Finnish population genetics in a forensic context

Finland’s unusual history and resulting genetic structure have a number of consequences for the practical applications of genetic testing in Finland today, including forensic analysis. The objective of this study was to characterize coding and noncoding genetic variation in the Finnish gene pool using forensic markers, in order to improve the efficiency of forensic testing in Finland while simultaneously broadening our understanding of its history. Finland is characterized by a clear genetic delineation between Eastern and Western regions of the country, the origins of which have heretofore remained undetermined. Here, patterns of distribution observed in markers of prehistoric association suggest this delineation represents the vestiges of an ancient border between Mesolithic hunter-gatherer and Neolithic farmer populations, undetectable in other regions of Europe. This study provides further insight into the development of the current population structure and clarifies the resolution of uniparental marker variation in contemporary Finland, with implications for forensic applications such as ancestry- informative testing. Along with the aforementioned population stratification, Finland’s unusual history has also left its mark on the population in the form of reduced diversity, visible especially in the Y-chromosome. In order to improve the efficiency of Finnish Y-profiling, novel multiplex panels of highly polymorphic Y-microsatellite markers were developed and evaluated. The new 7- and 24-locus Y-STR panels demonstrate improved suitability for practical forensic applications, with enhanced discrimination power and a reduction in regional subdivision compared to commercial sets. In order to assess the applicability of a novel commercial panel of insertion-deletion markers in Finnish forensic profiling, the Investigator DIPplex kit was evaluated in the Finnish population. Earlier studies of the applicability of insertion/deletion polymorphisms as a tool of forensics had indicated that they were likely to be beneficial for casework analysis both in individual identification as well as the testing of familial relationships. The results suggest that while these markers were well suited for individualization purposes, they were inefficient for paternity testing in the Finnish population. These two studies highlight the need for careful population-specific validation of commercial marker sets widely in use in forensics. Historical population bottlenecks can result in the enrichment of mutations, including those with clinical effects. The assessment of metabolic gene ABCB1 polymorphisms in Finns found increased frequency of these mutations in comparison to other populations, suggesting that Finns may demonstrate an increased susceptibility to drug intoxication. A further investigation performed on post-mortem samples revealed a positive correlation between mutation frequency and level of blood digoxin, confirming previous results of the adverse effect of ABCB1 mutations on metabolic processes. These findings will aid forensic medicine by providing valuable additional evidence for molecular autopsies. A thorough understanding of underlying patterns of genetic variation and the history that created them is vital in recognizing the factors affecting practical forensic analysis today. In these studies, the deep genetic delineation between Eastern and Western regions of Finland was observed in a variety of forensic loci, and shown for the first time to extend also to mitochondrial markers, giving further evidence of its ancient history. The results of this thesis thus reveal new information about the history and demographics of the Finnish population while offering globally applicable improvements to forensic typing. The end result is more straightforward analysis and improved reliability for a spectrum of forensic applications ranging from individualization to cause of death determinations.Väitöskirjatutkimus käsittelee suomalaisen väestön populaatiogenetiikkaa oikeuslääketieteellisessä kontekstissa. Suomen omintakeinen historia on jättänyt jälkensä väestön geneettiseen rakenteeseen vaikuttaen siten myös oikeusgeneettiseen yksilöntunnistukseen suomalaisessa väestössä. Tämän tutkimuksen tarkoituksena on luonnehtia Suomen geneettistä muuntelua forensisilla DNA-merkeillä, tavoitteena lisätä oikeusgeneettisen testauksen tehokkuutta sekä tuottaa lisätietoa Suomen historian vaiheista. Aikaisemmissa tutkimuksissa havaittua selkeää geneettistä jakautumista itäisen ja läntisen Suomen välillä tarkasteltiin mitokondrio- ja Y-kromosomimerkeillä, tavoitteena alueellisen rajan alkuperän selkeytyminen. Kromosomimerkkien esihistoriallisten ryhmien jakolinjat viittaavat siihen, että jakautuminen edustaa muinaista rajaa mesoliittisten metsästäjä-keräilijä- ja neoliittisten maanviljelijäryhmien välillä. Tutkimus antaa lisätietoa nykyisen väestörakenteen kehityksestä ja valottaa sukulinjamarkkereiden jakautumaa Suomessa. Suomen väestölle ominaisen alhaisen Y-kromosomimuuntelun takia suomalaisessa oikeusgenetiikassa on tarve korkeamman erottelutehon Y-merkeille. Tehokkuuden parantamiseksi arvioimme uusien monimuotoisten Y-mikrosatelliittimarkkereiden soveltuvuutta suomalaiseen Y-profilointiin. Tutkimuksessa kehiteltiin uusi Y-tunnistepaneeli, jonka erotteluvoima suomalaisväestössä on parempi kuin esim. kaupallisissa Y-kromosomipaneeleissa. Myös uuden kaupallisen insertio-deleetiomarkkerisarjan soveltuvuutta isyystutkimukseen arvioitiin. Tulokset osoittavat, että vaikka markkerit sopivat hyvin yksilöllistämiseen suomalaisessa väestössä, niiden erotteluteho isyyskokeissa on selvästi alentunut muihin eurooppalaisiin verrattuna. Historialliset tapahtumat voivat vaikuttaa myös kliinisesti merkittävien mutaatioiden yleistymiseen. Muihin väestöihin verrattuna suomalaisilla havaittiin aineenvaihduntageeni ABCB1-mutaatioiden lisääntynyt esiintyminen, indikoiden kohonnutta myrkytysriskiä. Lisäksi post-mortem-näytteistä tehty geenityypitys paljasti positiivisen korrelaation mutaatiofrekvenssin ja veren digoksiinipitoisuuden välillä, vahvistaen aikaisempia havaintoja ABCB1-mutaatioiden negatiivisesta vaikutuksesta aineenvaihduntaan. Nämä tulokset tarjoavat arvokkaita lisätodisteita oikeuslääketieteellisiin tutkimuksiin. Tutkimuksen tulokset paljastavat uutta tietoa Suomen väestöhistoriasta ja tarjoavat globaalisti sovellettavia parannuksia rikosteknisiin tutkimuksiin. Tutkimustulokset auttavat oikeuslääketieteellisten sovellusten eri osa-alueita yksilöntunnistamisesta kuolemansyyn määrittämiseen, selkeyttäen analyysia ja kasvattaen luotettavuutta

