase chain reaction sequence analysis from 32 HCV genotype 1-infected patients with well-characterized outcomes after liver transplantation. Serum samples were analyzed for HCV sequence the day of OLT and at least one time point post-OLT. To construct evolutionary relationships among the different patient samples, phylogenetic analyses of core and NS3 sequences were performed using a matrix fed into a neighbor-joining tree algorithm. RESULTS: The phylogenetic analyses revealed remarkable conservation within a given individual and no significant differences when comparing patients with severe versus mild recurrence. Accordingly, the synonymous mutation rate was consistently greater than the nonsynonymous substitution rate. The nine epitopic regions analyzed were also preserved so that, with the exception of one patient with mild recurrence, none of the patients demonstrated a shift in viral peptide sequence. CONCLUSIONS: HCV core and NS3 viral peptide sequences are identical before and after OLT in most patients, suggesting that the prevalent sequence is preserved in most cases, and viral variants are competent to establish infection after OLT. Although these results do not support viral mutation as a dominant pathogenic mechanism after OLT, other viral regions need to be analyzed.

Adult↗
PubMed2025

Characterisation of a persistent SARS-CoV-2 infection lasting more than 750 days in a person living with HIV: a genomic analysis.

BACKGROUND: People who are immunocompromised can develop persistent SARS-CoV-2 infections. Several viral mutations accumulated during the course of such persistent infections have also been observed in prominent variants of concern (VOCs). Here, we characterise persistent infection and viral evolution of SARS-CoV-2 lasting more than 750 days in a person with advanced HIV-1 infection. METHODS: Between March, 2021, and July, 2022, eight clinical specimens were collected from a person living with HIV, neither receiving antiretroviral therapy nor virally suppressed, and presumed to have been initially infected with SARS-CoV-2 in mid-May, 2020. Viral RNA was extracted from each swab and an amplicon-based sequencing approach was used for genomic analysis of SARS-CoV-2. Variable sites were characterised at the consensus and subconsensus levels, and phylogenetic tools were applied to analyse viral evolution. Publicly available SARS-CoV-2 sequences from GenBank were leveraged to contextualise our sequenced samples and identify any potential evidence of transmission. FINDINGS: Genomes formed a monophyletic cluster in the B.1 lineage. 68 consensus and 67 subconsensus single nucleotide variants were observed over the course of infection. The intrahost clock rate remained similar to that of the interhost rate in contemporaneous community sequences (6·74 × 10-4 [95% credible interval 5·05 × 10-4 to 8·54 × 10-4] substitutions per site per year vs 6·11 × 10-4 [5·54 × 10-5 to 6·66 × 10-4]). Mutations grouped into two distinct subpopulations present throughout infection. 10 non-synonymous mutations in the spike protein gene were at positions in common with those defining the omicron lineage (BA.1 or BA.2), of which nine were present before November, 2021. Nine of 18 substitutions present throughout infection were rare in online databases, suggesting a lack of long transmission chains descending from this individual. INTERPRETATION: Convergent SARS-CoV-2 evolution, both in and outside the spike protein, observed in this study suggests parallels with the evolutionary process leading to emergence of the omicron VOC. The inferred absence of onward infections might indicate a loss of transmissibility during adaptation to a single host. Our results underscore the importance of appropriate treatment to cure persistent SARS-CoV-2 infections and monitoring them to understand how mutations contribute to viral adaptation. FUNDING: National Institute of General Medical Sciences of the National Institutes of Health, Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, MassCPR, and Morris Singer Foundation.

Humans↗
PubMed1998

Genomic organization and chromosomal localization of the human peroxisomal membrane protein-1-like protein (PXMP1-L) gene encoding a peroxisomal ABC transporter.

