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PubMed2000

Mutation analysis of the entire mitochondrial genome using denaturing high performance liquid chromatography.

In patients with mitochondrial disease a continuously increasing number of mitochondrial DNA (mtDNA) mutations and polymorphisms have been identified. Most pathogenic mtDNA mutations are heteroplasmic, resulting in heteroduplexes after PCR amplification of mtDNA. To detect these heteroduplexes, we used the technique of denaturing high performance liquid chromatography (DHPLC). The complete mitochondrial genome was amplified in 13 fragments of 1-2 kb, digested in fragments of 90-600 bp and resolved at their optimal melting temperature. The sensitivity of the DHPLC system was high with a lowest detection of 0.5% for the A8344G mutation. The muscle mtDNA from six patients with mitochondrial disease was screened and three mutations were identified. The first patient with a limb-girdle-type myopathy carried an A3302G substitution in the tRNA(Leu(UUR)) gene (70% heteroplasmy), the second patient with mitochondrial myopathy and cardiomyopathy carried a T3271C mutation in the tRNA(Leu(UUR)) gene (80% heteroplasmy) and the third patient with Leigh syndrome carried a T9176C mutation in the ATPase6 gene (93% heteroplasmy). We conclude that DHPLC analysis is a sensitive and specific method to detect heteroplasmic mtDNA mutations. The entire automatic procedure can be completed within 2 days and can also be applied to exclude mtDNA involvement, providing a basis for subsequent investigation of nuclear genes.

Adenosine Triphosphatases↗

PubMed2005

Relationship between the extent of chromosomal losses and the pattern of CpG methylation in gastric carcinomas.

The extent of unilateral chromosomal losses and the presence of microsatellite instability (MSI) have been classified into high-risk (high- and baseline-level loss) and low-risk (low-level loss and MSI) stem-line genotypes in gastric carcinomas. A unilateral genome-dosage reduction might stimulate compensation mechanism, which maintains the genomic dosage via CpG hypomethylation. A total of 120 tumor sites from 40 gastric carcinomas were examined by chromosomal loss analysis using 40 microsatellite markers on 8 chromosomes and methylation analysis in the 13 CpG (island/non-island) regions near the 10 genes using the bisulfite-modified DNAs. The high-level-loss tumor (four or more losses) showed a tendency toward unmethylation in the Maspin, CAGE, MAGE-A2 and RABGEF1 genes, and the other microsatellite-genotype (three or fewer losses and MSI) toward methylation in the p16, hMLH1, RASSF1A, and Cyclin D2 genes (p<0.05). The non-island CpGs of the p16 and hMLH1 genes were hypomethylated in the high-level-loss and hypermethylated in the non-high-level-loss sites (p<0.05). Consequently, hypomethylation changes were related to a high-level loss, whereas the hypermethylation changes were accompanied by a baseline-level loss, a low-level loss, or a MSI. This indicates that hypomethylation compensates the chromosomal losses in the process of tumor progression.

Chromosome Aberrations↗

PubMed2000

A two-stage variable-stringency semiparametric method for mapping quantitative-trait loci with the use of genomewide-scan data on sib pairs.

Genomewide scans for mapping loci have proved to be extremely powerful and popular. We present a semiparametric method of mapping a quantitative-trait locus (QTL) or QTLs with the use of sib-pair data generated from a two-stage genomic scan. In a two-stage genomic scan, either the entire genome or a large portion of the genome is saturated with low-density markers at the first stage. At the second stage, the intervals that are identified as probable locations of the trait loci, by means of analysis of data from the first stage, are then saturated with higher-density markers. These data are then analyzed for fine mapping of the loci. Our statistical strategy for analysis of data from the first stage is a low-stringency method based on the rank correlation of squared trait-difference values of the sib pairs and the estimated identity-by-descent scores at the marker loci. We suggest the use of a low-stringency method at the first stage, to save on computational time and to avoid missing any marker interval that may contain the trait loci. For analysis of data from the second stage, we have developed a high-stringency nonparametric-regression approach, using the kernel-smoothing technique. Through extensive simulations, we show that this approach is more powerful than is a currently used method for mapping QTLs by use of sib pairs, particularly in the presence of dominance and epistatic effects at the trait loci.

Alleles↗

PubMed2006

Detecting statistically significant common insertion sites in retroviral insertional mutagenesis screens.