Vestiges of an Ancient Border in the Contemporary Genetic Diversity of North-Eastern Europe

It has previously been demonstrated that the advance of the Neolithic Revolution from the Near East through Europe was decelerated in the northernmost confines of the continent, possibly as a result of space and resource competition with lingering Mesolithic populations. Finland was among the last domains to adopt a farming lifestyle, and is characterized by substructuring in the form of a distinct genetic border dividing the northeastern and southwestern regions of the country. To explore the origins of this divergence, the geographical patterns of mitochondrial and Y-chromosomal haplogroups of Neolithic and Mesolithic ancestry were assessed in Finnish populations. The distribution of these uniparental markers revealed a northeastern bias for hunter-gatherer haplogroups, while haplogroups associated with the farming lifestyle clustered in the southwest. In addition, a correlation could be observed between more ancient mitochondrial haplogroup age and eastern concentration. These results coupled with prior archeological evidence suggest the genetic northeast/southwest division observed in contemporary Finland represents an ancient vestigial border between Mesolithic and Neolithic populations undetectable in most other regions of Europe.Peer reviewe

Diurnal Cortisol Patterns and Dexamethasone Suppression Test Responses in Healthy Young Adults Born Preterm at Very Low Birth Weight

BACKGROUND: Early life stress, such as painful and stressful procedures during neonatal intensive care after preterm birth, can permanently affect physiological, hormonal and neurobiological systems. This may contribute to altered programming of the hypothalamic-pituitary-adrenal axis (HPAA) and provoke changes in HPAA function with long-term health impacts. Previous studies suggest a lower HPAA response to stress in young adults born preterm compared with controls born at term. We assessed whether these differences in HPAA stress responsiveness are reflected in everyday life HPAA functioning, i.e. in diurnal salivary cortisol patterns, and reactivity to a low-dose dexamethasone suppression test (DST), in unimpaired young adults born preterm at very low birth weight (VLBW; <1500 g). METHODS: The participants were recruited from the Helsinki Study of Very Low Birth Weight Adults cohort study. At mean age 23.3 years (2.1 SD), 49 VLBW and 36 controls born at term participated in the study. For cortisol analyzes, saliva samples were collected on two consecutive days at 0, 15, 30 and 60 min after wake-up, at 12:00 h, 17:00 h and 22:00 h. After the last salivary sample of the first study day the participants were instructed to take a 0.5 mg dexamethasone tablet. RESULTS: With mixed-effects model no difference was seen in overall diurnal salivary cortisol between VLBW and control groups [13.9% (95% CI: -11.6, 47.0), P = 0.31]. Salivary cortisol increased similarly after awakening in both VLBW and control participants [mean difference -2.9% (29.2, 33.0), P = 0.85]. Also reactivity to the low-dose DST (awakening cortisol ratio day2/day1) was similar between VLBW and control groups [-1.1% (-53.5, 103.8), P = 0.97)]. CONCLUSIONS: Diurnal cortisol patterns and reactivity to a low-dose DST in young adulthood were not associated with preterm birth.Peer reviewe

