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PubMed1994

Possible loss of length conservation and reciprocity during recombination or conversion in tandem arrays.

Recombination or conversion between arrays of repeated sequences need not be conservative for length because two single strands of DNA from one chromatid may form heteroduplexes in different registers on the other participating duplex. This can cause an overall change in repeat number. Loss of length conservation is equally possible whether models of recombination initiated by single-strand transfer or double-strand break are applicable. Length changing conversion will frequently produce a characteristic insertion within a deletion, often appearing as a double deletion such as are frequently found in new variants of human minisatellite MS32. There is no apparent means of preserving parity during length-changing conversion or recombination, and if the changes are biased then the overall copy number will increase or decrease according to that bias. The observation that arrays persist suggests that any bias in these arrays will be toward gains. An equilibrium may be reached where gains, which may be largely independent of array length, equal losses from the array-length-dependent processes of intrachromatid recombination and repeated unequal sister chromatid exchanges.

Base Sequence↗
PubMed2006

Novel mitochondrial DNA length variants and genetic instability in a family with diabetes and deafness.

We have identified two locations with novel multiplasmic length variants in the mitochondrial DNA of a family with diabetes and deafness. At nt568 in the D-loop, the 6-bp polycytidine tract was found to be variable in length up to a total of 12 residues. A second region with length variants was found at nt8281 in the intergenic COII-tRNA(Lys) region, which consists of two copies of the 9-bp repeat CCCCCTCTA. Only the second repeat occurs in a heteroplasmic C(9-14)A form with both T residues largely deleted. In addition, the mtDNA contained a number of new homoplasmic point mutations. Both length variants are stably inherited in a maternal way with no major changes in their length distribution. In contrast, during culture of fibroblasts from the proband the average length of the polycytidine tracts is increased at both locations indicating a fibroblast-specific genetic instability. Cybrid cells containing mtDNA from the proband proliferate less efficient than cybrids with wild-type mtDNA in co-culture experiments, suggesting functional consequences of the mtDNA length variants or the additional homoplasmic point mutations. Since oxygen consumption was not severely affected, these mutation seem less detrimental for mitochondrial function than the A3243G diabetogenic mutation and most other pathogenic mtDNA mutations. The contribution of mtDNA length variants to the phenotype of members of this family is discussed.

Adult↗
PubMed1988

Structure and expression of rodent genes encoding the testis-specific cytochrome c. Differences in gene structure and evolution between somatic and testicular variants.

Mammalian testis contains two forms of cytochrome c, one identical to the form found in somatic tissues and a second that is expressed in a stage-specific manner during spermatogenic differentiation. We have isolated both rat and mouse cDNA clones and the rat gene encoding the testis-specific cytochrome c and determined their DNA sequences. The testicular variant displays a number of notable differences with its somatic counterpart. 1) In contrast to the multipseudogene family derived from mammalian somatic cytochrome c genes, the testis gene is single-copy in genomic DNA with no detectable pseudogenes. 2) The rat testis gene is approximately 7 kilobases (kb) long with three introns totaling nearly 6.5 kb whereas the two introns dividing the 2.1-kb somatic gene occupy only 0.9 kb. Introns differ in position as well as size. 3) The testicular variant has a longer 5'-untranslated leader (230 versus 70 base pairs for the somatic gene) with an upstream open reading frame of 129 base pairs beginning with an AUG in a favorable translational context. 4) A single polyadenylation site in the testicular mRNA (approximately 900 nucleotides) contrasts with the three functionally equivalent sites observed in rat somatic messages. 5) Finally, rat and mouse testis cytochromes c differ at 4 amino acid residues as opposed to the complete sequence identity found in the somatic proteins suggesting a shorter unit evolutionary period for these molecules. These observations are consistent with a duplication of an ancestral cytochrome c gene leading to the emergence of novel structural features and regulatory properties likely associated with the striking tissue specificity of the testicular cytochrome c.

Amino Acid Sequence↗
PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗
PubMed1983

Unequal exchanges and the coevolution of X and Y rDNA arrays in Drosophila melanogaster.

