Increased Expression of MERTK is Associated with a Unique Form of Canine Retinopathy

Progressive retinal degenerations are among the most common causes of blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) resembles human retinitis pigmentosa (RP) and is typically characterized by a progressive loss of rod photoreceptors followed by a loss of cone function. The disease gradually progress from the loss of night and day vision to a complete blindness. We have recently described a unique form of retinopathy characterized by the multifocal gray/brown discoloration and thinning of the retina in the Swedish Vallhund (SV) breed. We aimed to identify the genetic cause by performing a genome wide association analysis in a cohort of 18 affected and 10 healthy control dogs using Illumina's canine 22k SNP array. We mapped the disease to canine chromosome 17 (p = 7.7×10−5) and found a 6.1 Mb shared homozygous region in the affected dogs. A combined analysis of the GWAS and replication data with additional 60 dogs confirmed the association (p = 4.3×10−8, OR = 11.2 for homozygosity). A targeted resequencing of the entire associated region in four cases and four controls with opposite risk haplotypes identified several variants in the coding region of functional candidate genes, such as a known retinopathy gene, MERTK. However, none of the identified coding variants followed a compelling case- or breed-specific segregation pattern. The expression analyses of four candidate genes in the region, MERTK, NPHP1, ANAPC1 and KRCC1, revealed specific upregulation of MERTK in the retina of the affected dogs. Collectively, these results indicate that the retinopathy is associated with overexpression of MERTK, however further investigation is needed to discover the regulatory mutation for the better understanding of the disease pathogenesis. Our study establishes a novel gain-of-function model for the MERTK biology and provides a therapy model for retinopathy MERTK inhibitors. Meanwhile, a marker-based genetic counseling can be developed to revise breeding programs.Peer reviewe

Environmental effects on compulsive tail chasing in dogs

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Evidence for genetic regulation of the human parieto-occipital 10-Hz rhythmic activity

Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable (h(2)>0.75). Variance component-based analysis of 28000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 (LOD=2.814, nominal PPeer reviewe

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene

Background: Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results: We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions: These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.Peer reviewe

Jamipaja : Kehollisuuteen, osallistavuuteen ja vertaisoppijuuteen perustuvaa kansanmusiikkipedagogiikkaa

Opinnäytetyömme keskeisenä tavoitteena oli suunnitella, toteuttaa ja arvioida kansanmusiikkipedagoginen konsepti, Jamipaja. Opinnäytetyössämme kuvailemme Jamipaja-konseptin, raportoimme ja pohdimme sen toteutusta sekä tarkastelemme työtämme teoreettisten käsitteiden kautta. Jamipajan keskeinen lähtökohta oli kansanmusiikin ymmärtäminen osallistavana ja kehollisena taidemuotona. Jamipajan keskeisiä piirteitä olivat vertaisoppimisen käyttäminen keskeisenä menetelmänä; musiikin ja liikkeen, erityisesti kansanmusiikin ja -tanssin, ymmärtäminen erottamattomina; ja musiikillisen ohjelmiston oppiminen korvakuulolta sekä tanssien oppiminen näkemällä ja kokeilemalla. Työllämme vastasimme tutkimuskysymykseen: Millaisella pedagogisella otteella ja konseptilla voidaan siirtää eteenpäin kansanmusiikille – tässä tapauksessa lähinnä pelimannimusiikille) olennaisia piirteitä? Tutkimusotettamme voi luonnehtia laadulliseksi toimintatutkimukseksi. Keskeisiä menetelmiämme olivat reflektiivinen praktiikka, osallistuva havainnointi, palautekeskustelut ja kysely. Saatuja tutkimusmateriaalejamme analysoimme aluksi ilman teoreettista viitekehystä. Tämän ensimmäisen tarkastelun jälkeen hyödynsimme käsitteitä meille olennaisesta kirjallisuudesta. Nämä kolme käsitettä olivat kehollisuus, osallisuus ja vertaisoppijuus. Tulostemme valossa kokonaisvaltainen kehollinen oppiminen, jossa tanssi ja soitto pidetään pedagogisesti yhdessä mahdollisimman pitkälti, on tehokas oppimisen ja tiedon tuottamisen menetelmä; ainekset siihen, miten pelimannimusiikin soittamista voi lähestyä löytyvät tanssilajin liikkeestä, ilmaisusta ja rytmiikasta. Näiden opiskeleminen yhdessä rakensi opiskelijoiden omaa asiantuntemusta ja luottamusta omiin taitoihin. Vertaisoppiminen ja korvakuulolta oppiminen antoivat osallistujille sosiaalisessa musisoinnissa tarvittavia taitoja. Työmme täydentää osaltaan kansanmusiikkipedagogiikan kentän kirjallisuutta ja menetelmäkenttää tavalla, joka näkemyksemme mukaan soveltuu erityisen hyvin kansanmusiikin opiskeluun. Opinnäytetyömme myös selventää kansanmusiikkipegogiikan erityisluonnetta, sekä avaa mahdollisuuksia kansanmusiikkipedagogiikan erityispiirteiden pohtimiseen, kehittämiseen, vahvistamiseen ja soveltamiseen muille aloille.The aim of our thesis was to design, implement and evaluate a folk music pedagogy concept, the Jam Workshop (JW). Thus, in this thesis, we describe JW, report and reflect on its implementation as a case study and examine it through theoretical concepts. The central point of departure for our work was an understanding of folk music as a participatory and embodied art form. The core features of JW were: the utilization of peer learning as a method; an understanding of music and dance as inseparable; and the learning of musical repertoire by ear as well as the learning of dance through seeing and experimenting without notation. Through our work, we aimed to answer the question: What kind of a pedagogical approach and concept could be used to pass on (Finnish) folk music and its essential characteristics? We utilized participatory action research to answer this question. Our specific methods were reflective practice, participatory observation, feedback sessions and a questionnaire. We analyzed our research materials first without any theoretical lenses; however, later we employed the concepts of embodiment, participation and peer learning to gain and organize findings. Our findings suggest that our holistic embodied approach, where dance and music are kept together as extensively as possible, is an effective method of learning and knowledge production in Finnish folk music. The answers to the question of how to approach folk music are often found in the movements, expression and rhythms of the dances. Studying these built up our students’ own expertise and confidence in their skills. Peer learning and aural learning gave our students the skills necessary for social music- making. Our work contributes to the literature and methodology of folk music pedagogy in a manner that we deem especially suited to the study of folk music. Additionally, our thesis explores the specific characteristics of folk music pedagogy and opens up novel opportunities to both strengthen these characteristics, enable deeper learning experiences. Additionally, we suggest that these principles could be applied to other musical genres and pedagogical disciplines

