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PubMed2006

Phylogenetic analysis of polyomavirus BK sequences.

Polyomavirus BK (BKV) has emerged as an important pathogen in kidney transplant patients. Existing taxonomic classifications of BKV come from conventional DNA sequence alignments based on limited data derived from the VP1 gene. We have used a phylogenetic whole-genome approach to examine the pattern of diversity and evolutionary relationships between 45 BKV strains isolated from multiple clinical settings. This analysis supports the classification of BKV into six genotypes, of which types V and VI have not been previously recognized. BKV strains hitherto classified as type I are, in fact, quite heterogeneous, and several cluster with our newly defined genotypes V and VI. The sequence information needed for assigning genotypes can be captured by VP1, VP2, VP3, or large T-gene sequencing. The most polymorphic coding region in the viral genome is VP1, but significant variation is also present in the large T-antigen gene, wherein polymorphisms are found in 11.39% of all nucleotide sites, 46.22% of which are cluster specific. Type-specific amino acid changes within the VP1 region are predicted to map to the BC and DE loops. The number of taxonomically informative amino acid changes in the large T antigen exceeds even that of the VP1 region. Viral strains isolated from healthy subjects and from patients with human immunodeficiency virus infection, Wiskott-Aldrich syndrome, and vasculopathy with capillary leak syndrome formed distinct subclusters. However, within the kidney transplant population, BKV strains derived from patients with asymptomatic viruria did not show complete separation from strains associated with allograft nephropathy.

Antigens, Viral, Tumor↗
PubMed2001

Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy.

PURPOSE: To investigate the segregation pattern of the mitochondrial DNA mutation at nucleotide position 3460 responsible for Leber's hereditary optic neuropathy (LHON) and to determine the prevalence of heteroplasmy for the three primary LHON mutations at positions 11778, 3460, and 14484. METHODS: Segregation analysis was performed in a cross-sectional study by determining the level of heteroplasmy in blood leukocytes of 23 LHON patients and unaffected carriers from four unrelated families. One family comprising two affected and three unaffected carriers was followed over 5.5 years for a longitudinal segregation analysis of heteroplasmy. The percentage of mutant mtDNA was determined using a novel procedure of fluorescence-based primer extension and restriction fragment length polymorphism analysis. The prevalence of heteroplasmy was assessed by determining the number of genealogically unrelated LHON pedigrees with heteroplasmic maternal family members from the LHON patient records of the Department of Ophthalmology, University of Tübingen, Germany. RESULTS: The authors observed a marked variability in the degree of heteroplasmy levels within each pedigree and a tendency toward a higher mutant allele frequency in offspring generations. Disease expression was correlated with higher levels of mutant mtDNA molecules. Longitudinal analysis revealed no statistically significant decrease in the heteroplasmy level in the family studied but a reduction of 11% and 12% in one affected and one unaffected individual, respectively. In 167 genealogically unrelated LHON families the prevalence of heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 LHON mutations, respectively. CONCLUSIONS: Cross-sectional studies of heteroplasmy for the 3460 LHON mutation suggest that the genotype shifts toward a higher mutational load in offspring generations. Long-term decrease in the blood mutant load in single cases indicates negative selection of the mutant allele in the hematopoietic cell system. The prevalence of heteroplasmy varies significantly between the different primary LHON mutations, suggesting genotypical differences in disease expression.

Chromosome Segregation↗
PubMed1996

Genetic recombination at the human RH locus: a family study of the red-cell Evans phenotype reveals a transfer of exons 2-6 from the RHD to the RHCE gene.