We have examined the molecular basis of the response of individuals of D. melanogaster to artificial selection for high and low abdominal bristles. By monitoring the fate of particular rDNA spacer length variants associated with individually isolated X and Y chromosomes, we show that flies from the low bristle number selection lines have undergone an unequal exchange between the X and Y rDNA arrays. Such exchanges result in translocations between X and Y chromosomes, visualised as X.Y compound chromosomes at mitosis. Transfer of few copies of a length variant between X and Y indicates a clustering of variants. Flies that have reverted back to wild-type seemingly have undergone a second unequal exchange, giving rise to a compound X.Y chromosome containing Y rDNA of normal amounts. Unequal exchanges between X and Y rDNA arrays could contribute to the observed coevolution of rDNA sequences on these chromosomes. The biological significance of this outcome is discussed.

Animals↗
PubMed2006

Cellular and reticular variants of hemangioblastoma differ in their cytogenetic profiles.

Capillary hemangioblastomas of the central nervous system are benign tumors and occur either sporadically or as a manifestation of von Hippel-Lindau disease. A rarer cellular and a more common reticular variant can be distinguished on the basis of the abundance of the stromal cell component, with the cellular variant being significantly associated with a greater probability of recurrence. To investigate whether these subtypes differ in their cytogenetic profile, a comparative genomic hybridization analysis of 10 cellular and 10 reticular hemangioblastomas was undertaken. Comparative genomic hybridization revealed DNA copy number changes in 14 of 20 cases (8 of 10 cellular and 6 of 10 reticular hemangioblastomas). The most common changes overall were losses of chromosomes 19 (35%), 6 (30%), and 22q (15%), whereas loss of 3 and gain of 4 were encountered in one case each (5%). The cellular variant showed losses of chromosomes 6 (60%), 22q and 19 (20% each), as well as gain of 4 (10%), whereas the reticular variant presented with losses of chromosomes 19 (50%), 22q and 3 (10% each). Loss of chromosome 6 was significantly associated with the cellular subtype (P < .005), whereas loss of 19/19p was found more frequently in the reticular variant, albeit not significantly (P = .16). In conclusion, our data may point toward different genetic pathways in the pathogenesis of the 2 histologic subtypes of capillary hemangioblastoma.

Adolescent↗
PubMed2006

Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect.

Extra euchromatic material was found within the major heterochromatic block of chromosome 16 (16qh) in one de novo case and seven members of two families. In contrast to the euchromatic variants of chromosome 9 (9qh), which are derived from pericentromeric euchromatin, molecular cytogenetics confirmed that these duplications were of 16q11.2-->q12.2 in the de novo case, of 16q11.2-->q13 in three members of family 1 and 16q11.2-->q12.1 in four members of family 2. The duplication had arisen as a post-zygotic mitotic event in the mother of family 1 and been transmitted paternally in family 2. An insertional mechanism of origin is proposed for the duplications in case 1 and family 1. Expression at the 16q13 matrix metalloproteinase-2 (MMP2)locus in families 1 and 2 was proportional to genomic copy number and not therefore consistent with position effect silencing due to the flanking blocks of heterochromatin. We conclude that proximal 16q duplications within 16qh are not novel euchromatic variants but associated with a variable phenotype including developmental delay, speech delay, learning difficulties and behavioural problems. The behavioural problems in families ascertained through affected children are much less severe than those encountered in previous patients ascertained as adults.

Adolescent↗
PubMed2004

The tolerance of a modular protein to duplication and deletion of internal repeats.

Ankyrin repeat polypeptides contain repeated structural elements that pack to produce modular architectures lacking in close contacts between distant segments of the polypeptide chain. Despite this lack of sequence-distant contacts, ankyrin repeat polypeptides have been shown to fold in a cooperative manner. To determine the distance over which cooperative interactions can be propagated in a repeat protein, and to investigate the tolerance to internal duplication and deletion of modules, we have constructed a series of ankyrin repeat variants of the Notch ankyrin domain in which repeat number is varied by duplication and deletion of internal repeats. A construct with two copies of the fifth ankyrin repeat shows a modest increase in stability compared to the parent construct and retains apparent two-state unfolding behavior. Although constructs containing three and four copies of the fifth repeat retain this increased resistance to urea, they exhibit broad, multi-state unfolding transitions compared to the parent construct. For the Notch ankyrin domain, these larger constructs may represent a limit beyond which full cooperativity cannot be maintained. Deletions of internal repeats from the Notch ankyrin domain significantly destabilize the domain. This severe destabilization, which is larger than that resulting from end-repeat deletion, may arise from unfavorable interactions within the new non-native interfaces produced by internal repeat deletion. These results demonstrate both an asymmetry between the duplication and deletion of internal repeats, and a difference between deletion of internal and end-repeats, suggesting preferred mechanisms for evolution of repeat proteins.

