Molecular Genetics of Schizophrenia and Related Intermediate Phenotypes in a Founder Population

Schizophrenia, affecting about 1% of population worldwide, is a severe mental disorder characterized by positive and negative symptoms, such as psychosis and anhedonia, as well as cognitive deficits. At present, schizophrenia is considered a complex disorder of neurodevelopmental origin with both genetic and environmental factors contributing to its onset. Although a number of candidate genes for schizophrenia have been highlighted, only very few schizophrenia patients are likely to share identical genetic liability. This study is based on the nation-wide schizophrenia family sample of the National Institute for Health and Welfare, and represents one of the largest and most well-characterized familial series in the world. In the first part of this study, we investigated the roles of the DTNBP1, NRG1, and AKT1 genes in the background of schizophrenia in Finland. Although these genes are associated with schizophrenia liability in several populations, any significant association with clinical diagnostic information of schizophrenia remained absent in our sample of 441 schizophrenia families. In the second part of this study, we first replicated schizophrenia linkage on the long arm of chromosome 7 in 352 schizophrenia families. In the following association analysis, we utilized additional clinical disorder features and intermediate phenotypes – endophenotypes - in addition to diagnostic information from altogether 290 neuropsychologically assessed schizophrenia families. An intragenic short tandem repeat allele of the regional RELN gene, supposed to play a role in the background of several neurodevelopmental disorders, showed significant association with poorer cognitive functioning and more severe schizophrenia symptoms. Additionally, this risk allele was significantly more prevalent among the individuals affected with schizophrenia spectrum disorders. We have previously identified linkage of schizophrenia and its cognitive endophenotypes on the long arms of chromosomes 2, 4, and 5. In the last part of this study, we selected altogether 104 functionally relevant candidate genes from the linked regions. We detected several promising associations, of which especially interesting are the ERBB4 gene, showing association with the severity of schizophrenia symptoms and impairments in traits related to verbal abilities, and the GRIA1 gene, showing association with the severity of schizophrenia symptoms. Our results extend the previous evidence that the genetic risk for schizophrenia is at least partially mediated via the effects of the candidate genes and their combinations on relevant brain systems, resulting in alterations in different disorder domains, such as the cognitive deficits.

Uniparental DNA markers and forensic genetics in Finland

Over the years, a wide range of methods to verify identity have been developed. Molecular markers have been used for identification since the 1920s, commencing with blood types and culminating with the advent of DNA techniques in the 1980s. Identification is required by authorities in many occasions, e.g. in disputed paternity cases, identification of deceased, or crime investigation. To clarify maternal and paternal lineages, uniparental DNA markers in mtDNA and Y-chromosome can be utilized. These markers have several advantages: male specific Y-chromosome can be used to identify a male from a mixture of male and female cells, e.g. in rape cases. MtDNA is durable and has a high copy number, allowing analyses even from old or degraded samples. However, both markers are lineage-specific, not individualizing, and susceptible to genetic drift. Prior to the application of any DNA marker in forensic casework, it is of utmost importance to investigate its qualities and peculiarities in the target population. Earlier studies on the Finnish population have shown reduced variation in the Y-chromosome, but in mtDNA results have been ambiguous. The obtained results confirmed the low diversity in Y-chromosome in Finland. Detailed population analysis revealed large regional differences, and extremely reduced diversity especially in East Finland. Analysis of the qualities affecting Y-chromosomal short tandem repeat (Y-STR) variation and mutation frequencies, and search of new polymorphic markers resulted a set of Y-STRs with especially high diversity in Finland. Contrary to Y-chromosome, neither reduced diversity nor regional differences were found in mtDNA within Finland. In fact, mtDNA diversity was found similar to other European populations. The revealed peculiarities in the uniparental markers are a legacy of the Finnish population history. The obtained results challenge the traditional explanation which emphasizes relatively recent founder effects creating the observed east-west patterns. Uniparentally inherited markers, both mtDNA and Y-chromosome, are applicable for identification purposes in Finland. By adjusting the analysed Y marker set to meet the characteristics of Finnish population, Y-chromosomal diversity increases and the regional differentiation decreases, resulting increase in discrimination power and thus usefulness of Y-chromosomal analysis in forensic casework.

Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Genetic alterations in microsatellite-unstable colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in Finland. Of all CRC tumors, 15% display microsatellite-instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations genome-wide, especially in short repeat areas, microsatellites. When targeting genes essential for cell growth or death, MSI can promote tumorigenesis. In non-coding areas, microsatellite mutations are generally considered as passenger events. Since the discovery of MSI and its linkage to cancer, more that 200 genes have been investigated for a role in MSI tumorigenesis. Although various criteria have been suggested for MSI target gene identification, the challenge has been to distinguish driver mutations from passenger mutations. This study aimed to clarify these key issues in the research field of MSI cancer. Prior to this, background mutation rate in MSI cancer has not been studied in a large-scale. We investigated the background mutation rate in MSI CRC by analyzing the spectrum of microsatellite mutations in non-coding areas. First, semenogelin I was studied for a possible role in MSI carcinogenesis. The intronic T9 repeat of semenogelin I was frequently mutated but no evidence for selection during tumorigenesis was obtained. Second, a sequencing approach was utilized to evaluate the general background mutation rate in MSI CRC. Both intronic and intergenic repeats harbored extremely high mutation rates of ≤ 87% and intergenic repeats were more unstable than the intronic repeats. As mutation rates of presumably neutral microsatellites can be high in MSI CRC in the absence of apparent selection pressure, high mutation frequency alone is not sufficient evidence for identification of driver MSI target genes. Next, an unbiased approach was designed to identify the mutatome of MSI CRC. By combining expression array data and a database search we identified novel genes possibly related to MSI CRC carcinogenesis. One of the genes was studied further. In the functional analysis this gene was observed to cause an abnormal cancer-prone cellular phenotype, possibly through altered responses to DNA damage. In our recent study, smooth muscle myosin heavy chain 11 (MYH11) was identified as a novel MSI CRC gene. Additionally, MYH11 has a well established role in acute myeloid leukemia (AML) through an oncogenic fusion protein CBFB-MYH11. We investigated further the role of MYH11 in AML by sequencing. Three novel missense variants of MYH11 were identified. None of the variants were present in the population-based control material. One of the identified variants, V71A, lies in the N-terminal SH3-like domain of MYH11 of unknown function. The other two variants, K1059E and R1792Q are located in the coil-coiled myosin rod essential for the regulation and filament formation of MYH11. The variant K1059E lies in the close proximity of the K1044N that has been functionally assessed in our earlier work of CRC and has been reported to cause total loss of MYH11 protein regulation. As the functional significance of the three novel variants examined in this work remains unknown, future studies should clarify the further role of MYH11 in AML leukaemogenesis and in other malignancies.

The Structure and Short-Term Development of Finnish Industries in the 1920s and 1930s : An Input-output Approach