The human RH locus appears to consist of two structural genes, D and CE, which map on the short arm p34-36 of chromosome 1 and specify a most complex system of blood-group genetic polymorphisms. Here we describe a family study of the Evans (also known as "D..") phenotype, a codominant trait associated with both qualitative and quantitative changes in D-antigen expression. A cataract-causing mutation was also inherited in this family and was apparently cotransmitted with Evans, suggesting a chromosomal linkage of these two otherwise unrelated traits. Southern blot analysis and allele-specific PCR showed the linkage of Evans with a SphI RFLP marker and the presence of a hybrid gene in the RH locus. To delineate the pattern of gene expression, the composition and structure of Rh-polypeptide transcripts were characterized by reverse transcriptase-PCR and nucleotide sequencing. This resulted in the identification of a novel Rh transcript expressed only in the Evans-positive erythroid cells. Sequence analysis showed that the transcript maintained a normal open reading frame but occurred as a CE-D-CE composite in which exons 2-6 of the CE gene were replaced by the homologous counterpart of the D gene. This hybrid gene was predicted to encode a CE-D-CE fusion protein whose surface expression correlates with the Evans phenotype. The mode and consequence of such a recombination event suggest the occurrence, in the RH locus, of a segmental DNA transfer via the mechanism of gene conversion.

Adult↗
PubMed1986

T cell receptor genes in an alloreactive CTL clone: implications for rearrangement and germline diversity of variable gene segments.

Both cDNA and genomic clones of the T cell receptor (TCR) alpha- and beta-chain genes of the alloreactive cytotoxic T lymphocyte (CTL) clone F3 were examined. Two distinct rearrangement events, one functional and one non-functional, were found for both the alpha and beta loci. Thus only a single functional TCR alpha beta heterodimer could be defined, consistent with allelic exclusion in the TCR genes. The V alpha gene employed by F3 is part of a six-member V alpha subfamily. Genomic clones containing each member of this subfamily were isolated and the V alpha nucleotide sequences determined. Five of these six genes are functional; these genes differ from each other by 7-14% at the amino acid level. A single dominant hypervariable region was defined within this subfamily, in contrast to the pattern of variability seen between V alpha genes in general.

Alleles↗
PubMed1990

Signature patterns of DNA restriction fragments of Helicobacter pylori before and after treatment.

The genomic DNA of Helicobacter pylori was studied by electrophoretic analysis of restriction endonuclease fragments. Twenty seven isolates from eight patients in the United Kingdom, obtained before and after treatment with nitrofurantoin, and two reference strains from Australia and Peru were investigated. Digestion of DNA with HaeIII, which gave the clearest band pattern of the 20 enzymes tested, showed that each set of isolates from a single patient had a unique band pattern. The DNA signature band patterns of strains from different patients were less than or equal to 62% similar (average 43%); similarities of patterns from the same patient were generally greater than or equal to 86%. Some minor but reproducible polymorphisms (less than or equal to five bands) in the signature region were detected in most consecutive isolates. Plasmid DNA was detected in isolates from five patients, but major pattern differences were attributed to genomic variation. It is concluded that the HaeIII DNA digest signature fingerprints provide a reproducible and sensitive method of discriminating between isolates of H pylori.

Campylobacter↗
PubMed2005

Analysis of single-locus tests to detect gene/disease associations.

A goal of association analysis is to determine whether variation in a particular candidate region or gene is associated with liability to complex disease. To evaluate such candidates, ubiquitous Single Nucleotide Polymorphisms (SNPs) are useful. It is critical, however, to select a set of SNPs that are in substantial linkage disequilibrium (LD) with all other polymorphisms in the region. Whether there is an ideal statistical framework to test such a set of 'tag SNPs' for association is unknown. Compared to tests for association based on frequencies of haplotypes, recent evidence suggests tests for association based on linear combinations of the tag SNPs (Hotelling T(2) test) are more powerful. Following this logical progression, we wondered if single-locus tests would prove generally more powerful than the regression-based tests? We answer this question by investigating four inferential procedures: the maximum of a series of test statistics corrected for multiple testing by the Bonferroni procedure, T(B), or by permutation of case-control status, T(P); a procedure that tests the maximum of a smoothed curve fitted to the series of of test statistics, T(S); and the Hotelling T(2) procedure, which we call T(R). These procedures are evaluated by simulating data like that from human populations, including realistic levels of LD and realistic effects of alleles conferring liability to disease. We find that power depends on the correlation structure of SNPs within a gene, the density of tag SNPs, and the placement of the liability allele. The clearest pattern emerges between power and the number of SNPs selected. When a large fraction of the SNPs within a gene are tested, and multiple SNPs are highly correlated with the liability allele, T(S) has better power. Using a SNP selection scheme that optimizes power but also requires a substantial number of SNPs to be genotyped (roughly 10-20 SNPs per gene), power of T(P) is generally superior to that for the other procedures, including T(R). Finally, when a SNP selection procedure that targets a minimal number of SNPs per gene is applied, the average performances of T(P) and T(R) are indistinguishable.

