Completed suicides of citalopram users-the role of CYP genotypes and adverse drug interactions.

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31-0.41] vs. 0.265 [0.24-0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.

Bones hold the key to DNA virus history and epidemiology.

DNA in human skeletal remains represents an important historical source of host genomic information and potentially of infecting viruses. However, little is known about viral persistence in bone. We searched ca. 70-year-old long bones of putative Finnish casualties from World War II for parvovirus B19 (B19V) DNA, and found a remarkable prevalence of 45%. The viral sequences were exclusively of genotypes 2 (n = 41), which disappeared from circulation in 1970´s, or genotype 3 (n = 2), which has never been reported in Northern Europe. Based on mitochondrial and Y-chromosome profiling, the two individuals carrying B19V genotype 3 were likely from the Soviet Red Army. The most recent common ancestor for all genotypes was estimated at early 1800s. This work demonstrates the forms of B19V that circulated in the first half of the 20(th) century and provides the first evidence of the suitability of bone for exploration of DNA viruses.

European Network of Forensic Science Institutes (ENFSI): Evaluation of new commercial STR multiplexes that include the European Standard Set (ESS) of markers.

To support and to underpin the European initiative to increase the European set of standard markers (ESS), by the addition of five new loci, a collaborative project was organised by the European Network of Forensic Science Institutes (ENFSI) DNA working group in order to assess the new multiplex kits available. We have prepared allele frequency databases from 26 EU populations. Concordance studies were carried out to verify that genotyping results were consistent between kits. Population genetics studies were conducted and it was estimated that F(ST)<0.001. The results showed that the kits were comparable to each other in terms of performance and major discrepancy issues were highlighted. We provide details of allele frequencies for each of the populations analysed per laboratory.

Dissecting the Finnish male uniformity: the value of additional Y-STR loci.

The forensic use of Y-chromosomal markers can be hampered by reduced diversity and geographical subdivision in some populations. In Finland both of these confounding factors are well documented, but it is also shown that increase of data could resolve or at least alleviate these problems. In order to increase the forensic usability of Y-chromosomal data in Finland, we have here evaluated the diversity at a number of additional Y-STRs. A seven Y-STR locus panel ("FY7": DYS449, DYS460, DYS505, DYS522, DYS576, DYS612 and DYS627) was found to reveal higher diversity levels among Finns than the substantially larger commercial multiplexes commonly in use. The Y-STR data augmented with the FY7 panel shows substantially higher discrimination capacity and lower levels of geographical structure among Finns. Amplifiable in one multiplex, this set of loci offers an informative and easy-to-use supplementary for the commercial Y-STR kits.

Pharmacogenetics in medico-legal context.

Medico-legal autopsy is the primary method in determining the cause and manner of death when the death is suspected to be unnatural. In some of these autopsies, the death remains ambiguous, even after a complete autopsy including histological investigation and toxicological screenings. In cases where there are no morphological abnormalities, medico-legal genetics may offer additional means to provide knowledge of possible genetic mutations, which may have initiated the process or predisposed the individual to stress risk conditions leading to death. One class of ambiguous deaths consists of drug-related deaths where the interpretation of the toxicological results are not clear. In such situations post mortem genotyping and the analysis of metabolite rations may provide an insight to the findings. A few cases demonstrating the potential strength of pharmacogenetics in medico-legal context has been published. However, there is a paramount need for serious scientific studies before the field of post mortem pharmacogenetics can be utilized in routine medico-legal analyses casework and brought routinely into courtroom.

X-STR diversity patterns in the Finnish and the Somali population.

Autosomal and Y-chromosomal STR markers have been routinely used in kinship analyses already for over a decade, augmented by mitochondrial DNA in more complex cases questioning the maternal relationships of the samples. Recently, a commercial X-chromosome typing kit Mentype Argus X-8 was introduced to supplement the existing forensic toolkit. In this study, X-STR allele frequencies and population diversity indices in two ethnic groups, the Finnish and the Somali, are reported. Several previously unreported alleles and features in the allelic distribution were observed, some of which were further investigated with a small set of family data. Most notably, several alleles showed significant frequency differences between sexes, yet no obvious explanation for this discrepancy was found. As a demonstration of X-chromosome analysis in practice, we describe two family reunion cases, where the X-STR data was successfully utilized.

Finnish mitochondrial DNA HVS-I and HVS-II population data.

