Dynamics of a sex-linked deleterious mutation in populations subject to sex reversal

Peer reviewe

Tilastollisia menetelmiä luonnonvalinnan signaalien havaitsemiseksi luonnonpopulaatioissa

Much of evolutionary biology attempts to explain why the phenotypes of local populations have diverged from a common ancestral type. It is often tempting to explain the observed pattern of differentiation by natural selection, but this often lacks scientific justification, because random genetic drift i.e. the gradual change of allelic frequencies due to random sampling of alleles from parents to offspring can cause striking phenotypic differentiation, being arguably a simpler and a more eloquent explanation. Random genetic drift needs to be ruled out as an explanation to argue for a scenario of phenotypic differentiation based on natural selection. The rate of random drift in a study system can be measured by using neutral DNA markers, such as microsatellites. Subsequently, these measurements can be compared with the observed pattern of phenotypic differentiation. This is usually done by using so-called QST-FST comparisons. However, these comparisons suffer from a number of conceptual limitations, and their power to detect signals of natural selection is relatively low. This thesis presents a re-thinking of the neutral DNA-phenotype comparison. To this end, the Chapters of this thesis discuss the evolution of randomly drifting quantitative traits, resulting in a probability distribution over the evolutionary process. I use this distribution to construct statistical tests that can be used to detect signals of natural selection in quantitative traits. The method of this thesis is derived from the first principles of quantitative genetics (assuming diploidism and additive genetic architecture), and it is developed into two R-software packages (driftsel and RAFM), intended for users without extensive skills in Bayesian statistics. This thesis also investigates the performance of the methods and the interpretation of the model estimates obtained as a by-product of the neutrality tests. As it turns out, the method developed here can detect signals of natural selection even in cases where usual QST-FST comparisons fail. In addition to the methodological contributions, the work included into this thesis has also an empirical dimension demonstrating occurrence of adaptive differentiation among three-spined (Gasterosteus aculeatus) and environmental adaptation in nine-spined stickleback (Pungitius pungitius) populations.Evoluutiobiologian yksi keskeinen tavoite on selvittää, miksi ja miten paikallispopulaatioiden fenotyypit ovat eriytyneet yhteisestä alkumuodosta. Usein on houkuttelevaa selittää havaittu eriytyminen luonnonvalinnan perusteella, mutta tämä ei ole oikeutettua ilman lisäselvityksiä, koska geneettinen satunnaisajautuminen, eli geenifrekvenssien satunnainen muuttuminen, pystyy tuottamaan samantapaista eriytymistä. Satunnaisajautuminen on yksinkertaisempi ja siksi elegantimpi selitysmalli. Geneettisen satunnaisajautumisen mahdollisuus on suljettava pois, jotta voidaan perustellusti väittää, että fenotyyppien eriytymisen johtuu luonnonvalinnasta. Satunnaisajautumisen nopeutta voidaan tarkastella neutraalien DNA-markkereiden, eli ns. roska-DNA:n avulla. Näin saatavia arvioita voidaan verrata havaittuun fenotyyppien vaihteluun. Tämä tehdään useimmiten niin sanottujen QST-FST-testien avulla. Nämä testeihin liittyy kuitenkin tiettyjä teoreettisia ongelmia, ja niiden tilastollinen voima on suhteellisen huono. Tämä väitöskirja esittää uuden tavan vertailla neutraalia DNA:ta ja fenotyyppejä keskenään. Väitöskirjassa tarkastellaan kvantitatiivisten ominaisuuksien (esim. pituus tai paino) geneettistä satunnaisajautumista ja johdetaan niiden todennäköisyysjakauma evolutiivisen prosessin suhteen. Tästä jakaumasta johdetaan tilastollisia testejä, joiden avulla luonnonvalinnan signaalit voidaan havaita kvantitatiivisessa aineistossa. Tässä väitöskirjassa kehitety metodit on tuotteistettu ohjelmoimalla ne kahdeksi R-ohjelmistopaketiksi (driftsel ja RAFM). Nämä ohjelmistopaketit on suunnattu myös sellaisille käyttäjille, joilla ei ole laajaa kokemusta bayesiläisestä tilastoanalyysista. Lisäksi tässä työssä on tarkasteltu kehitettyjen menetelmien toimivuutta ja niiden tilastollisia ominaisuuksia. Osoittautui, että tässä työssä kehitetyn metodin avulla pystytään osoittamaan luonnonvalinnan signaaleja myös sellaisissa tapauksissa, joissa QST-FST -testit eivät toimi. Menetelmäkehityksen lisäksi tämä työ sisältää myös muutamia käytännön sovelluksia. Työssä on pystytty osoittamaan fenotyyppien adaptiivinen eriytyminen kahdella ekologisella mallilajilla, kolmipiikeillä (Gasterosteus aculeatus) ja kymmenpiikeillä (Pungitius pungitius)