The cDNA of the peroxisomal membrane protein-1-like protein (PXMP1-L, synonyms: PMP69, P70R), a novel peroxisomal ATP binding cassette transporter of yet unknown function, has recently been cloned. The best known peroxisomal member of this protein family is the adrenoleukodystrophy protein, defects of which are the underlying cause of X-linked adrenoleukodystrophy (X-ALD). Here we describe the complete exon-intron structure (19 exons and 18 introns covering 16.0 kb) of the human PXMP1-L gene, transcript variants, the localization on chromosome 14q24 by cytogenetic analysis and sequencing of the putative promoter region. PXMP1-L has been proposed to play a role as a modifier in determining the phenotypic variations observed in X-ALD. The data presented will enable sequence analysis of the PXMP1-L gene in X-ALD patients and facilitate the analysis of PXMP1-L function.

ATP-Binding Cassette Transporters↗
PubMed2006

Examination of PPP1R3B as a candidate gene for the type 2 diabetes and MODY loci on chromosome 8p23.

The product of the PPP1R3B gene (G(L)) is the regulatory subunit of PP1 - a serine/threonine phosphatase involved in the modulation of glycogen synthesis in the liver and skeletal muscle. The PPP1R3B gene is located on chromosome 8p23 in a region that has been linked with type 2 diabetes and maturity-onset diabetes of the young (MODY). We examined whether sequence variants at the PPP1R3B locus are responsible for the linkage with diabetes observed at this location. RT-PCR analysis revealed the existence of two alternative promoters. These and the two exons of this gene were sequenced in the probands of 13 Joslin families showing the strongest evidence of linkage at 8p23. A total of 20 variants were observed: two in the 5' flanking region, one in the intron (9 bp 5' of exon 2), and 17 in the 3' UTR. The intronic variant generated a new acceptor splice site, resulting in an alternative splice variant with a longer 5' UTR. However, neither this nor other variants segregated with diabetes in the 13 'linked' families. Furthermore, allele frequencies were similar in 90 family probands from the Joslin Study and 347 unrelated controls. Thus, genetic variability in the PPP1R3B gene does not appear to contribute to diabetes in our mostly Caucasian families. However, a role cannot be excluded in other populations such as the Japanese, among whom linkage to diabetes is also observed at 8p23 and a non-synonymous mutation has been detected in the PPP1R3B gene.

5' Untranslated Regions↗
PubMed2000

Evolution of circulating wild poliovirus and of vaccine-derived poliovirus in an immunodeficient patient: a unifying model.

We determined nucleotide sequences of the VP1 and 2AB genes and portions of the 2C and 3D genes of two evolving poliovirus lineages: circulating wild viruses of T geotype and Sabin vaccine-derived isolates from an immunodeficient patient. Different regions of the viral RNA were found to evolve nonsynchronously, and the rate of evolution of the 2AB region in the vaccine-derived population was not constant throughout its history. Synonymous replacements occurred not completely randomly, suggesting the need for conservation of certain rare codons (possibly to control translation elongation) and the existence of unidentified constraints in the viral RNA structure. Nevertheless the major contribution to the evolution of the two lineages came from linear accumulation of synonymous substitutions. Therefore, in agreement with current theories of viral evolution, we suggest that the majority of the mutations in both lineages were fixed as a result of successive sampling, from the heterogeneous populations, of random portions containing predominantly neutral and possibly adverse mutations. As a result of such a mode of evolution, the virus fitness may be maintained at a more or less constant level or may decrease unless more-fit variants are stochastically generated. The proposed unifying model of natural poliovirus evolution has important implications for the epidemiology of poliomyelitis.

Adolescent↗
PubMed2000

Papio cynocephalus endogenous retrovirus among old world monkeys: evidence for coevolution and ancient cross-species transmissions.

To study the evolutionary history of Papio cynocephalus endogenous retrovirus (PcEV), we analyzed the distribution and genetic characteristics of PcEV among 17 different species of primates. The viral pol-env and long terminal repeat and untranslated region (LTR-UTR) sequences could be recovered from all Old World species of the papionin tribe, which includes baboons, macaques, geladas, and mangabeys, but not from the New World monkeys and hominoids we tested. The Old World genera Cercopithecus and Miopithecus hosted either a PcEV variant with an incomplete genome or a virus with substantial mismatches in the LTR-UTR. A complete PcEV was found in the genome of Colobus guereza-but not in Colobus badius-with a copy number of 44 to 61 per diploid genome, comparable to that seen in papionins, and with a sequence most closely related to a virus of the papionin tribe. Analysis of evolutionary distances among PcEV sequences for synonymous and nonsynonymous sites indicated that purifying selection was operational during PcEV evolution. Phylogenetic analysis suggested that possibly two subtypes of PcEV entered the germ line of a common ancestor of the papionins and subsequently coevolved with their hosts. One strain of PcEV was apparently transmitted from a papionin ancestor to an ancestor of the central African lowland C. guereza.