Retroviral insertional mutagenesis screens, which identify genes involved in tumor development in mice, have yielded a substantial number of retroviral integration sites, and this number is expected to grow substantially due to the introduction of high-throughput screening techniques. The data of various retroviral insertional mutagenesis screens are compiled in the publicly available Retroviral Tagged Cancer Gene Database (RTCGD). Integrally analyzing these screens for the presence of common insertion sites (CISs, i.e., regions in the genome that have been hit by viral insertions in multiple independent tumors significantly more than expected by chance) requires an approach that corrects for the increased probability of finding false CISs as the amount of available data increases. Moreover, significance estimates of CISs should be established taking into account both the noise, arising from the random nature of the insertion process, as well as the bias, stemming from preferential insertion sites present in the genome and the data retrieval methodology. We introduce a framework, the kernel convolution (KC) framework, to find CISs in a noisy and biased environment using a predefined significance level while controlling the family-wise error (FWE) (the probability of detecting false CISs). Where previous methods use one, two, or three predetermined fixed scales, our method is capable of operating at any biologically relevant scale. This creates the possibility to analyze the CISs in a scale space by varying the width of the CISs, providing new insights in the behavior of CISs across multiple scales. Our method also features the possibility of including models for background bias. Using simulated data, we evaluate the KC framework using three kernel functions, the Gaussian, triangular, and rectangular kernel function. We applied the Gaussian KC to the data from the combined set of screens in the RTCGD and found that 53% of the CISs do not reach the significance threshold in this combined setting. Still, with the FWE under control, application of our method resulted in the discovery of eight novel CISs, which each have a probability less than 5% of being false detections.

Chromosome Mapping↗

PubMed1999

Familial paragangliomas: the emerging impact of molecular genetics on evaluation and management.

HYPOTHESIS: Advancements in molecular genetics has direct impact on the evaluation and management of patients and family members with familial paragangliomas (FP). BACKGROUND: Familial paragangliomas. in contrast to sporadic cases, are commonly multiple, bilateral, and present at an earlier age. Familial tumors are inherited in an autosomal dominant pattern with genomic imprinting of the paternal allele. Mapping studies have identified regions on chromosome 11q as harboring the genetic defect responsible for paraganglioma formation. METHODS: A multigenerational family with five affected females with head and neck paragangliomas underwent clinical and genetic evaluation. Genetic mapping was performed with microsatellite markers froin chromosome 11q13 and q23. Nonaffected individuals were screened for carrying the affected haplotype. In addition, by using DNA obtained from an amniotic fluid sample. in utero screening of a fetus was performed. RESULTS: The most common complaints were hearing loss and neck masses that usually manifested by age 25. Genetic mapping identified loci 11q13 and q23 as sites likely responsible for tumorogenesis. Three unaffected family members, including a fetus, were identified as carriers of the affected haplotype. The genetic findings were used to design a screening protocol for family members at risk for developing glomus tumors. CONCLUSIONS: Genetic screening of unaffected family members can identify individuals harboring the mutated allele. Identification of family members at risk for developing FP by molecular genetic techniques may lead to early detection of head and neck paragangliomas and may directly impact morbidity from glomus tumors and their treatment.

Adult↗

PubMed2000

Genetic dissection of the multiple functions of alfalfa mosaic virus coat protein in viral RNA replication, encapsidation, and movement.

Coat protein (CP) of alfalfa mosaic virus (AMV) binds as a dimer to the 3' termini of the three genomic RNAs and is required for initiation of infection, asymmetric plus-strand RNA accumulation, virion formation, and spread of the virus in plants. A mutational analysis of the multiple functions of AMV CP was made. Mutations that interfered with CP dimer formation in the two-hybrid system had little effect on the initiation of infection or plus-strand RNA accumulation but interfered with virion formation and reduced or abolished cell-to-cell movement of the virus in plants. Six of the 7 basic amino acids in the N-terminal arm of CP (positions 5, 6, 10, 13, 16, and 25) could be deleted or mutated into alanine without affecting any step of the replication cycle except systemic movement in plants. Mutation of Arg-17 interfered with initiation of infection (as previously shown by others) and cell-to-cell movement of the virus but not with plus-strand RNA accumulation or virion formation. The results indicate that in addition to the RNA-binding domain, different domains of AMV CP are involved in initiation of infection, plus-strand RNA accumulation, virion formation, cell-to-cell movement, and systemic spread of the virus.

