Eesti siirdemeditsiini maastiku ja võimaluste kompamine projektis „Happy Pregnancy”

Eesti Arst 2015; 94(8):460–46

Mapping genes through the use of linkage disequilibrium generated by genetic drift: 'Drift mapping' in small populations with no demographic expansion

Linkage disequilibrium has been a powerful tool in identifying rare disease alleles in human populations. To date, most research has been directed to isolated populations which have undergone a bottleneck followed by rapid exponential expansion. While this strategy works well for rare diseases in which all disease alleles in the population today are clonal copies of some common ancestral allele, for common disease genes with substantial allelic heterogeneity, this approach is not predicted to work. In this paper, we describe the dynamics of linkage disequilibrium in populations which have not undergone a demographic expansion. In these populations, it is shown that genetic drift creates disequilibrium over time, while in expanded populations, the disequilibrium decays with time. We propose that common disease alleles might be more efficiently identified by drift mapping - linkage disequilibrium mapping in small, old populations of constant size where the disequilibrium is the result of genetic drift, not founder effect. Theoretical models, empirical data, and simulated population models are presented as evidence for the utility of this approach

Human CuZn superoxide dismutase enzymatic activity in cells is regulated by the length of the mRNA

AbstractSingle functional human CuZnSOD gene encodes two species of mRNA differing in size by 200 nucleotides in the 3′-untranslated region (UTR). We studied the expression of the CuZnSOD cDNA with different 3′- and 5′-UTR. Deletion in the 5′-end does not affect the expression of the enzyme, however, deletion in the 3′-UTR decreases the level of expression of CuZnSOD. The plasmids containing the long CuZnSOD cDNA with all polyadenylation signal sequences utilize primarily the last polyadenylation site and give a long mRNA, which produces three times more enzyme than the short mRNA lacking the last polyadenylation site and the AU-rich region

Natural antisense transcript of natriuretic peptide precursor A (NPPA): structural organization and modulation of NPPA expression

<p>Abstract</p> <p>Background</p> <p>Mammalian transcriptome contains a large proportion of diverse and structurally complex noncoding RNAs. One class of such RNAs, natural antisense transcripts (NATs), are derived from the opposite strand of many protein-coding genes. Although the exact structure and functional relevance of most of the NATs is unknown, their emerging role as gene expression regulators raises the hypothesis that NATs might contribute to development of complex human disorders. The goal of our study was to investigate the involvement of NATs in regulation of candidate genes for blood pressure.</p> <p>Results</p> <p>First we analysed blood pressure candidate genes for the presence of natural antisense transcripts. <it>In silico </it>analysis revealed that seven genes (<it>ADD3</it>, <it>NPPA</it>, <it>ATP1A1</it>, <it>NPR2</it>, <it>CYP17A1</it>, <it>ACSM3</it>, <it>SLC14A2</it>) have an antisense partner transcribed from the opposite strand. We characterized <it>NPPA </it>and its antisense transcript (<it>NPPA-AS</it>) in more detail. We found that <it>NPPA-AS </it>is expressed in a number of human tissues as a collection of alternatively spliced isoforms and that <it>NPPA-AS </it>and <it>NPPA </it>can form RNA duplexes <it>in vivo</it>. We also demonstrated that a specific <it>NPPA-AS </it>isoform is capable of down-regulating the intron-retained <it>NPPA </it>mRNA variant. We studied the evolutionary conservation of <it>NPPA-AS </it>and were able to detect the presence of <it>Nppa-as </it>transcript in mouse.</p> <p>Conclusion</p> <p>Our results demonstrate functional interaction of <it>NPPA-AS </it>with <it>NPPA </it>at the RNA level and suggest that antisense transcription might be an important post-transcriptional mechanism modulating <it>NPPA </it>expression.</p