Two novel genomic regions associated with fearfulness in dogs overlap human neuropsychiatric loci

Anxiety disorders are among the leading health issues in human medicine. The complex phenotypic and allelic nature of these traits as well as the challenge of establishing reliable measures of the heritable component of behaviour from the associated environmental factors hampers progress in their molecular aetiology. Dogs exhibit large natural variation in fearful and anxious behaviour and could facilitate progress in the molecular aetiology due to their unique genetic architecture. We have performed a genome-wide association study with a canine high-density SNP array in a cohort of 330 German Shepherds for two phenotypes, fear of loud noises (noise sensitivity) and fear of strangers or in novel situations. Genome-widely significant loci were discovered for the traits on chromosomes 20 and 7, respectively. The regions overlap human neuropsychiatric loci, including 18p11.2, with physiologically relevant candidate genes that contribute to glutamatergic and dopaminergic neurotransmission in the brain. In addition, the noise-sensitivity locus includes hearing-related candidate genes. These results indicate a genetic contribution for canine fear and suggest a shared molecular aetiology of anxiety across species. Further characterisation of the identified loci will pave the way to molecular understanding of the conditions as a prerequisite for improved therapy.Peer reviewe

Novel protective and risk loci in hip dysplasia in German Shepherds

Canine hip dysplasia is a common, non-congenital, complex and hereditary disorder. It can inflict severe pain via secondary osteoarthritis and lead to euthanasia. An analogous disorder exists in humans. The genetic background of hip dysplasia in both species has remained ambiguous despite rigorous studies. We aimed to investigate the genetic causes of this disorder in one of the high-risk breeds, the German Shepherd. We performed genetic analyses with carefully phenotyped case-control cohorts comprising 525 German Shepherds. In our genome-wide association studies we identified four suggestive loci on chromosomes 1 and 9. Targeted resequencing of the two loci on chromosome 9 from 24 affected and 24 control German Shepherds revealed deletions of variable sizes in a putative enhancer element of the NOG gene. NOG encodes for noggin, a well-described bone morphogenetic protein inhibitor affecting multiple developmental processes, including joint development. The deletion was associated with the healthy controls and mildly dysplastic dogs suggesting a protective role against canine hip dysplasia. Two enhancer variants displayed a decreased activity in a dual luciferase reporter assay. Our study identifies novel loci and candidate genes for canine hip dysplasia, with potential regulatory variants in the NOG gene. Further research is warranted to elucidate how the identified variants affect the expression of noggin in canine hips, and what the potential effects of the other identified loci are.Peer reviewe

Results of the genome-wide association study.

<p>Genome-wide association analysis identifies the retinopathy locus in the SV breed. <b>A</b>) Manhattan plot with tentative association on CFA17 (p_raw = 7.7×10⁻⁵), replication analysis supported the association (p_repl = 2.7×10⁻⁵) and was confirmed by combined analysis (p = 4.3×10⁻⁸). CFA39 represent the X chromosome. <b>B</b>) A close-up of the associated region on CFA17, which spans from 38.16 Mb to 43.64 Mb. <b>C</b>) The associated region harbors over hundred genes, including a known PRA gene, <i>MERTK</i>.</p

Retinal upregulation of <i>MERTK</i> in the affected SVs.

<p>The retinal mRNA levels of <i>MERTK</i>, <i>NPHP1</i>, <i>ANAPC1</i> and <i>KRCC1</i> genes were compared between affected (n = 4) and unaffected dogs (n = 2). A specific overexpression of <i>MERTK</i> was found in the affected SVs. The relative mRNA expression levels are represented as a fold change. Error bars denote the standard error of normalized Ct-values. *p≤0.0001 (two-tailed t-test p-value).</p