Likelihood contrasts: a machine learning algorithm for binary classification of longitudinal data

Machine learning methods have gained increased popularity in biomedical research during the recent years. However, very few of them support the analysis of longitudinal data, where several samples are collected from an individual over time. Additionally, most of the available longitudinal machine learning methods assume that the measurements are aligned in time, which is often not the case in real data. Here, we introduce a robust longitudinal machine learning method, named likelihood contrasts (LC), which supports study designs with unaligned time points. Our LC method is a binary classifier, which uses linear mixed models for modelling and log-likelihood for decision making. To demonstrate the benefits of our approach, we compared it with existing methods in four simulated and three real data sets. In each simulated data set, LC was the most accurate method, while the real data sets further supported the robust performance of the method. LC is also computationally efficient and easy to use.</p

Social Distancing and SARS-CoV-2 Transmission Potential Early in the Epidemic in Finland

Background:Information about social mixing patterns under heavy social distancing is needed to model the impact of nonpharmaceutical interventions on SARS-CoV-2 transmission.Methods:We conducted a survey on daily person-to-person contacts during the early phase of the SARS-CoV-2 epidemic in Finland, one month after strong social distancing measures had been introduced nationwide. We defined a contact as exchange of at least a few words in proximity of another person. We also considered physical (“skin-to-skin”) contacts separately. Based on 3,171 reported contacts by 1,320 participants of 1–79 years of age, we estimated age-stratified contact matrices essential in modeling virus transmission.Results:Compared with contacts during prepandemic conditions, as learned from the Finnish part of the Polymod study, there was a 72% (95% credible interval, CI = 71, 74) reduction in the daily number of all contacts and a 69% (95% CI = 66, 73) reduction in the daily number of physical contacts in April 2020. The largest reduction, of almost 90%, occurred in physical contacts by individuals more than 70 years of age. The estimated reduction in the transmission potential of the virus attributable solely to reduced contact frequencies varied between 59% (whole population; physical contacts; 95% CI = 52, 68) and 77% (over 20-year olds; physical contacts; 95% CI = 70, 89).Conclusions:We surmise that the large reduction in the daily numbers of social contacts in the early part of the SARS-CoV-2 epidemic in Finland was likely a major contributor to the steady decline of the epidemic in the country since early April.</p

Maatalouden monivaikutteisten kosteikkojen suunnittelu ja mitoitus

Kosteikkojen määrän odotetaan kasvavan maatalouden vesiensuojelun menetelmänä merkittävästi lähivuosina. Tähän tarpeeseen koottiin viimeisin tutkimus- ja kokemuspohjainen tieto uusiksi suunnittelu- ja mitoitusohjeistoiksi. Hankkeen tavoitteena oli i) luoda kosteikkojen alueellista ja paikallista yleissuunnittelua koskevat periaatteet ja kriteerit sekä ii) laatia monivaikutteisten vesiensuojelukosteikkojen tavoitteisiin perustuva suunnittelu- ja mitoitusohjeisto käytännön suunnittelijoille. Tässä julkaisussa esitetään rakennettujen kosteikkojen ratkaisuja ja niiden rakenteellisia yksityiskohtia, käydään läpi suunnittelun ja mitoituksen keskeiset periaatteet, käsitellään kenttätutkimusta ja suunnittelussa tarvittavia taustatietoja sekä arvioidaan kosteikkojen avulla saatavia ympäristö- ja muita hyötyjä. Kosteikkojen puhdistusmekanismeja ja niiden vaikutuksia esitetään suunnittelun ja mitoituksen taustatiedoiksi. Julkaisussa käsitellään pelkästään maatalouden monivaikutteisia kosteikoita, joissa vesiensuojelutavoitteet yhdistetään useisiin muihin tavoitteisiin, kuten esim. luonnon monimuotoisuuden lisääntyminen, tulvien hallinta, virkistyskäyttö ja metsästys. Hanke oli MMM:n rahoittama ja toteutettiin yhteistyössä Lounais-Suomen ympäristökeskuksen (LOS) kanssa.Yleissuunnittelua koskevasta ohjeistosta vastasi LOS ja tästä julkaisusta Suomen ympäristökeskus (SYKE)