Pitkän aikavälin politiikalla läpi murroksen – tahtotiloja työn tulevaisuudesta

Olemme keskellä suurta työn murrosta. Työn tulevaisuuteen liittyviä haasteita on helppoa nimetä, mutta työn muutoksen kaltaiset monimutkaiset pitkäaikaiset muutosilmiöt eivät helposti käänny politiikkatoimiksi ja konkreettisiksi ratkaisuiksi. Muutosta on silti mahdollista ohjata yhteisesti tunnistettujen pitkän aikavälin tahtotilojen avulla. Tämän tutkimuksen tavoitteena on ollut tunnistaa työhön liittyviä toivottavia tulevaisuuksia, päätöksentekotarpeita sekä yhteiskunnallisia ratkaisuja asiantuntijahaastatteluihin ja kansallisen tason kyselytutkimukseen perustuen. Lisäksi raportissa ehdotetaan toimintamallia, jolla pitkän aikavälin keskustelua työn tulevaisuudesta voidaan käydä myös jatkossa. Raportti pohjautuu käsiteltyjen viiden teeman osalta Tulevaisuusselonteon 1. osaan (VNK 2017). Tutkimuksesta vastasi ajatushautomo Demos Helsinki yhteistyössä Teknologian tutkimuskeskus VTT:n kanssa. Tutkimuksesta keskeiset havainnot ovat seuraavat: Työn tekemisen muodot ja työsuhteet moninaistuvat, mikä edellyttää muutoksia esimerkiksi lainsäädännössä ja sosiaaliturvassa. Työn aika- ja paikkasidonnaisuus heikkenee, mutta muutos ei ole yhtä voimakas tai samantahtinen kaikilla aloilla. Koulutuksessa korostuu jatkuva oppiminen: Tarvitsemme Suomeen koko väestön kattavan, laadukkaan elinikäisen oppimisen järjestelmän. Toimeentulo muuttuu niin, että työmarkkinoiden ja koko työelämän joustavuus lisääntyy. Päätöksentekijöiden on tärkeää ymmärtää työn useita erilaisia ja muuttuvia välinearvoja taloudellisten arvojen lisäksi, jotta emme edistä keskenään ristiriitaisia tavoitteit

Effect of fluconazole dose on the extent of fluconazole-triazolam interaction

1Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases

Stress-Dose Corticosteroid Versus Placebo in Neonatal Cardiac Operations : A Randomized Controlled Trial

Background. Corticosteroids can improve the hemodynamic status of neonates with postoperative low cardiac output syndrome after cardiac operations. This study compared a prophylactically administered stress-dose corticosteroid (SDC) regimen against placebo on inflammation, adrenocortical function, and hemodynamic outcome. Methods. Forty neonates undergoing elective open heart operations were randomized into two groups. The SDC group received perioperatively 2 mg/kg methylprednisolone, and 6 hours after the operation, a hydrocortisone infusion (0.2 mg/kg/h) was started with tapering doses for 5 days. Placebo was administered in a similar fashion. An adrenocorticotropic hormone stimulation test was performed after the therapy. The primary endpoint of the study was plasma concentration of interleukin (IL-6). Secondary clinical outcomes included plasma cortisol, IL-10, C-reactive protein, echocardiographic systemic ventricle contractility evaluated by the Velocity Vector Imaging program, the inotropic score, and time of delayed sternal closure. Results. The IL-6 values of the SDC group were significantly lower postoperatively than in the placebo group. Significantly lower inotropic scores (p <0.05), earlier sternal closure (p = 0.03), and less deterioration in the systemic ventricle mean delta strain values between the preoperative and the first postoperative assessment (p = 0.01) were detected for the SDC group. The SDC therapy did not suppress the hypothalamic-pituitary-adrenal axis more than placebo. The mean plasma cortisol level did not decline in the placebo group after the operation. Conclusions. The SDC regimen for 5 days post-operatively in neonates was safe and did not cause suppression of the hypothalamic-pituitary-adrenal axis. Furthermore, the open heart operation per se did not lead to adrenal insufficiency in neonates. (C) 2017 by The Society of Thoracic SurgeonsPeer reviewe

Logistic regression estimates representing the difference in haplogroup frequencies between the SW & NE subpopulations.

<p>Above X-axis: SW dominance, below: NE dominance. The results are shown for division (cf. Fig 2) that maximized the difference. Error bars denote standard deviation, statistical significance is marked with stars. No statistically significant values were obtained in randomized, non-continuous divisions.</p

Bayesian Skyline Plots for mtDNA haplogroups H and U in Finland, with European reference data from Fu et al. 2012.

<p>The hatched lines denote 95% confidence intervals. A: MtDNA haplogroups H (red) and U (blue) in Finland. B: Haplogroup H in Finland (red) and in Europe (grey). C: Haplogroup U in Finland (blue) and in Europe (grey).</p