We have analyzed the two hypervariable regions HVS-I and HVS-II of 200 Finnish male individuals for forensic purposes. The distribution of the haplotypes within Finland was determined by the geographical knowledge of the donors' maternal ancestors. In our population sample, we identified 135 different mtDNA haplotypes. Different mtDNA sequences were further divided to haplogroups using the EMPOP software. The most common haplogroups were H (40.0%) and U (27.5%). Subgroup U5b, which contains earlier described "Saami motif", consisted majority (65.5%) of the sample in the U haplogroup. Analysis of the mtDNA sequence hypervariable regions I and II showed that the mtDNA diversity within the Finnish population sample was comparable to other European populations and uniformly distributed. This is contrary to the Y-STR "minimal haplotype" diversity, which in Finland is lower than in any of the other European populations studied so far.

Microsatellite marker data suggest sex-biased dispersal in the common frog Rana temporaria.

Despite being important models in ecological, evolutionary and conservation biology research, very little is known about the dispersal in anuran amphibians, and juvenile dispersal in particular. Using microsatellite data, we assessed signatures of sex-biased migration in the common frog (Rana temporaria) in Scandinavia. Significant heterozygosity deficiency (FIS) and lower assignment value (mAIc) among females suggest that dispersal in R. temporaria is female biased. Also variance of assignment (vAIc), estimated separately for the two sexes, was consistent with this inference, although the difference was not statistically significant. Possible proximate and ultimate explanations for female-biased dispersal in amphibians are discussed.

Latitudinal divergence of common frog (Rana temporaria) life history traits by natural selection: evidence from a comparison of molecular and quantitative genetic data.

The relative roles of natural selection and direct environmental induction, as well as of natural selection and genetic drift, in creating clinal latitudinal variation in quantitative traits have seldom been assessed in vertebrates. To address these issues, we compared molecular and quantitative genetic differentiation between six common frog (Rana temporaria) populations along an approximately 1600 km long latitudinal gradient across Scandinavia. The degree of population differentiation (QST approximately 0.81) in three heritable quantitative traits (age and size at metamorphosis, growth rate) exceeded that in eight (neutral) microsatellite loci (FST = 0.24). Isolation by distance was clear for both neutral markers and quantitative traits, but considerably stronger for one of the three quantitative traits than for neutral markers. QST estimates obtained using animals subjected to different rearing conditions (temperature and food treatments) revealed some environmental dependency in patterns of population divergence in quantitative traits, but in general, these effects were weak in comparison to overall patterns. Pairwise comparisons of FST and QST estimates across populations and treatments revealed that the degree of quantitative trait differentiation was not generally predictable from knowledge of that in molecular markers. In fact, both positive and negative correlations were observed depending on conditions where the quantitative genetic variability had been measured. All in all, the results suggest a very high degree of genetic subdivision both in neutral marker genes and genes coding quantitative traits across a relatively recently (< 9000 years) colonized environmental gradient. In particular, they give evidence for natural selection being the primary agent behind the observed latitudinal differentiation in quantitative traits.

Microsatellite variation in ringed seals (Phoca hispida): genetic structure and history of the Baltic Sea population.

Genetic variability and population structure of Baltic ringed seals and an Arctic reference population were assessed using eight microsatellite loci. Ringed seals colonized the Baltic Sea basin soon after deglaciation 11 500 years ago and are supposed to have remained largely isolated from the main Arctic stock since then, approximately 1000 generations. In the 1900s the Baltic population declined rapidly, and is now confined to three distinct breeding areas, with N < 6000 seals altogether. Microsatellite heterozygosity in ringed seals was higher than that in the closely related, boreal harbour seal and grey seal, for which the markers were initially developed. This is plausibly attributed to an overall greater population (species) size of ringed seals during the Quaternary. Allele frequency differentiation between the Baltic and Arctic ringed seals, conventionally treated as different subspecies, was weak. Assuming complete isolation, the divergence (FST=0.023) would imply a notably high postglacial effective population size, approximately 20 000 for the Baltic population. The isolation assumption however, seems unrealistic in the light of the data: a coalescent-based simulation approach to the likelihood of alternative demographic histories clearly favoured a scenario with recurrent gene flow to the Baltic, over one of complete isolation (drift only). Within the Baltic Sea, no differentiation was found between the Gulf of Finland and the Gulf of Bothnia breeding areas; the recent population decline and split have not yet affected the inbreeding levels of the disjunct breeding stocks.