Alfalfa mosaic virus↗

PubMed2004

Genomic organization and in vivo characterization of proteolytic activity of FtsH of Mycobacterium smegmatis SN2.

The ftsH gene of Mycobacterium smegmatis SN2 (MsftsH) was cloned from two independent partial genomic DNA libraries and characterized, along with the identification of ephA and folE as the neighbouring upstream and downstream genes respectively. The genomic organization of the MsftsH locus was found to be identical to that of the Mycobacterium tuberculosis ftsH gene (MtftsH) and similar to that of other bacterial genera, but with divergence in the upstream region. The MsftsH gene is 2.3 kb in size and encodes the AAA (ATPases Associated with diverse cellular Activities) family Zn(2+)-metalloprotease FtsH (MsFtsH) of 85 kDa molecular mass. This was demonstrated from the expression of the full-length recombinant gene in Escherichia coli JM109 cells and from the identification of native MsFtsH in M. smegmatis SN2 cell lysates by Western blotting with anti-MtFtsH and anti-EcFtsH antibodies respectively. The recombinant and the native MsFtsH proteins were found localized to the membrane of E. coli and M. smegmatis cells respectively. Expression of MsFtsH protein in E. coli was toxic and resulted in growth arrest and filamentation of cells. The MsftsH gene did not complement lethality of a DeltaftsH3 : : kan mutation in E. coli, but when expressed in E. coli cells, it efficiently degraded conventional FtsH substrates, namely sigma(32) protein and the protein translocase subunit SecY, of E. coli cells.

ATP-Dependent Proteases↗

PubMed2005

CGH analysis of familial non-BRCA1/BRCA2 breast tumors and mutation screening of a candidate locus on chromosome 17q11.2-12.

Mutations in the known predisposing breast cancer genes BRCA1 and BRCA2 account for only a small proportion (<10%) of breast cancer families in the Stockholm region of Sweden. This study aims to identify novel predisposing genes in non-BRCA1/BRCA2 breast cancer families. We have employed comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) data in combination with data from a recently carried out genome wide linkage scan, in an effort to identify chromosomal regions harboring potential breast cancer genes. CGH revealed loss of chromosome 17 and chromosome 6q to be a frequent event in high-risk breast cancer families, while gain of 8q was most prevalent in low-risk families. The loss of chromosome 17 was consistent with previous LOH studies and so this region was investigated further. Disease was shown to be linked to chromosome 17 in those families exhibiting loss of the chromosome in both CGH and LOH analyses. An overlapping region of linkage was determined to lie between markers D17S1294 and D17S1293, fine mapping of the region delineated a region between markers D17S1880 and D17S1293. Ten genes were determined to lie within this 1.5 Mb region and families were screened for germline mutations in these genes. In conclusion, we have investigated one possible small region on chromosome 17 for its involvement in high-risk non-BRCA1/BRCA2 breast cancer families. No predisposing mutations were identified in the 10 genes investigated in this study, however further analysis of chromosome 17 is warranted.

BRCA1 Protein↗

PubMed1997

The nucleocapsid protein specifically anneals tRNALys-3 onto a noncomplementary primer binding site within the HIV-1 RNA genome in vitro.

HIV type 1 (HIV-1) specifically uses host cell tRNALys-3 as a primer for reverse transcription. The 3' 18 nucleotides of this tRNA are complementary to a region on the HIV RNA genome known as the primer binding site (PBS). HIV-1 has a strong preference for maintaining a lysine-specific PBS in vivo, and viral genomes with mutated PBS sequences quickly revert to be complementary to tRNALys-3. To investigate the mechanism for the observed PBS reversion events in vitro, we examined the capability of the nucleocapsid protein (NC) to anneal various tRNA primer sequences onto either complementary or noncomplementary PBSs. We show that NC can anneal different full-length tRNAs onto viral RNA transcripts derived from the HIV-1 MAL or HXB2 isolates, provided that the PBS is complementary to the tRNA used. In contrast, NC promotes specific annealing of only tRNALys-3 onto an RNA template (HXB2) whose PBS sequence has been mutated to be complementary to the 3' 18 nt of human tRNAPro. Moreover, HIV-1 reverse transcriptase extends this binary complex from the proline-specific PBS. The formation of the noncomplementary binary complex does not occur when a chimeric tRNALys/Pro containing proline-specific D and anticodon domains is used as the primer. Thus, elements outside the acceptor-TPsiC domains of tRNALys-3 play an important role in preferential primer use in vitro. Our results support the hypothesis that mutant PBS reversion is a result of tRNALys-3 annealing onto and extension from a PBS that specifies an alternate host cell tRNA.