Animals↗
PubMed2004

A cell-based screen for function of the four-helix bundle protein Rop: a new tool for combinatorial experiments in biophysics.

Combinatorial methodologies have revolutionized studies in biomolecular function, but they have so far proven less useful for understanding macromolecular structure and stability. This is largely because of the difficulty of screening libraries of molecules for biophysical properties, and the difficulty of interpreting structural effects in complicated molecules. Here, we report a novel, robust, cell-based screen for function of the four-helix bundle protein, Rop. By expression of green fluorescent protein from a ColE1 plasmid, the screen reports the copy number of the plasmid, which is modulated in Escherichia coli by Rop. We have engineered the screen so that the fluorescent phenotype can correspond to either Rop activity or lack thereof. We have used the screen to demonstrate with systematically constructed Rop core variants that not all molecules that bind small stem-loop RNAs in vitro are active in vivo. Rop is well understood from structural work and systematic mutations, which makes it possible to construct rational, targeted libraries. This screen makes it possible to rapidly interrogate such libraries effectively for proper protein folding and stability. In addition to its intended utility for combinatorial experiments in biophysics, the screen will allow further dissection of the mechanism of Rop-mediated plasmid copy number regulation in vivo.

Bacterial Proteins↗
PubMed1995

A role for recombination junctions in the segregation of mitochondrial DNA in yeast.

In S. cerevisiae, mitochondrial DNA (mtDNA) molecules, in spite of their high copy number, segregate as if there were a small number of heritable units. The rapid segregation of mitochondrial genomes can be analyzed using mtDNA deletion variants. These small, amplified genomes segregate preferentially from mixed zygotes relative to wild-type mtDNA. This segregation advantage is abolished by mutations in a gene, MGT1, that encodes a recombination junction-resolving enzyme. We show here that resolvase deficiency causes a larger proportion of molecules to be linked together by recombination junctions, resulting in the aggregation of mtDNA into a small number of cytological structures. This change in mtDNA structure can account for the increased mitotic loss of mtDNA and the altered pattern of mtDNA segregation from zygotes. We propose that the level of unresolved recombination junctions influences the number of heritable units of mtDNA.

Cytoplasm↗
PubMed1998

Comparative analysis of Epstein-Barr virus (EBV) detection by nested-PCR and non-isotopic in situ hybridization in nasopharyngeal carcinoma (NPC).

The aims of this study were two-fold: first, to assess the relative diagnostic performance of non-isotopic in situ hybridization (ISH) and the nested polymerase chain reaction (nested-PCR) applied to Epstein-Barr virus (EBV) detection in a series of 55 unselected nasopharyngeal carcinoma (NPC) cases and, secondly, to correlate these data with histopathological classification. Our study shows that in 76.36% of NPC cases positive nuclear signals were observed using EBV-ISH. Overall, EBV-ISH positivity varied according to histological type, in that undifferentiated carcinomas showed a higher proportion of positive cases than differentiated cell carcinomas, although ISH results do not show significant differences in relation to histological types when employing two different schemes (WHO and Micheau). However, in adequate quality DNA samples (54 NPC cases), EBV-DNA was detected in 100% of cases using a nested-PCR, supporting the previous view that all histological types of NPC are in reality variants of EBV-infected neoplasia. ISH-negative cases probably reflect a lower sensitivity than PCR, particularly when a small number of viral copies are present, as well as a variable technical effectiveness for detected EBV, independent of the NPC histological type.

Adolescent↗
PubMed1989

Epidermal growth factor receptor gene expression, protein kinase activity, and terminal differentiation of human malignant epidermal cells.