Tutkimuksen tavoitteena on tuottaa uutta tietoa Suomen kansantalouden rakenteesta ja lyhyen aikavälin kehityksestä 1920- ja 1930-luvulla. Tutkimus toteutettiin laatimalla kansantaloutta kuvaava panos-tuotostaulu vuodelle 1928 sekä sen laajennus, panos-tuotosmalli. Aineiston avulla kuvataan kansantalouden rakenteellisia riippuvuuksia, tuotannon avaintoimialoja sekä näiden vaikutusta kansantalouteen. Lisäksi tutkimuksessa tarkastellaan kansantalouden tuontiriippuvuutta sekä tuontitullien vaikutusta hintoihin 1930-luvun laman aikana. Tutkimuksen perusteella voitiin identifioida Suomen kansantalouden avaintoimialat vuonna 1928: maatalous, metsätalous, elintarviketeollisuus, puuteollisuus, paperiteollisuus ja rakennustoiminta. Erityisesti elintarviketeollisuuden vahva rooli kansantaloudessa oli kenties yllättävää, erityisesti kun huomioidaan kuinka vähän toimiala on saanut huomiota osakseen taloushistorian tutkimuksessa. Tutkimus osoitti, että Suomen vienti oli pääomavaltaisempaa kuin tuonti. Vaikka tämän tuloksen tulkinta on varauksellinen, tutkimus pystyi osoittamaan ja kvantifioimaan toimialojen työ- ja pääomapanoksen osuuden tuotoksesta yksityiskohtaisesti. Panos-tuotosmallilla arvioitiin puuteollisuuden, paperiteollisuuden ja rakennustoiminnan ajanjaksona 1928-32 tapahtuneen loppukäytön muutoksen vaikutusta kansantalouteen. Merkittävä havainto on, että rakennustoiminnan loppukäytön muutoksella oli erittäin suuri kasvua vähentävä vaikutus koko kansantaloudessa. Talonrakennusinvestointien romahtaminen aiheutti lähes 13 prosentin tuotannon laskun kansantaloudessa. Vaikutus oli jopa suurempi kuin puuteollisuuden viennin romahtamisen. Tulokset osoittavat toisaalta, että yksityisen kulutuksen merkitys kansantaloudelle oli erittäin vahva. Esimerkiksi puuteollisuuden viennin romahtaminen aiheutti yli 4 % tuotannon vähenemisen mutta huomioitaessa mallissa myös yksityisen kulutuksen väheneminen, oli kokonaisvaikutus yli 10 %. Yksityisen kulutuksen huomioiminen mallissa siis yli kaksinkertaisti toimialojen vaikutukset kansantalouteen. Tulokset vahvistivat aiemmissa tutkimuksissa esitettyjä johtopäätöksiä tullipolitiikasta ja osoittivat maatalouteen läheisesti liittyvän elintarviketeollisuuden olleen eniten suojeltu toimiala kansantaloudessa. Muut kotimarkkinoiden toimialat eivät kuitenkaan hyötyneet tullipolitiikasta lamakauden aikana. Panos-tuotoshintamallilla osoitettiin, ettei tullipolitiikka ollut niin onnistunutta kuin aikalaistutkimuksissa väitettiin, vaan tullit korkeintaan pystyivät hidastamaan hintojen alenemista. Tutkimuksen liitteenä esitetään kaikki keskeiset Suomen kansantaloutta vuonna 1928 kuvaavat tilastolliset taulukot, mukaan lukien käyttö- ja tarjontataulukot, panos-tuotostaulukot, panoskertoimet, Leontiefin käänteismatriisi sekä työ- ja pääomapanoskertoimet.

Short-term effects of variable retention on epigaeic spiders and carabid beetles in Finland

Forestry has influenced forest dwelling organisms for centuries in Fennoscandia. For example, in Finland ca. 30% of the threatened species are threatened because of forestry. Nowadays forest management recommendations include practices aimed at maintaining biodiversity in harvesting, such as green-tree retention. However, the effects of these practices have been little studied. In variable retention, different numbers of trees are retained, varying from green-tree retention (at least a few live standing trees in clear-cuts) to thinning (only individual trees removed). I examined the responses of ground-dwelling spiders and carabid beetles to green-tree retention (with small and large tree groups), gap felling and thinning aimed at an uneven age structure of trees. The impacts of these harvesting methods were compared to those of clear-cutting and uncut controls. I aimed to test the hypothesis that retaining more trees positively affects populations of those species of spiders and carabids that were present before harvesting. The data come from two studies. First, spiders were collected with pitfall traps in south-central Finland in 1995 (pre-treatment) and 1998 (after-treatment) in order to examine the effects of clear-cutting, green-tree retention (with 0.01-0.02-ha sized tree groups), gap felling (with three 0.16-ha sized openings in a 1-ha stand), thinning aiming at an uneven age structure of trees and uncut control. Second, spiders and carabids were caught with pitfall traps in eastern Finland in 1998-2001 (pre-treatment and three post-treatment years) in eleven 0.09-0.55-ha sized retention-tree groups and clear-cuts adjacent to them. Original spider and carabid assemblages were better maintained after harvests that retained more trees. Thinning maintained forest spiders well. However, gap felling and large retention-tree groups maintained some forest spider and carabid species in the short-term, but negatively affected some species over time. However, use of small retention-tree groups was associated with negative effects on forest spider populations. Studies are needed on the long-term effects of variable retention on terrestrial invertebrates; especially those directed at defining appropriate retention patch size and on the importance of structural diversity provided by variable retention for invertebrate populations. However, the aims of variable retention should be specified first. For example, are retention-tree groups planned to constitute life-boats , stepping-stones or to create structural diversity? Does it suffice that some species are maintained, or do we want to preserve the most sensitive ones, and how are these best defined? Moreover, the ecological benefits and economic costs of modified logging methods should be compared to other approaches aimed at maintaining biodiversity.