Base Sequence↗

PubMed2003

Genome-wide linkage scan for genes affecting longitudinal trends in systolic blood pressure.

Only one genome scan to date has attempted to make use of the longitudinal data available in the Framingham Heart Study, and this attempt yielded evidence of linkage to a gene for mean systolic blood pressure. We show how the additional information available in these longitudinal data can be utilized to examine linkages for not only mean systolic blood pressure (SBP), but also for its trend with age and its variability. Prior to linkage analysis, individuals treated for hypertension were adjusted to account for right-censoring of SBP. Regressions on age were fitted to obtain orthogonal measures of slope, curvature, and residual variance of SBP that were then used as dependent variables in the model-free linkage program SIBPAL. We included mean age, gender, and cohort as covariates in the analysis. To improve power, sibling pairs were weighted for informativity using weights derived from both the marker and trait. The most significant results from our analyses were found on chromosomes 12, 15, and 17 for mean SBP, and chromosome 20 for both SBP slope and curvature.

Adult↗

PubMed1999

Complementation and characterization of the nested Rz and Rz1 reading frames in the genome of bacteriophage lambda.

Transposon insertions in the Rz gene of bacteriophage lambda block lysis if the medium contains divalent cations at concentrations greater than 5 mM, but otherwise cause no change in phenotype. The Rz protein is thought to have an endopeptidase activity, previously reported in lambda lysates, which might be involved in cleavage of oligopeptide crosslinks between glycosidic strands in the peptidoglycan and the Lpp lipoproteins of the outer bacterial membrane. Recently, a small lipoprotein has been reported as the product of a short reading frame, designated Rz1, in the +1 register within Rz. This protein has been detected in membranes of induced lambda lysogens. To determine whether Rz1 has a function in the lambda vegetative cycle, amber nonsense alleles of Rz and Rz1 have been constructed by site-directed mutagenesis and used for complementation and suppression analysis. Both Rzam and Rz1am alleles have phenotypes identical to those of the original Rz insertion alleles, and complement and are fully suppressed in a supE host, indicating that the two genes are independent, trans-acting genes encoding proteins required for lysis in the presence of cations. Moreover, supF suppresses Rzam but not the Rz1am mutation, and the defective Rz1am product in the supF host shows a partially dominant character and significantly retards lysis even in the absence of additional cations in the medium. Rz and Rz1 represent a unique example of two genes located in different reading frames in the same nucleotide sequence, which encode different proteins that are both required in the same physiological pathway.

Amino Acid Sequence↗

PubMed2006

Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases.

Accumulated evidence from searching for candidate gene-disease associations of complex diseases can offer some insights as the field moves toward discovery-oriented approaches with massive genome-wide testing. Meta-analyses of 50 non-human lymphocyte antigen gene-disease associations with documented overall statistical significance (752 studies) show summary odds ratios with a median of 1.43 (interquartile range, 1.28-1.65). Many different biases may operate in this field, for both single studies and meta-analyses, and these biases could invalidate some of these seemingly "validated" associations. Studies with a sample size of >500 show a median odds ratio of only 1.15. The median sample size required to detect the observed summary effects in each population addressed in the 752 studies is estimated to be 3,535 (interquartile range, 1,936-9,119 for cases and controls combined). These estimates are steeply inflated in the presence of modest bias. Population heterogeneity, as well as gene-gene and gene-environment interactions, could steeply increase these estimates and may be difficult to address even by very large biobanks and observational cohorts. The one visible solution is for a large number of teams to join forces on the same research platforms. These collaborative studies ideally should be designed up front to also assess more complex gene-gene and gene-environment interactions.

Alleles↗

PubMed2003

Results of a high-resolution genome screen of 437 Alzheimer's disease families.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Aged↗

PubMed1995

Molecular cloning and expression of biotin sulfoxide reductase from Rhodobacter sphaeroides forma sp. denitrificans.