Computer Simulation↗
PubMed2004

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0.04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P = 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.

Arginine↗
PubMed2003

Excess of nonsynonymous polymorphism at Acph-1 in different gene arrangements of Drosophila subobscura.

Nucleotide variation in the Acph-1 gene region was analyzed in a natural population of Drosophila subobscura from Bizerte (Tunisia). The lines studied differed in their gene arrangement for segment I of the O chromosome: 21 lines were O3+4+8, 21 were O3+4+23, and 3 were O3+4. According to chromosomal phylogenies, O3+4 is a central arrangement from which O3+4+8 and O3+4+23 originated. Strong genetic differentiation at Acph-1 was detected among the different arrangements, which is reflected in strong linkage disequilibrium between the variants at informative polymorphic sites and the type of arrangement. Estimates of silent nucleotide diversity are slightly lower within O3+4+23 (pisilent = 0.0166) than within O3+4+8 (pisilent = 0.0228) or O3+4 (pisilent = 0.0234). In contrast, nonsynonymous nucleotide diversity estimates (around 0.1%) are similar in the three arrangements. Most nonsynonymous rare variants are singletons, which results in highly significant Tajima's neutrality tests within the young O3+4+8 and O3+4+23 arrangements. This test is not significant for nonsynonymous mutations within a large Spanish O3+4 sample. In addition, a significant and marginally significant excess of nonsynonymous polymorphism was detected by the McDonald and Kreitman test within O3+4+23 and O3+4+8, respectively. This excess results in a rather high neutrality index (NI = 5.25) when both arrangements are jointly analyzed, in contrast to its value within the old O3+4 arrangement (NI = 1.74). The pattern of variation at Acph-1 within the young arrangements is unusual for nuclear genes and has the same characteristics previously detected in most genes of the mitochondrial genome. Assuming that most nonsynonymous mutations at Acph-1 are under weak negative selection, a smaller effective size of the young arrangements relative to O3+4 might explain the observed results. The relatively low frequency of O3+4+8 and O3+4+23 in the distribution area of D. subobscura, the more recent origin of these arrangements relative to O3+4 and the suppression of recombination in heterokaryotypes might contribute to the relatively small effective size of the young arrangements. Therefore, present results indicate that the differences in effective size and recombination caused by chromosomal arrangements are modulating nonsynonymous variation at Acph-1.

Acid Phosphatase↗
PubMed1996

Characterization of streptomycin resistance mechanisms among Mycobacterium tuberculosis isolates from patients in New York City.

From a collection of 367 isolates of Mycobacterium tuberculosis from patients in New York City in 1994, 45 isolates (12.3%) were resistant in vitro to 2 micrograms or more of streptomycin (SM) per ml. We further evaluated these isolates for levels of SM resistance and for mutations previously associated with resistance in the rpsL (S12 ribosomal protein) gene and the rrs (16S rRNA)-coding region. Twenty-four isolates, representing nine distinct patterns of susceptibility to antituberculosis drugs, were resistant to 500 micrograms of SM per ml and shared a common point mutation at nucleotide 128 in the rpsL gene. This mutation, which substitutes lysine for arginine in the S12 ribosomal binding protein, was not present in isolates with low-level SM resistance or in SM-susceptible control isolates. Among 20 isolates with low-level SM resistance, one possessed a substitution (C-->G865) in the 912 loop of the rrs gene. No mutations in the 530 loop of the rrs coding region were detected, suggesting the presence of an alternative SM resistance mechanism in 19 isolates. Single-strand conformation polymorphisms of mutants were readily detected by a nonradioactive gel screen.