A number of epidermal growth factor (EGF)-resistant clones have been isolated from human epidermoid carcinoma A431 cells (I. King and A. C. Sartorelli, Biochem. Biophys. Res. Commun., 140: 837, 1986). These cells had a higher capacity to enter a pathway of terminal differentiation, as determined by their ability to form cornified envelopes. Thus, after 6 days in culture, 10% of parental A431 cells expressed a differentiated phenotype, while more than 50% of each of the EGF-resistant variants (M1, A5, and A7) formed cornified envelopes. These EGF-resistant clones expressed fewer EGF receptors and had a lower capacity for EGF receptor autophosphorylation than parental A431 cells. Clone M1 had the highest capacity to form cornified cell envelopes and expressed about 10% of the EGF receptor autophosphorylation activity of parental cells. The decrease in the level of EGF receptor autophosphorylation appeared to be due to a decrease in EGF receptor number rather than to a lowering of enzyme activity per se. Southern analysis demonstrated that all of the EGF-resistant variants contained fewer copies of the EGF receptor gene and no apparent gene rearrangement was detected in these variant cells. A corresponding decrease in EGF receptor mRNA was also observed in M1, A5, and A7 cells, with a ratio of 18:1:10:5 for A431, M1, A5, and A7 cells, respectively. In addition, two other malignant epithelial cell lines, SqCC/Y1 and FaDu, contained relatively few copies of EGF receptor genes, had low EGF receptor kinase activity and showed a relatively high capacity to form cornified envelopes. These findings suggest that the level of the EGF receptor was critical to the regulation of the degree of maturation of malignant epidermal cells.

Blotting, Northern↗
PubMed1976

[Resistance to beta-lactam antibiotics and aminoglycosides in gram negative bacteria. 1. Molecular and genetic characterization of R-factors (author's transl)].

With frequent use of aminoglycoside antimicrobials and beta-lactam antibiotics in hospitals in the last few years, the number of bacterial strains resistant to these chemotherapeutics increased. Lately, strains of E. coli, Klebsiella, Enterobacter, Serratia, Proteus and Pseudomonas resistant to many antimicrobials (ampicillin, carbenicillin, cephalothin, chloramphenicol, gentamycin, tobramycin, sisomycin, neomycin, paromomycin, kanamycin, streptomycin, spectinomycin, tetracycline, sulphonamides) were isolated from patients of the university hospital in Zuerich. The resistant phenotype of two representative strains (Klebsiella pneumoniae 1 and Serratia marcescens 2) could be transferred by mixed cultivation to E. coli K-12. Multiple resistance of strain 1, and addition, could be transferred to Salmonella typhimurium, Serratia marcescens, Providencia, Proteus mirabilis and Klebsiella pneumoniae in varying frequencies. Transfer to Pseudomonas aeruginosa, however, could not be achieved. Spontaneous instability of resistance was observed in 0.15% of the cells of an overnight brothe culture and in 90% of the cells of a three months old culture. Conjugation, instability and the response to the sex phages MS-2 and If-1 suggested that resistance was mediated by a monomolecular R-factor, belonging to the fi+-type. This suggestion was confirmed by molecular characterization of the resistance plasmids. After transfer of the R-factors of K. pneumoniae 1 (R-FK 1) and Serratia marcescens 2 (R-FK2) into E. coli K-12, plasmid DNA was labelled with (methyl-3H) thymidine, and isolated by isopycnic centrifugation in cesiumchlorid-ethidium-bromide. Analysis of plasmid DNA then was carried out by sedimentation in a 5-20% neutral sucrose gradient together with reference plasmids of known molecular weights and sedimentation constants. The analysis revealed that R-FK1 had a molecular weight of 54 X 10(6) and R-FK2 of 50 X 10(6) daltons. The values were confirmed by contour length measurements of open circular forms with an electron microscope. A comparison of the sedimentation profile of labelled plasmid DNA from strain 1 and 14C-labelled DNA of E. coli K-12 (R-FK1) showed that the wild-type strain contained, besides the large resistance plasmid, at least two smaller "cryptic" plasmids. These smaller plasmid molecules were also found in antibiotic susceptible variants of strain 1, which did not contain the 54 X 10(6) dalton plasmid molecule, responsible for the resistant phenotype. The number of copies of R-FK1 in E. coli K-12 was determined to be 2, indicating stringent control of replication. It is discussed that the growing number of isolations of strains of Escherichia, Klebsiella, Serratia, Proteus, Providencia and Pseudomonas, exhibiting the same resistance phenotype, results from the spread of the R-factor described above among the hospital bacterial flora.