Short-term plant-decomposer feedbacks in grassland plants

Plant species differ in their effects on ecosystem productivity and it is recognised that these effects are partly due to plant species-specific influences on soil processes. Until recently, however, not much attention was given to the potential role played by soil biota in these species-specific effects. While soil decomposers are responsible for governing the availability of nutrients for plant production, they simultaneously depend on the amount of carbon provided by plants. Litter and rhizodeposition constitute the two basal resources that plants provide to soil decomposer food webs. While it has been shown that both of these can have effects on soil decomposer communities that differ among plant species, the putative significance of these effects for plant nitrogen (N) acquisition is currently understudied. My PhD work aimed at clarifying whether the species-specific influences of three temperate grassland plants on the soil microfood-web, through rhizodeposition and litter, can feed back to plant N uptake. The methods and approach used (15N labelling of plant litter in microcosm experiments) revealed to be an effective combination of tools in studying these feedbacks. Plant effects on soil organisms were shown to differ significantly between plant species and the effects could be followed across several trophic levels. The labelling of litter further permitted the evaluation of plant acquisition of N derived from soil organic matter. The results show that the structure of the soil microfood-web can have a significant role in plant N acquisition when the structure is experimentally manipulated, such as when comparing systems consisting of microbes to those consisting of microbes and their grazers. However, despite this, the results indicate that differences in N uptake from soil organic matter between different plant species are not related to the effects these species exert on the structure of the soil microfood-web. Rather, these differences in N uptake seem to be determined by other species-specific traits of live plants and their litter. My results thus indicate that different resources provided by different plant species may not induce species-specific decomposer feedbacks on plant N uptake from soil organic matter. This further suggests that the species-specific plant effects on soil decomposer communities may not, at least in the short term, have significant consequences on plant production.

Short- and long-term consequences of food resources on Ural owl Strix uralensis reproduction

Life-history theory states that although natural selection would favour a maximisation of both reproductive output and life-span, such a combination can not be achieved in any living organism. According to life-history theory the reason for the fact that not all traits can be maximised simultaneously is that different traits compete with each other for resources. These relationships between traits that constrain the simultaneous evolution of two or more traits are called trade-offs. Therefore, during different life-stages an individual needs to optimise its allocation of resources to life-history components such as growth, reproduction and survival. Resource limitation acts on these traits and therefore investment in one trait, e.g. reproduction, reduces the resources available for investment in another trait, e.g. residual reproduction or survival. In this thesis I study how food resources during different stages of the breeding event affect reproductive decisions in the Ural owl (Strix uralensis) and the consequences of these decisions on parents and offspring. The Ural owl is a suitable study species for such studies in natural populations since they are long-lived, site-tenacious, and feed on voles. The vole populations in Fennoscandia fluctuate in three- to four-year cycles, which create a variable food environment for the Ural owls to cope with. The thesis gives new insight in reproductive costs and their consequences in natural animal populations with emphasis on underlying physiological mechanisms. I found that supplementary fed Ural owl parents invest supplemented food resources during breeding in own self-maintenance instead of allocating those resources to offspring growth. This investment in own maintenance instead of improving current reproduction had carry-over effects to the following year in terms of increased reproductive output. Therefore, I found evidence that reduced reproductive costs improves future reproductive performance. Furthermore, I found evidence for the underlying mechanism behind this carry-over effect of supplementary food on fecundity. The supplementary-fed parents reduced their feeding investment in the offspring compared to controls, which enabled the fed female parents to invest the surplus resources in parasite resistance. Fed female parents had lower blood parasite loads than control females and this effect lasted until the following year when also reproductive output was increased. Hence, increased investment in parasite resistance when resources are plentiful has the potential to mediate positive carry-over effects on future reproduction. I further found that this carry-over effect was only present when potentials for future reproduction were good. The thesis also provides new knowledge on resource limitation on maternal effects. I found that increased resources prior to egg laying improve the condition and health of Ural owl females and enable them to allocate more resources to reproduction than control females. These additional resources are not allocated to increase the number of offspring, but instead to improve the quality of each offspring. Fed Ural owl females increased the size of their eggs and allocated more health improving immunological components into the eggs. Furthermore, the increased egg size had long-lasting effects on offspring growth, as offspring from larger eggs were heavier at fledging. Limiting resources can have different short- and long-term consequences on reproductive decisions that affect both offspring number and quality. In long-lived organisms, such as the Ural owl, it appears to be beneficial in terms of fitness to invest in long breeding life-span instead of additional investment in current reproduction. In Ural owls, females can influence the phenotypic quality of the offspring by transferring additional resources to the eggs that can have long-lasting effects on growth.

