Differences in molecular evolutionary rates among microRNAs in the human and chimpanzee genomes

[Background] The rise of the primate lineage is accompanied by an outstanding emergence of microRNAs, small non-coding RNAs with a prominent role in gene regulation. In spite of their biological importance little is known about the way in which natural selection has influenced microRNAs in the human lineage. To study the recent evolutionary history of human microRNAs and to analyze the signatures of natural selection in genomic regions harbouring microRNAs we have investigated the nucleotide substitution rates of 1,872 human microRNAs in the human and chimpanzee lineages.[Results] We produced a depurated set of microRNA alignments of human, chimpanzee and orang-utan orthologs combining BLAT and liftOver and selected 1,214 microRNA precursors presenting optimal secondary structures. We classified microRNAs in categories depending on their genomic organization, duplication status and conservation along evolution. We compared substitution rates of the aligned microRNAs between human and chimpanzee using Tajima’s Relative Rate Test taking orang-utan as out-group and found several microRNAs with particularly high substitution rates in either the human or chimpanzee branches. We fitted different models of natural selection on these orthologous microRNA alignments and compared them using a likelihood ratio test that uses ancestral repeats and microRNA flanking regions as neutral sequences. We found that although a large fraction of human microRNAs is highly conserved among the three species studied, significant differences in rates of molecular evolution exist among microRNA categories. Particularly, primate-specific microRNAs, which are enriched in isolated and single copy microRNAs, more than doubled substitution rates of those belonging to older, non primate-specific microRNA families.[Conclusions] Our results corroborate the remarkable conservation of microRNAs, a proxy of their functional relevance, and indicate that a subset of human microRNAs undergo nucleotide substitutions at higher rates, which may be suggestive of the action of positive selection.This work was supported by the Ministerio de Ciencia e Innovación, España (BFU2012-38236, BFU2010-18477, BFU2009-06974, and CGL2009-09013), Direcció General de Recerca de la Generalitat de Catalunya” (2009SGR-1101, 2014SGR-866 and SGR2014-1311) and European Union Seventh Framework Programme (PIOF-GA-2009-236836 and PIRSES-GA-2013-612583). This publication has been cofinanced by FEDER —European Regional Development Fund “A way to build Europe.” MLV is funded by a Beca per a la Formació de Personal Investigador (FI) fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya.Peer reviewe

Functional Implications of Human-Specific Changes in Great Ape microRNAs

microRNAs are crucial post-transcriptional regulators of gene expression involved in a wide range of biological processes. Although microRNAs are highly conserved among species, the functional implications of existing lineage-specific changes and their role in determining differences between humans and other great apes have not been specifically addressed. We analyzed the recent evolutionary history of 1,595 human microRNAs by looking at their intra-and inter-species variation in great apes using high-coverage sequenced genomes of 82 individuals including gorillas, orangutans, bonobos, chimpanzees and humans. We explored the strength of purifying selection among microRNA regions and found that the seed and mature regions are under similar and stronger constraint than the precursor region. We further constructed a comprehensive catalogue of microRNA species-specific nucleotide substitutions among great apes and, for the first time, investigated the biological relevance that human-specific changes in microRNAs may have had in great ape evolution. Expression and functional analyses of four microRNAs (miR-299-3p, miR-503-3p, miR508-3p and miR-541-3p) revealed that lineage-specific nucleotide substitutions and changes in the length of these microRNAs alter their expression as well as the repertoires of target genes and regulatory networks. We suggest that the studied molecular changes could have modified crucial microRNA functions shaping phenotypes that, ultimately, became human-specific. Our work provides a frame to study the impact that regulatory changes may have in the recent evolution of our species.Peer reviewe

Ancient genomes in South Patagonia reveal population movements associated with technological shifts and geography