Animals↗
PubMed1992

Classification of the suprapatellar septum considering ontogenetic development.

At the end of the 4th fetal month, the suprapatellar septum completely separates the knee joint cavity from the suprapatellar bursa. A perforation of the septum normally occurs at the end of the 5th fetal month. Mechanical factors, such as the pressure and friction of the quadriceps tendon on the condylar surface, are said to determine the form and extent of the perforation. Anatomic studies of adult knee joints revealed four variants in the further development of the suprapatellar septum, namely, a completely preserved septum (complete septum), a perforated septum with the communication between suprapatellar bursa and knee joint cavity differing in localization and number (perforated septum), a residual septum in the form of a fold that is almost always in a medial localization (residual septum), or a completely involuted septum (extinct septum). The clinical term "suprapatellar synovial plica" should not be used as a synonym for the expression "suprapatellar septum." The suprapatellar synovial fold corresponds to the residual septum and thus is only one of the four types of the suprapatellar septum.

Aged↗
PubMed2005

A novel CYP2A6*20 allele found in African-American population produces a truncated protein lacking enzymatic activity.

Human CYP2A6 is a cytochrome P450 (CYP) isoform responsible for the metabolism of nicotine, coumarin, tegafur, and valproic acid, and metabolic activation of nitrosamines. Genetic polymorphisms of the CYP2A6 gene are a major causal factor of the large interindividual differences in nicotine metabolism. In the present study, we identified a novel allele, termed CYP2A6*20, in an African-American population. The allele possesses the deletion of two nucleotides in exon 4 resulting in a frame-shift from codon 196 and an early stop codon at 220 (exon 5) as well as three synonymous SNPs of G51A (G51A in cDNA), T5684C (T1191C), and C6692G (C1546G, 3'-untranslated region). The allele frequency in the African-American population (n=96) was 1.6% (95% confidence interval, 0.6-4.5%). In contrast, the CYP2A6*20 allele was not found in Caucasians (European-American) (n=185), Japanese (n=184) and Korean (n=209) populations. To investigate the effects of the polymorphism on the enzymatic activities, we expressed a wild type or variant (deletion of two nucleotides) CYP2A6 together with NADPH-CYP reductase in Escherichia coli. SDS-PAGE and immunoblot analyses demonstrated that truncated CYP2A6 protein was produced from the variant allele, although detected mRNA was the predicted size by reverse transcriptional-polymerase chain reaction. Coumarin 7-hydroxylation and nicotine C-oxidation, which are typical CYP2A6 activities, were completely abolished in the E. coli membrane expressing the variant allele. In vivo nicotine metabolism was evaluated using the cotinine/nicotine ratio 2 h after the chewing of one piece of nicotine gum. Two CYP2A6*1/CYP2A6*20 heterozygotes and a single CYP2A6*17/CYP2A6*20 heterozygote revealed lower cotinine/nicotine ratios compared with CYP2A6*1/CYP2A6*1 subjects (1.6 and 4.5, and 1.8 versus 9.5+/-5.4, n=52, respectively). We found a novel CYP2A6*20 allele in African-American subjects which codes a truncated protein lacking enzymatic activity.

Black or African American↗
PubMed1996

Polymorphism of the apolipoprotein A-IV gene and its significance in lipid metabolism and coronary heart disease in a Japanese population.