Biotin sulfoxide reductase catalyzes the conversion of d-biotin d-sulfoxide (BSO) to d-biotin. Oligonucleotides directed against common sequences in Escherichia coli biotin sulfoxide reductase and in Rhodobacter sphaeroides f.sp. denitrificans dimethyl sulfoxide reductase have been utilized to amplify by PCR a 651-bp fragment from R. sphaeroides total genomic DNA that showed a high degree of sequence similarity with both E. coli biotin sulfoxide reductase and R. sphaeroides dimethyl sulfoxide reductase. Screening of a genomic cosmid library, prepared from R. sphaeroides genomic DNA, with this probe resulted in the isolation of a 7-kb EcoRI-EcoRI fragment that contained the complete coding region for R. sphaeroides BSO reductase which has been sequenced. The sequence data indicated a single open reading frame of 2231 nucleotides encoding a protein of 744 amino acid residues corresponding to a subunit molecular weight of 80,234 Da. The translated protein sequence contained the prokaryotic Mo-pterin signatures 2 and 3 (Mo-cofactor binding motifs) and a ATP/GTP-binding P-loop. The R. sphaeroides BSO reductase sequence showed 51% sequence similarity with the corresponding E. coli enzyme. In addition, there were only two conserved cysteines between the two BSO reductase sequences. The R. sphaeroides gene was demonstrated, by complementation, to rescue a mutant E. coli strain that was deficient in BSO reductase when grown on BSO as the sole source of biotin. When expressed from the FLAG*Shift 12c expression vector, in the presence of IPTG, the BSO reductase gene encoded a protein of approximately 80 kDa, which cross-reacted with the anti-FLAG monoclonal antibody and exhibited BSO reductase activity by the disk microbiological assay.

Amino Acid Sequence↗

PubMed1994

Cloning and characterisation of genes for tetrapyrrole biosynthesis from the cyanobacterium Anacystis nidulans R2.

The genes for 5-aminolevulinic acid dehydratase (ALAD) and uroporphyrinogen III synthase (UROS), two enzymes in the biosynthetic pathway for tetrapyrroles, were independently isolated from a plasmid-based genomic library of Anacystis nidulans R2 (also called Synechococcus sp. PCC7942), by their ability to complement Escherichia coli strains carrying mutations in the equivalent genes (hemB and hemD respectively). The identity of the genes was confirmed by comparing the appropriate enzyme activities in complemented and mutant strains. Subclones of the original plasmids that were also capable of complementing the mutants were sequenced. The inferred amino acid sequence of the cyanobacterial HemB protein indicates a significant difference in the metal cofactor requirement from the higher-plant enzymes, which was confirmed by overexpression and biochemical analysis. The organisation of the cyanobacterial hemD locus differs markedly from other prokaryotes. Two open reading frames were found immediately upstream of hemD. The product of one shows considerable similarity to published sequences from other organisms for uroporphyrinogen III methylase (UROM), an enzyme involved in the production of sirohaem and cobalamins (including vitamin B-12). The product of the other shows motifs which are similar to those found in proteins responsible for metabolic regulation in yeast and indicates that this family of transcription control proteins, which has previously been reported only from eukaryotes, is also represented in prokaryotes.

Amino Acid Sequence↗

PubMed2026

Longitudinal surveillance of antibiotic resistance and virulence evolution in Clostridioides difficile: a 4-year retrospective study of hospitalized patients in a tertiary hospital in China.