Word order and tonal shape in the production of focus in short Finnish utterances

This paper presents results from a study on the production of Finnish prosody. The effect of word order and the tonal shape in the production of Finnish prosody was studied as produced by 8 native Finnish speakers. Predictions formulated with regard to results from an earlier study pertaining to the perception of promi- nence were tested. These predictions had to do with the tonal shape of the utterances in the form of a flat hat pattern and the effect of word order on the so called top-line declination within an adver- bial phrase in the utterances. The results from the experiment give support to the following claims: the temporal domain of prosodic focus is the whole utterance, word order reversal from unmarked to marked has an effect on the production of prosody, and the pro- duction of the tonal aspects of focus in Finnish follows a basic flat hat pattern. That is the prominence of a word can be produced by an f 0 rise or a fall, depending on the location of the word in an utterance. The basic accentual shape of a Finnish word is then not a pointed rise/fall hat shape as claimed before since it can vary depending on the syllable structure and the position within an ut- terance.

A Comparison of Managers’ Perception of Short-Termism in Finland, Sweden and the U.S

Increased media exposure to layoffs and corporate quarterly financial reporting have created arguable a common perception – especially favored by the media itself – that the companies have been forced to improve their financial performance from quarter to quarter. Academically the relevant question is whether companies themselves feel that they are exposed to short-term pressure to perform even if it means that they have to compromise company’s long-term future. This paper studies this issue using results from a survey conducted among the 500 largest companies in Finland. The results show that companies in general feel moderate short-term pressure, with reasonable dispersion across firms. There seems to be a link between the degree of pressure felt, and the firm’s ownership structure, i.e. we find support for the existence of short-term versus long-term owners. We also find significant ownership related differences, in line with expectations, in how such short-term pressure is reflected in actual decision variables such as the investment criteria used.

Finnish Short-Term Stock Returns

Functioning capital markets are a crucial part of a competitive economy since they provide the mechanisms to allocate resources. In order to be well functioning a capital market has to be efficient. Market efficiency is defined as a market where prices at any time fully reflect all available information. Basically, this means that abnormal returns cannot be predicted since they are dependent on future, presently unknown, information. The debate of market efficiency has been going on for several decades. Most academics today would probably agree that financial markets are reasonably efficient since virtually nobody has been able to achieve continuous abnormal positive returns. However, it is clear that a set of return anomalies exists, although they are apparently to small to enable substantial economic profit. Moreover, these anomalies can often be attributed to market design. The motivation for this work is to expand the knowledge of short-term trading patterns and to offer some explanations for these patterns. In the first essay the return pattern during the day is examined. On average stock prices move during two time periods of the day, namely, immediately after the opening and around the formal close of the market. Since stock prices, on average, move upwards these abnormal returns are generally positive and cause the distinct U-shape of intraday returns. In the second essay the results in the first essay are examined further. The return pattern around the former close is shown to partly be the result of manipulative action by market participants. In the third essay the focus is shifted towards trading patterns of the underlying stocks on days when index options and index futures on the stocks expire. Generally no expiration day effect was found. However, some indication of an expiration day effect was found when a large amount of open in- or at-the-money contracts existed. Also, the effects were likelier to be found for shares with high index-weight but fairly low trading volume. Last, in the forth essay the attention is turned to the behaviour of different tax clienteles around the dividend ex-day. Two groups of investors showed abnormal trading behaviour. Domestic non-financial investors, especially domestic companies, showed a dividend capturing behaviour, i.e. buying cum-dividend and selling ex-dividend shares. The opposite behaviour was found for foreign investors and domestic financial institutions. The effect was more notable for high yield, high volume stocks.