Apolipoprotein A-IV (apo A-IV) is involved in the metabolism of both triglycerides and high-density lipoproteins (HDLs). Apo A-IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A-IV has made the use of genetic apo A-IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon -8 (G-->A, non-synonymous) allele 2 = 0 (n = 105); (b) codon 9 (A-->G, synonymous) allele 2 = 0.388 (n = 152); (c) codon 347 (A-->T, non-synonymous) allele 2 = 0 (n = 900); (d) codon 360 (T-->G, non-synonymous) allele 2 = 0 (n = 800); (e) VNTR exon 3 [(CTGT)3 and (CTGT)4] (CTGT)3 = 0.262 (n = 105); and (f) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2 = 0.096 (n = 193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A-IV. The apo A-IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2 = 0.329 (n = 217); VNTR exon 3 (CTGT)3 = 0.262 (n = 84); MspI within intron 2, allele 2 = 0.092 (n = 222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender-specific effects of apo A-IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A-IV gene is not a major determinant of the risk for CHD in Japanese.

Adult↗
PubMed2005

Prediction of the phenotypic effects of non-synonymous single nucleotide polymorphisms using structural and evolutionary information.

MOTIVATION: There has been great expectation that the knowledge of an individual's genotype will provide a basis for assessing susceptibility to diseases and designing individualized therapy. Non-synonymous single nucleotide polymorphisms (nsSNPs) that lead to an amino acid change in the protein product are of particular interest because they account for nearly half of the known genetic variations related to human inherited diseases. To facilitate the identification of disease-associated nsSNPs from a large number of neutral nsSNPs, it is important to develop computational tools to predict the phenotypic effects of nsSNPs. RESULTS: We prepared a training set based on the variant phenotypic annotation of the Swiss-Prot database and focused our analysis on nsSNPs having homologous 3D structures. Structural environment parameters derived from the 3D homologous structure as well as evolutionary information derived from the multiple sequence alignment were used as predictors. Two machine learning methods, support vector machine and random forest, were trained and evaluated. We compared the performance of our method with that of the SIFT algorithm, which is one of the best predictive methods to date. An unbiased evaluation study shows that for nsSNPs with sufficient evolutionary information (with not <10 homologous sequences), the performance of our method is comparable with the SIFT algorithm, while for nsSNPs with insufficient evolutionary information (<10 homologous sequences), our method outperforms the SIFT algorithm significantly. These findings indicate that incorporating structural information is critical to achieving good prediction accuracy when sufficient evolutionary information is not available. AVAILABILITY: The codes and curated dataset are available at http://compbio.utmem.edu/snp/dataset/

Algorithms↗
PubMed2003

Evidence that Egfr contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster.

One objective of quantitative genetics is to identify the nucleotide variants within genes that contribute to phenotypic variation and susceptibility [1]. In an evolutionary context, this means characterizing the molecular polymorphisms that modify the penetrance and expressivity of perturbed traits. A survey of association between 267 SNPs in almost 11 kb of the D. melanogaster Egfr and the degree of eye roughening due to a gain-of-function Egfr(E1) allele crossed into 210 isogenic wild-type lines provides evidence that a handful of synonymous substitutions supply cryptic variation for photoreceptor determination. Ten sites exceed Bonferroni threshold for association in two sets of crosses to different Egfr(E1) backgrounds including a particularly significant cluster of sites in tight linkage disequilibrium toward the 3' end of the coding region. Epistatic interaction of this cluster with one other site enhances the expressivity of this haplotype. Replication of the strongest associations with an independent sample of 302 phenotypically extreme individuals derived from 1000 crosses of Egfr(E1) to freshly trapped males was achieved using modified case-control and transmission-disequilibrium tests. A tendency for the rarer alleles to have more disrupted eye development suggests that mutation-selection balance is a possible mechanism contributing to maintaining cryptic variation for Egfr.

Alleles↗
PubMed2004

Aryl hydrocarbon receptor polymorphisms and dioxin resistance in Atlantic killifish (Fundulus heteroclitus).