Antibiotics, Antitubercular↗
PubMed2005

Contribution of transcriptional regulation to natural variations in Arabidopsis.

BACKGROUND: Genetic control of gene transcription is a key component in genome evolution. To understand the transcriptional basis of natural variation, we have studied genome-wide variations in transcription and characterized the genetic variations in regulatory elements among Arabidopsis accessions. RESULTS: Among five accessions (Col-0, C24, Ler, WS-2, and NO-0) 7,508 probe sets with no detectable genomic sequence variations were identified on the basis of the comparative genomic hybridization to the Arabidopsis GeneChip microarray, and used for accession-specific transcriptome analysis. Two-way ANOVA analysis has identified 60 genes whose mRNA levels differed in different accession backgrounds in an organ-dependent manner. Most of these genes were involved in stress responses and late stages of plant development, such as seed development. Correlation analysis of expression patterns of these 7,508 genes between pairs of accessions identified a group of 65 highly plastic genes with distinct expression patterns in each accession. CONCLUSION: Genes that show substantial genetic variation in mRNA level are those with functions in signal transduction, transcription and stress response, suggesting the existence of variations in the regulatory mechanisms for these genes among different accessions. This is in contrast to those genes with significant polymorphisms in the coding regions identified by genomic hybridization, which include genes encoding transposon-related proteins, kinases and disease-resistance proteins. While relatively fewer sequence variations were detected on average in the coding regions of these genes, a number of differences were identified from the upstream regions, several of which alter potential cis-regulatory elements. Our results suggest that nucleotide polymorphisms in regulatory elements of genes encoding controlling factors could be primary targets of natural selection and a driving force behind the evolution of Arabidopsis accessions.

Arabidopsis↗
PubMed1987

The human and rodent intestinal fatty acid binding protein genes. A comparative analysis of their structure, expression, and linkage relationships.

Intestinal fatty acid binding protein (I-FABP) is believed to participate in the uptake, intracellular metabolism, and/or transport of long chain fatty acids within enterocytes. The 15.1-kDA rodent proteins is a member of a family of low Mr cytoplasmic proteins that have evolved to bind different ligands. We have now determined the nucleotide sequence of the gene encoding human I-FABP and defined the primary structure of its protein product. The human I-FABP gene spans 3382 nucleotides and contains 4 exons (103 or 128, 173, 108, and 312 base pairs). interrupted by 3 introns (1194, 1023, and 444 base pairs). The 132-residue rat and human I-FABPs have 82% amino acid sequence identity. Blot hybridization studies of RNAs prepared from a variety of adult rhesus monkey tissues as well as human intestine and liver indicate that I-FABP mRNA is confined to the intestine. I-FABP mRNA was not detectable in a number of cultured human enterocyte-like cell lines, suggesting it may be a sensitive marker for differentiated, villus-associated, small intestinal lining cells. Given the similar patterns of tissue-specific expression exhibited by the rat and human genes, we compared their 5' nontranscribed regions. Optimal alignments of the two sequences disclosed 64% identity among the 260 nucleotides immediately 5' to the start site of transcription. Matrix plots revealed a 14-nucleotide long repeated sequence (5'-TGAACTTTGAACTT-3') in the 5' nontranscribed region of both genes as well as in a comparable region of another family member that is expressed in enterocytes, cellular retinol binding protein II. The linkage relationships between I-FABP and the homologous liver FABP (L-FABP) gene were defined in mice and humans. The mouse genes were mapped using restriction fragment length polymorphisms and recombinant inbred strains. The I-FABP gene is located on mouse chromosome 3 between the amylase 1,2 (Amy 1,2) and alcohol dehydrogenase 3 (Adh-3) loci while the L-FABP gene is on mouse chromosome 6 within 3 centimorgans of the lymphocyte antigen-2 (Ly-2) locus. Mouse L-FABP may be identical to the major liver protein-1 (Lvp-1) which is encoded by a gene situated within a centimorgan of Ly-2. Human gene mapping studies were carried out using a panel of mouse-human somatic cell hybrid clones as well as in situ hybridization to metaphase chromosomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1999

Characterization of a new HLA-B*38 allele (B*3803) in a Spanish Caucasian individual which is closely related to the Oriental B*38021 and B*39021 alleles.