Aminoglycosides↗
PubMed2006

BEAMing up for detection and quantification of rare sequence variants.

BEAMing allows the one-to-one conversion of a population of DNA fragments into a population of beads. We used rolling circle amplification to increase the number of copies bound to such beads by more than 100-fold. This allowed enumeration of mutant and wild-type sequences even when they were present at ratios less than 1:10,000 and was sensitive enough to directly quantify the error rate of DNA polymerases used for PCR.

DNA↗
PubMed2006

Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter.

Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-gamma (PPAR-gamma) coactivator-1 alpha (PGC-1alpha) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1alpha coding region and insulin resistance has been reported in some ethnic groups. In this study, we investigated whether a change of glycine to serine at codon 482 of PGC-1alpha affected the Tfam promoter activity. The cDNA of PGC-1alpha variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1alpha protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1alpha genotype G1444A and mitochondrial DNA (mtDNA) copy number from 229 Korean leukocyte genomic DNAs. Subjects with Gly/Gly had a 20% lower amount of peripheral blood mtDNA than did subjects with Gly/Ser and Ser/Ser (p<0.05). No correlation was observed between diabetic parameters and PGC-1alpha genotypes in Koreans. These results suggest that PGC-1alpha variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication.

Amino Acid Substitution↗
PubMed2004

Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an independent prognostic marker.

Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21-31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

Carcinoma, Papillary↗
PubMed1999

Two sensitive PCR-based methods for detection of hepatitis B virus variants associated with reduced susceptibility to lamivudine.

Two novel assays, a restriction fragment length polymorphism (RFLP) assay and an assay based on the 5'-nuclease activity of Taq DNA polymerase, were developed for screening viral variants in lamivudine-treated patients' sera containing <1,000 copies of the hepatitis B virus (HBV) genome per ml. Both assays were designed to detect single-nucleotide changes within the HBV DNA polymerase gene that are associated with lamivudine resistance in vitro and have been used to screen a number of patients' sera for variant virus. Results obtained with these assays and standard sequencing technology were compared with regard to throughput, ability to detect individual virus species present at low concentrations, and ability to detect, distinguish, and quantitate wild-type (wt) and HBV tyrosine methionine(552) aspartate aspartate motif variants in mixed viral populations. Unlike DNA sequencing, both assays are amenable to high-throughput screening and were shown to be able to quantitatively detect variant virus in the presence of a background of wt virus. As with DNA sequencing, both new assays incorporate a PCR amplification step and are able to detect the relatively low amounts of virus found in lamivudine-treated patients' sera. However, these assays are far less labor intensive than the DNA-sequencing techniques presently in use. Overall, the RFLP assay was more sensitive than DNA sequencing in detecting and determining the ratios of wt to variant virus. Furthermore, the RFLP assay and 5'-nuclease assay were equally sensitive in the detection of mixed viral species, but the RFLP assay was superior to the 5'-nuclease assay in the quantitation of mixed viral species. These assays should prove useful for further understanding of virological response to therapy and disease progression.

Antiviral Agents↗
PubMed2005

STin2 variant and family history of suicide as significant predictors of suicide completion in major depression.

BACKGROUND: Suicide is the most serious outcome of major depression, yet not all depressed patients will commit suicide. Genes, along with other factors, might account for this difference. Serotonergic alterations have been observed in suicide and depression and impulsive-aggressive behaviors. Therefore, we aimed to identify predictors of suicide, considering genetic variation at the serotonin transporter (5-HTT) gene. METHODS: We investigated the 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide in a sample of depressed suicides (n =106) and depressed control subjects (n =152), diagnosed by means of proxy-based interviews. RESULTS: We found a significant association of suicide completion with having at least one copy of the STin2 10 allele [chi(2)(1) = 10.833, p = .002]. No differences were found for the 5-HTTLPR variable number of tandem repeats. After controlling for behavioral and clinical risk factors for suicide, the STin2 variant remained a significant predictor of suicide in major depression when jointly considered with a family history of suicide (odds ratio 5.560, 95% confidence interval 1.057-29.247). CONCLUSIONS: The STin2 locus might account, at least in part, for the observed familial aggregation of suicidal behavior. These results should be further explored in families where clustering of suicidal behavior is observed.

Adolescent↗