Beta-fibrinogen gene promoter A-455 allele associated with poor longterm survival among 55-71 years old Caucasian women in Finnish stroke cohort

Peer reviewe

Haptoglobin Hp1 Variant Does Not Associate with Small Vessel Disease

Haptoglobin (Hp) is a plasma protein that binds free hemoglobin and protects tissues from oxidative damage. An Hp2 allele has been associated with an increased risk of cardiovascular complications. On the other hand, recent studies have suggested that Hp1 allele increases risk to develop severe cerebral small vessel disease. We aimed to replicate this finding in a first-ever stroke patient cohort. Hp was genotyped by PCR and gel electrophoresis in the Helsinki Stroke Aging Memory Study in patients with DNA and magnetic resonance imaging (MRI) available (SAM; n = 316). Lacunar infarcts and white matter lesions (WML) classified by Fazekas grading from brain MRI were associated with Hp genotypes. As population controls, we used participants of Cardiovascular diseases—a sub study of Health 2000 Survey (n = 1417). In the SAM cohort, 63.0% of Hp1-1 carriers (n = 46), 52.5% of Hp1-2 carriers (n = 141) and 51.2% of Hp2-2 carriers (n = 129) had severe WML (p = 0.372). There was no difference in severe WMLs between Hp1-1 vs. Hp1-2 and Hp2-2 carriers (p = 0.201). In addition, 68.9% of Hp1-1 carriers (n = 45), 58.5% of Hp1-2 carriers (n = 135), and 61.8% of Hp2-2 carriers (n = 126) had one or more lacunar lesions (p = 0.472). There was no difference in the number of patients with at least one lacunar infarct between Hp1-1 vs. Hp1-2 and Hp2-2 groups (p = 0.322). Neither was there any difference when diabetic patients (type I and II) were examined separately. Hp1 allele is not associated with an increased risk for cerebral small vessel disease in a well-characterized Finnish stroke patient cohort

Haptoglobin Hp1 Variant Does Not Associate with Small Vessel Disease

Haptoglobin (Hp) is a plasma protein that binds free hemoglobin and protects tissues from oxidative damage. An Hp2 allele has been associated with an increased risk of cardiovascular complications. On the other hand, recent studies have suggested that Hp1 allele increases risk to develop severe cerebral small vessel disease. We aimed to replicate this finding in a first-ever stroke patient cohort. Hp was genotyped by PCR and gel electrophoresis in the Helsinki Stroke Aging Memory Study in patients with DNA and magnetic resonance imaging (MRI) available (SAM; n = 316). Lacunar infarcts and white matter lesions (WML) classified by Fazekas grading from brain MRI were associated with Hp genotypes. As population controls, we used participants of Cardiovascular diseases—a sub study of Health 2000 Survey (n = 1417). In the SAM cohort, 63.0% of Hp1-1 carriers (n = 46), 52.5% of Hp1-2 carriers (n = 141) and 51.2% of Hp2-2 carriers (n = 129) had severe WML (p = 0.372). There was no difference in severe WMLs between Hp1-1 vs. Hp1-2 and Hp2-2 carriers (p = 0.201). In addition, 68.9% of Hp1-1 carriers (n = 45), 58.5% of Hp1-2 carriers (n = 135), and 61.8% of Hp2-2 carriers (n = 126) had one or more lacunar lesions (p = 0.472). There was no difference in the number of patients with at least one lacunar infarct between Hp1-1 vs. Hp1-2 and Hp2-2 groups (p = 0.322). Neither was there any difference when diabetic patients (type I and II) were examined separately. Hp1 allele is not associated with an increased risk for cerebral small vessel disease in a well-characterized Finnish stroke patient cohort

HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first-or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.Peer reviewe