Sekkumistõhusad teisesed leiud geneetikas

Kliinilises praktikas kasutatakse üha enam haigusseoseliste geenivariantide tuvastamiseks eksoomi (1–2% genoomist) sekveneerimist, sest selle diagnostiline saagis on suur (ligikaudu 30%). See suur andmestik (üle 80 000 geenivariandi) võib sisaldada ka teiseseid leide – kliiniliselt olulisi geenivariante, mis ei ole seotud patsiendi esmase kliinilise näidustusega. Teiseste leidude alla kuuluvad sekkumistõhusad monogeensed ehk ühe geeni muutusestpõhjustatud haigused, mis on eraldiseisvalt harvad, kuid mõjutavad kokku umbes 1–3% inimestest. Need haigused avalduvad elu jooksul ja on mõningatel juhtudel kiiresti areneva sümptomaatikaga. Päriliku riski varane hindamine on oluline, sest mitmete haiguste puhul on juba enne sümptomite teket võimalik meditsiiniline sekkumine (nt ravidieet, ennetavad ravimid, kirurgia), mis aitab vähendada tüsistusi ja enneaegset suremust. Artiklis on antud ülevaade eksoomi andmetest tuvastatavatest sekkumistõhusatest pärilikest haigustest, nende esinemissagedusest ja võimalikest ennetusmeetmetest ning teisestest leidudest tagasiside andmise rahvusvahelistest seisukohtadest

FANCMi immunohistokeemiline ekspressioon väheneb eesnäärmevähi stroomas sõltuvalt diferentseerumisastme rühmast

Eesti Arst 2021; 100(5):324 &nbsp

Enneaegne munasarjapuudulikkus: geneetika kasvav roll diagnostikas ja kliinilises käsitluses

Enneaegne munasarjapuudulikkus on sündroom, mis põhjustab munasarjade funktsiooni häiret enne 40. eluaastat. Haigus mõjutab paljusid naisi (levimus ligikaudu 1%), kahjuks ei leita seitsmel patsiendil kümnest haiguse põhjust.Teadaolevatest põhjustest moodustavad geneetilised tegurid 20–25%. Nendest levinuimad on kromosomaalsed häired ja FMR1 geeni premutatsioon. Nüüdseks on teada 20 geeni, mille haigusseoselised variandid põhjustavad isoleeritud enneaegset munasarjapuudulikkust ja viljatust. Täiendavaid uuringuid vajavad veel kümned eksoomi sekveneerimise meetodil tuvastatud kandidaatgeenid, mis vastutavad munasarja arengu ja funktsiooni, meioosi ja DNA parandusprotsesside eest.Kliinilises praktikas on enneaegse munasarjapuudulikkuse geneetiliste põhjuste selgitamine muutumas aina olulisemaks, sest arvestatav hulk naisi soovib tänapäeval sünnitada pigem 30. eluaastates. Konkreetne geneetiline leid on oluline patsiendi käsitluses ja ravis, samuti on see hädavajalik perekondlikus nõustamises. Ka uute ravitaktikate väljatöötamisel on geneetilise etioloogia tundmisel lisandväärtus

High divergence in primate-specific duplicated regions: Human and chimpanzee Chorionic Gonadotropin Beta genes

<p>Abstract</p> <p>Background</p> <p>Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (<it>LHB</it>)/Chorionic Gonadotropin Beta (<it>CGB</it>) gene cluster as a model. The placental <it>CGB </it>genes that are essential for implantation have evolved from an ancestral pituitary <it>LHB </it>gene by duplications in the primate lineage.</p> <p>Results</p> <p>We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp) <it>LHB/CGB </it>regions and hereby present evidence for structural variation resulting in discordant number of <it>CGB </it>genes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions of <it>LHB/CGB </it>cluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped the <it>LHB/CGB </it>gene cluster. The substitution divergence (1.8–2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus ~30%). Despite the high sequence identity among <it>LHB/CGB </it>genes, there are signs of functional differentiation among the gene copies. Estimates for d_n/d_srate ratio suggested a purifying selection on <it>LHB </it>and <it>CGB8</it>, and a positive evolution of <it>CGB1</it>.</p> <p>Conclusion</p> <p>If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.</p

Gilles de la Tourette’i sündroomi perekondlik haigusjuht

Artiklis kirjeldatud haigusjuht täiendab Gilles de la Tourette’i sündroomi tänapäevase käsitluse ja probleemide ülevaadet, mis on avaldatud Eesti Arsti käesolevas numbris. Eesti haigusjuhu kirjelduse näitel on ühe võimaliku etioloogilise tegurina toodud välja perekondlik eelsoodumus ning rõhutatud sündroomi sagedast aladiagnoosimist ja puudulikku ravi. Kirjeldatud on 17 aasta vanuse Eesti naispatsiendi haigusjuhtu. &nbsp