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700–2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200–1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.Fil: Nakatsuka, Nathan. Harvard Medical School; Estados UnidosFil: Luisi, Pierre. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades; ArgentinaFil: Motti, Josefina María Brenda. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina. Universidad Nacional de Tierra del Fuego; ArgentinaFil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: D'angelo del Campo, Manuel Domingo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Grupo de Estudios Interdisciplinarios sobre Poblaciones Humanas de Patagonia Austral; Argentina. Universidad Autónoma de Madrid; EspañaFil: Vecchi, Rodrigo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur; ArgentinaFil: Espinosa Parrilla, Yolanda. Consejo Superior de Investigaciones Científicas; EspañaFil: Prieto, Alfredo. Universidad de Magallanes; ChileFil: Adamski, Nicole. Harvard Medical School; Estados UnidosFil: Lawson, Ann Marie. Harvard Medical School; Estados UnidosFil: Harper, Thomas K.. University of Pennsylvania; Estados UnidosFil: Culleton, Brendan J.. University of Pennsylvania; Estados UnidosFil: Kennett, Douglas J.. University of California; Estados UnidosFil: Lalueza Fox, Carles. Consejo Superior de Investigaciones Científicas; EspañaFil: Mallick, Swapan. Harvard Medical School; Estados UnidosFil: Rohland, Nadin. Harvard Medical School; Estados UnidosFil: Guichón, Ricardo A.. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Cabana, Graciela S.. University of Tennessee; Estados UnidosFil: Nores, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Reich, David. Harvard Medical School. Department Of Medicine; Estados Unido

Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Neurotrophins and their receptors are key molecules in the regulation of neuronal differentiation and survival. They mediate the survival of neurons during development and adulthood and are implicated in synaptic plasticity. The human neurotrophin-3 receptor gene <it>NTRK3 </it>yields two major isoforms, a full-length kinase-active form and a truncated non-catalytic form, which activates a specific pathway affecting membrane remodeling and cytoskeletal reorganization. The two variants present non-overlapping 3'UTRs, indicating that they might be differentially regulated at the post-transcriptional level. Here, we provide evidence that the two isoforms of <it>NTRK3 </it>are targeted by different sets of microRNAs, small non-coding RNAs that play an important regulatory role in the nervous system.</p> <p>Results</p> <p>We identify one microRNA (miR-151-3p) that represses the full-length isoform of <it>NTRK3 </it>and four microRNAs (miR-128, miR-485-3p, miR-765 and miR-768-5p) that repress the truncated isoform. In particular, we show that the overexpression of miR-128 - a brain enriched miRNA - causes morphological changes in SH-SY5Y neuroblastoma cells similar to those observed using an siRNA specifically directed against truncated <it>NTRK3</it>, as well as a significant increase in cell number. Accordingly, transcriptome analysis of cells transfected with miR-128 revealed an alteration of the expression of genes implicated in cytoskeletal organization as well as genes involved in apoptosis, cell survival and proliferation, including the anti-apoptotic factor <it>BCL2</it>.</p> <p>Conclusions</p> <p>Our results show that the regulation of <it>NTRK3 </it>by microRNAs is isoform-specific and suggest that neurotrophin-mediated processes are strongly linked to microRNA-dependent mechanisms. In addition, these findings open new perspectives for the study of the physiological role of miR-128 and its possible involvement in cell death/survival processes.</p

Variación de alelos del gen receptor de dopamina DRD4 en escolares chilenos de diferente origen étnico y su relación con riesgo de déficit atencional/hiperactividad

[Background] Worldwide diversity of alleles of D4 receptor gene (DRD4), linked to attention deficit hyperactivity disorder (ADHD), is mostly the result of length and single nucleotide polymorphisms in a 48-bp tandem repeat (VNTR). Alleles containing from two (2R) to eleven (11R) repeats have been identified. The most common are 4R, 7R and 2R.[Aim] To study the association of ADHD risk with DRD4 genotypes in Chilean students.[Subjects and Methods] ADHD risk data were obtained through the abbreviated Conner's Scale for School Teachers in 66 Aymara children (11 cases and 55 controls), 91 Rapa-Nui children (60 cases ad 31 controls) and 96 children from a mixed urban population from Santiago (51 cases and 45 controls). DNA extracted from saliva was amplified by polymerase chain reaction (PCR) to genotype the DRD4 VNTR.[Results] The distribution of DRD4 alleles reveals that, beneath the 4R allele, 7R exhibits the second highest frequencies in Aymara and Santiago children. In Polynesian children, 2R ranks after 4R. A statistically significant association between ADHD risk and 2R/4R genotype was identified in Polynesian children (p < 0.05; odds ratio = 3.7).[Conclusions] Different DRD4 genotypes are associated with ADHD phenotype in Chilean populations, probably as a consequence of their initial colonization history.Este trabajo ha sido financiado a través de fondos otorgados por los Proyecto Fondecyt # 1080219, el Convenio de Desempeño UTA/Mecesup 2 y el programa de la Unión Europea "European Union Seventh Framework Programme" (PIOF-GA-2009-236836).Peer Reviewe

Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways

Disponible desde www.ncbi.nlm.nih.gov. -- Autores: Muiños-Gimeno, Margarita ... [et al.][Background] The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder.[Methods] Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs.[Results] Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%–60%) several candidate genes for panic disorder—GABRA6, CCKBR and POMC, respectively—and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety.[Conclusions] This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.Este trabajo fue financiado por el "Instituto Carlos III y el Fondo de Investigaciones Sanitarias" (nº CIBER-CB06/02/0058, CIBER-SAM, FIS/ISCIII: P1052565, ISCIII: GO3/184, FI05/0006 para Margarita Muiños-Gimeno), la "Fundación Marató-TV3" (nº 014 331), el "Departament d'Universitats Innovació i Empresa, Generalitat de Catalunya" (nº 2005SGR00008 y 2009SGR1435), el Ministerio de Ciencia e Innovación (nº SAF2008-00357), Sexto Programa Marco de la Unión Europea Proyecto Integrado SIROCCO (nº LSHG-CT-2006-037900). Andres Metspalu fue apoyado por el Séptimo Programa Marco Unión de la Europea (nº ENGAGE 201413, ECOGENE # 205419 EBC, y OPENGENE # 245536), la Unión Europea a través del Fondo Europeo de Desarrollo Regional (Centro de Excelencia en Genómica) y el Gobierno de Estonia (nº SF0180142s08). El Centro Español Nacional de Genotipado (CeGen) fue apoyado por "Genoma España". Academia de Finlandia, Yrjö and Tuulikki Ilvonen Foundation y la Fundación Sigrid Juselius. Fundación Científica de Estonia (nº 7034).Peer reviewe

Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways

Disponible desde www.ncbi.nlm.nih.gov. -- Autores: Muiños-Gimeno, Margarita ... [et al.][Background] The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder.[Methods] Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs.[Results] Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%–60%) several candidate genes for panic disorder—GABRA6, CCKBR and POMC, respectively—and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety.[Conclusions] This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.Este trabajo fue financiado por el "Instituto Carlos III y el Fondo de Investigaciones Sanitarias" (nº CIBER-CB06/02/0058, CIBER-SAM, FIS/ISCIII: P1052565, ISCIII: GO3/184, FI05/0006 para Margarita Muiños-Gimeno), la "Fundación Marató-TV3" (nº 014 331), el "Departament d'Universitats Innovació i Empresa, Generalitat de Catalunya" (nº 2005SGR00008 y 2009SGR1435), el Ministerio de Ciencia e Innovación (nº SAF2008-00357), Sexto Programa Marco de la Unión Europea Proyecto Integrado SIROCCO (nº LSHG-CT-2006-037900). Andres Metspalu fue apoyado por el Séptimo Programa Marco Unión de la Europea (nº ENGAGE 201413, ECOGENE # 205419 EBC, y OPENGENE # 245536), la Unión Europea a través del Fondo Europeo de Desarrollo Regional (Centro de Excelencia en Genómica) y el Gobierno de Estonia (nº SF0180142s08). El Centro Español Nacional de Genotipado (CeGen) fue apoyado por "Genoma España". Academia de Finlandia, Yrjö and Tuulikki Ilvonen Foundation y la Fundación Sigrid Juselius. Fundación Científica de Estonia (nº 7034).Peer reviewe