The aryl hydrocarbon receptor (AHR) gene encodes a ligand-activated transcription factor through which planar halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as well as polynuclear aromatic hydrocarbons (PAHs) cause altered gene expression and toxicity. To understand the role of AHR genetic variability in differential sensitivity to HAHs and PAHs, we are currently studying a population of the teleost Fundulus heteroclitus (Atlantic killifish) that has evolved genetic resistance to the toxic and biochemical effects of these compounds. Here, we report that the killifish AHR1 locus is highly polymorphic and that the frequencies of the major allele types differ between dioxin-sensitive and dioxin-resistant populations. Twenty-five single nucleotide polymorphisms (SNPs), nine of which are non-synonymous, were identified in the AHR1 coding sequence. Seven identified alleles were assigned to three groups, designated AHR1*1, AHR1*2 and AHR1*3. AHR1*1 alleles were under-represented in a population of dioxin- and polychlorinated biphenyl (PCB)-resistant fish from a PCB-contaminated Superfund site (New Bedford Harbor, Massachusetts, USA) compared to dioxin-sensitive fish from a less contaminated reference site (Scorton Creek, Massachusetts, USA). To determine the possible role of these AHR1 variants in differential HAH sensitivity, we expressed representative variant proteins from the two most divergent allelic groups (AHR1*1 and AHR1*3) by in-vitro transcription and translation and assessed their functional properties. AHR1*1A and AHR1*3A proteins displayed similar binding capacities and affinities for [H]TCDD. In transient transfection assays using mammalian cells, AHR1*1A and AHR1*3A exhibited similar abilities to support TCDD-dependent transactivation of a luciferase reporter gene under control of AHR-responsive enhancer elements. We discuss the possibility of other functional differences in AHR1 variants or their interaction with other killifish loci (AHR2, AHRR) that may contribute to differences in dioxin sensitivity.

Animals↗
PubMed2005

Characterization of novel CYP2A6 polymorphic alleles (CYP2A6*18 and CYP2A6*19) that affect enzymatic activity.

Genetic polymorphisms of CYP2A6 gene are known as a causal factor of the interindividual differences in nicotine metabolism. We found three novel CYP2A6 alleles. The CYP2A6(*)18A allele has a single nucleotide polymorphism (SNP) of A5668T (A1175T, Y392F) in exon 8. The CYP2A6(*)18B allele has synonymous SNPs of G51A (G51A), T5684C (T1191C), and T5702C (T1209C) in addition to A5668T (A1175T, Y392F). The CYP2A6(*)19 allele has the SNPs of A5668T (A1175T, Y392F), T6354C (intron 8), and T6558C (T1412C, I471T) as well as the conversion with the CYP2A7 sequence in the 3'-untranslated region, in which the latter two changes correspond to CYP2A6(*)7. Ethnic differences in the frequencies of these alleles were observed between whites, African-Americans, Japanese, and Koreans. Wild or variant CYP2A6 (CYP2A6(*)18, CYP2A6(*)19, and CYP2A6(*)7) were expressed in Escherichia coli. For coumarin 7-hydroxylation and 5-fluorouracil formation from tegafur, the K(m) values were increased, and V(max) values were decreased in CYP2A6.18 compared with those in CYP2A6.1, resulting in decreased clearance to 50 and 35% of that of the wild type, respectively. The K(m) and V(max) values for nicotine C-oxidation were both increased, resulting in no change of clearance. In CYP2A6.19, the effects on the coumarin 7-hydroxylation and 5-fluorouracil formation (increased K(m) and decreased V(max)) were prominent, resulting in decreased clearance to 8% of those of the wild type. For nicotine C-oxidation, the K(m) and V(max) values were both decreased, resulting in decreased clearance to 30% of that of the wild type. The changes of the kinetics in CYP2A6.19 were similar to those in CYP2A6.7. In vivo nicotine metabolism was evaluated in whites (n = 56) and Koreans (n = 40). Although the CYP2A6(*)18 and CYP2A6(*)19 alleles were found only heterozygously, a subject with CYP2A6(*)7/CYP2A6(*)19 showed a lower cotinine/nicotine ratio of the plasma concentration compared with homozygotes of the CYP2A6(*)1A, supporting the in vitro results that the CYP2A6(*)19 allele leads to decreased enzymatic activity.

Black or African American↗