The broad HLA-B16 serologic specificity is divided into B38 and B39 splits associated to Bw4 and Bw6, respectively. Differential serologic variants have been defined for several molecular subtypes of B39 and for B38. We found a Spanish Caucasian individual carrying a B16 Bw4-associated antigen which was not recognized by reagents against B16 splits. Sequencing analysis showed a new B16 subtype termed B*3803. HLA class I sequence-based typing (SBT) analysis demonstrated that B*3803 co-segregates with A*2608 and Cw*1203, forming a common Caucasian haplotype. Sequence comparison with B*38 and B*39 subtypes evidences that although B*3803 is close related to B*3802, it only differs from B*39021 by six clustered nucleotide position in the Bw4/Bw6 motif, and strongly suggests that B*3803 could have evolved from, or be the ancestral gene of the Oriental-associated B*3802 and B*39021 alleles. However, more complex patterns of genetic events should be considered due to the Caucasian background of the B*3803 individual an its associated haplotype.

Alleles↗
PubMed2000

Identification of a novel allele, DRB1*1340, in two Brazilian individuals.

We identified a novel HLA-DRB1 allele, named DRB1*1340 by the WHO HLA Nomenclature Committee, in two Brazilian individuals. Typing by polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) showed a DRB1*13 allele with an unusual hybridization pattern. DNA sequencing of both strands and comparison of the sequence with previously described DRB1 alleles revealed that the most similar allele is DRB1*1301, from which DRB1*1340 differs by a single nucleotide (T-->A) in exon 2, at position 127, codon 47 (Phe-->Tyr). The sequence received accession number AJ237964 from the EMBL database.

Alleles↗
PubMed1999

Population genetic structure of the African elephant in Uganda based on variation at mitochondrial and nuclear loci: evidence for male-biased gene flow.

A drastic decline has occurred in the size of the Uganda elephant population in the last 40 years, exacerbated by two main factors; an increase in the size of the human population and poaching for ivory. One of the attendant consequences of such a decline is a reduction in the amount of genetic diversity in the surviving populations due to increased effects of random genetic drift. Information about the amount of genetic variation within and between the remaining populations is vital for their future conservation and management. The genetic structure of the African elephant in Uganda was examined using nucleotide variation of mitochondrial control region sequences and four nuclear microsatellite loci in 72 individuals from three localities. Eleven mitochondrial DNA (mtDNA) haplotypes were observed, nine of which were geographically localized. We found significant genetic differentiation between the three populations at the mitochondrial locus while three out of the four microsatellite loci differentiated KV and QE, one locus differentiated KV and MF and no loci differentiated MF and QE. Expected heterozygosity at the four loci varied between 0.51 and 0.84 while nucleotide diversity at the mitochondrial locus was 1.4%. Incongruent patterns of genetic variation within and between populations were revealed by the two genetic systems, and we have explained these in terms of the differences in the effective population sizes of the two genomes and male-biased gene flow between populations.

Animals↗
PubMed2005

Genes encoding catalytic subunits of protein kinase A and risk of spina bifida.

BACKGROUND: PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida. METHODS: We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination. RESULTS: Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida. CONCLUSIONS: Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.

Alleles↗
PubMed2003

A comparison of intraspecific patterns of DNA sequence variation in mitochondrial DNA, alpha-enolase, and MHC class II B loci in auklets (Charadriiformes: Alcidae).