UNLABELLED: Clostridioides difficile (C. difficile) is the primary pathogen responsible for nosocomial infectious diarrhea and pseudomembranous colitis. In China, metronidazole and vancomycin are the preferred treatments for C. difficile infection (CDI). This study aimed to investigate the evolution of vancomycin (VA) and metronidazole (MTZ) resistance, as well as the longitudinal changes in virulence over time, using next-generation sequencing, drug susceptibility tests, and analysis of resistance and virulence genes. Additionally, we monitored the emergence of the highly virulent C. difficile strain RT027 and the spread and potential outbreak of C. difficile in the hospital setting. A random stratified sampling method was used to select 114 fecal samples from inpatients at Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, between 2021 and 2024. Clinical data from the enrolled patients were also collected. We conducted antigen and toxin protein detection for C. difficile, strain isolation and identification, drug sensitivity tests, whole genome sequencing, and bioinformatics analysis. This included comparisons of drug resistance genes, detection of toxin genes, and the construction of phylogenetic trees based on pan-genome analysis to investigate the resistance and toxin gene variations in C. difficile. Among the 114 samples collected from Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, no vancomycin- or metronidazole-resistant strains were identified. However, the average minimum inhibitory concentration (MIC) of C. difficile to vancomycin increased annually (H = 33.208, P < 0.05). The average MIC of C. difficile to metronidazole was highest in 2022 but decreased in 2023 and 2024 (H = 41.990, P < 0.05). Notably, in 2024, one C. difficile strain exhibited an MIC for metronidazole at the resistance threshold (2.00 μg/mL). Further Spearman correlation analysis of the strain years with drug sensitivity results revealed a positive correlation between strain years and the MIC levels of vancomycin and metronidazole (r = 0.528, P < 0.05; r = 0.377, P < 0.05). The proportion of toxin-producing strains increased annually, with 100% of strains in 2024 producing toxins, representing the highest proportion compared to the previous three years (X² =11.75, P < 0.05). Both vancomycin and metronidazole remain effective for the treatment of CDI in clinical practice. However, the sensitivity of C. difficile to these two drugs is gradually decreasing, and the rate of toxin gene carriage is also rising in clinical cases. No hospital outbreaks of C. difficile infections were identified in this study. IMPORTANCE: Clostridioides difficile has developed resistance to multiple antibiotics, including cephalosporins, clindamycin, and fluoroquinolones. This has exacerbated the global antibiotic resistance crisis. In China, according to current treatment guidelines, vancomycin and metronidazole are the preferred first-line drugs for treating C. difficile infections. However, there are reports indicating the emergence of new resistance to both vancomycin and metronidazole. Although there is extensive research on the long-term antibiotic resistance of C. difficile abroad, research on the continuous monitoring of antibiotic resistance and potential outbreaks of C. difficile in China is relatively limited. To fill this gap, we studied positive C. difficile strains from a tertiary general hospital in China. Through Next-Generation Sequencing (NGS), drug sensitivity testing, and analysis of drug resistance and virulence genes, we revealed the evolution of C. difficile's resistance to vancomycin and metronidazole, as well as changes in virulence, and monitored the spread within the hospital and potential outbreaks of C. difficile.

Humans↗

PubMed2000

A genome screen of multiplex sibships with prostate cancer.

Analysis of a genome screen of 504 brothers with prostate cancer (CaP) who were from 230 multiplex sibships identified five regions with nominally positive linkage signals, on chromosomes 2q, 12p, 15q, 16p, and 16q. The strongest signal in these data is found on chromosome 16q, between markers D16S515 and D16S3040, a region suspected to contain a tumor-suppressor gene. On the basis of findings from previous genome screens of families with CaP, three preplanned subanalyses were carried out, in the hope of increasing the subgroup homogeneity. Subgroups were formed by dividing the sibships into a group with a positive family history (FH+) that met criteria for "hereditary" CaP (n=111) versus those which did not meet the criteria (n=119) and by dividing the families into those with a mean onset age below the median (n=115) versus those with a mean onset age above the median (n=115). A separate subanalysis was carried out for families with a history of breast cancer (CaB+ [n=53]). Analyses of these subgroups revealed a number of potentially important differences in regions that were nonsignificant when all the families were analyzed together. In particular, the subgroup without a positive family history (FH-) had a signal in a region that is proximal to the putative site of the HPC1 locus on chromosome 1, whereas the late-age-at-onset group had a signal on 4q. The CaB+ subgroup revealed a strong linkage signal at 1p35.1.

Age of Onset↗

PubMed2004

Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians.

Genome-wide scans were conducted for tuberculosis and leprosy per se in Brazil. At stage 1, 405 markers (10 cM map) were typed in 16 (178 individuals) tuberculosis and 21 (173 individuals) leprosy families. Nonparametric multipoint analysis detected 8 and 9 chromosomal regions respectively with provisional evidence (P<0.05) for linkage. At stage 2, 58 markers from positive regions were typed in a second set of 22 (176 individuals) tuberculosis families, with 22 additional markers typed in all families; 42 positive markers in 50 (192 individuals) new leprosy families, and 30 additional markers in all families. Three regions (10q26.13, 11q12.3, 20p12.1) retained suggestive evidence (peak LOD scores 1.31, 1.85, 1.78; P=0.007, 0.0018, 0.0021) for linkage to tuberculosis, 3 regions (6p21.32, 17q22, 20p13) to leprosy (HLA-DQA, 3.23, P=5.8 x 10(-5); D17S1868, 2.38, P=0.0005; D20S889, 1.51, P=0.004). The peak at D20S889 for leprosy is 3.5 Mb distal to that reported at D20S115 for leprosy in India. (151 words).

Brazil↗