Patterns of DNA sequence variation can be used to learn about mechanisms of organismal evolution, but only if mechanisms of sequence evolution are well understood. Although theories of molecular evolution are well developed, few empirical studies have addressed patterns and mechanisms of sequence evolution in nuclear genes within species. In the present study, we compared DNA sequences among three loci with different evolutionary constraints to determine the influences of effective population size, balancing selection, and linkage on intraspecific patterns of sequence variation. Specifically, we assessed the degree and nature of polymorphism in a 307-base pair (bp) fragment of the mitochondrial cytochrome b gene, intron VIII of the gene for alpha-enolase (a presumably neutral nuclear gene), and an approximately 600-bp fragment of an MHC class II B gene, including 155 bp of the hypervariable peptide binding region (a nuclear locus thought to be under balancing selection) for least and crested auklets (Aethia pusilla and A. cristatella; Charadriiformes: Alcidae). Transspecies polymorphism was found in both alpha-enolase and the MHC but not cytochrome b and, given estimates of effective population size, probably represents retained ancestral variation. Biases in nucleotide composition suggested that mutational bias, tRNA availability, and the secondary structure of mRNA and/or DNA may influence base usage. Several lines of evidence indicated that balancing selection may be acting on the MHC II B exon 2. However, no evidence of balancing selection was observed in the intron and exon sequences immediately downstream of MHC II B exon 2.

Animals↗
PubMed2001

Analysis of the TSC2 gene in human medulloblastoma.

Medulloblastoma (MB) represents the most frequent malignant brain tumor of childhood. Recent studies have shown that deregulation of developmental control genes may play an important role in its pathogenesis. Tuberous sclerosis is associated with hamartomas and cortical tubers, consisting of both glial and neuronal cellular components. MBs can also show markers of these lineages, raising the question of the potential involvement of TSC genes in these malignant tumors. Here we investigated tuberous sclerosis 2 (TSC2), one of the two genes responsible for tuberous sclerosis, in sporadic MBs. We analyzed MBs for allelic losses at the TSC2 locus and for the frequency of a polymorphism first described in gangliogliomas. Sixty-eight MBs were examined for this polymorphism located in intron 4, 3 base pairs 5' to the first coding nucleotide of exon 5. The distribution of the alleles was significantly different in MBs as compared to 208 control samples, (P=0.0017, Chi-square test). In MBs the frequency of the rare allele (A2) was 0.184 (18.4%), whereas in the control group it occurred in a frequency of 8.7%. Microsatellite analysis of the TSC2 region in 50 tumors did not identify allelic losses. TSC2 mRNA transcript was detectable via reverse transcription-PCR in all tumors as well as in normal cerebellum. Northern blot analysis of an MB cell line homozygous for the rare allele of the polymorphism and two other cell lines homozygous for the frequent allele revealed normal splicing patterns and normal expression levels of the TSC2 transcript. These findings may indicate that the presence of the rare TSC2 allele is associated with a predisposition for the development of MBs.

Blotting, Northern↗
PubMed2006

Association between serotonin transporter gene and borderline personality disorder.

Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. BPD affects about 1-2% of the general population and has a high mortality rate as a result of suicide and impulsive behaviour. The serotonin transporter gene (5-HTT) is considered as a candidate gene for BPD as multiple lines of evidence have suggested that it plays an important role in suicide, impulsive behaviour, and emotional liability. To test for an association between 5-HTT and BPD, we genotyped three common polymorphisms: the serotonin transporter linked promoter region (5-HTTLPR); a variable number of tandem repeat (VNTR) in intron 2, and a single nucleotide variant (A/G) within the LPR region. Eighty-nine Caucasian patients with BPD and 269 Caucasian healthy controls were analyzed. The program UNPHASED was used to compare allele and haplotype frequencies between cases and controls. Significant differences in allele frequencies of the VNTR marker (p=0.012) and haplotype frequencies (p=0.002) between patients and controls were found. Compared with healthy controls, patients with BPD showed higher frequencies of the 10 repeat of the VNTR marker and the S-10 haplotype, and lower 12 repeat and L(A)-12 haplotype. Our results suggest that the serotonin transporter gene may play a role in the aetiology of borderline personality disorder.

Adult↗