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News Article | February 15, 2017
Site: phys.org

For evolutionary biologists, islands are often intriguing, geographically isolated pockets with unique populations that can be ripe for exploration. Now, in a new study appearing in the advanced online edition of Molecular Biology and Evolution an international team led by geneticist Anna Olivieri from the University of Pavia tackles a highly interesting question: what were the origins of the Sardinian population in the context of European prehistory and ancient human migrations? The authors analyzed 3,491 modern, whole mitochondrial DNA genomes from Sardinia (which are only passed down maternally). These were compared with 21 samples of ancient mitogenomes from the island, a large panel of non-Sardinian mitogenomes —-and even Ötzi (the nickname of Europe's oldest natural mummy, the 3,300 BCE-year old "Tyrolean Iceman") —-to better understand their origins. Their findings show Sardinia as an outlier in the general European genetic landscape. Almost 80 percent of modern Sardinian mitogenomes belong to branches that cannot be found anywhere else outside the island. Thus, they were defined as Sardinian-Specific Haplogroups (SSHs) that most likely arose in the island after its initial occupation. Almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. However, some rare SSHs display age estimates older than 7,800 years ago, the postulated archeologically-based starting time of the Neolithic in Sardinia. "Our analyses raise the possibility that several SSHs may have already been present on the island prior to the Neolithic," said prof. Francesco Cucca, from the Institute of Genetic and Biomedical Research (IRGB), at the CNR in Cagliari (Sardinia). The most plausible candidates would include haplogroups K1a2d and U5b1i1, which together comprise almost 3 percent of modern Sardinians, and possibly others. Such a scenario would not only support archaeological evidence of a Mesolithic occupation of Sardinia, but could also suggest a dual ancestral origin of its first inhabitants. K1a2d is of Late Paleolithic Near Eastern ancestry, whereas U5b1i1 harbours deep ancestral roots in Paleolithic Western Europe. This work provides evidence that contemporary Sardinians harbour a unique genetic heritage, as a result of their distinct history and relative isolation from the demographic upheavals of continental Europe. Anna Olivieri stresses: "It now seems plausible that human mobility, inter-communication and gene flow around the Mediterranean from Late Glacial times onwards may well have left signatures that survive to this day. Some of these signals are still retained in modern Sardinians." "Although in the past the stress has often been on the spread of the Neolithic, genetic studies too are beginning to emphasize the complexity and mosaic nature of human ancestry in the Mediterranean, and indeed in Europe more widely," concludes prof. Antonio Torroni, from the University of Pavia. "Future work on ancient DNA should be able to test directly to what extent this more complex model is supported by genetic evidence, and whether our predictions of Mesolithic ancestry in contemporary Sardinians can be sustained." Explore further: Hair from mummy's clothes provides insights into red deer lineage More information: Anna Olivieri,† et al, Mitogenome Diversity in Sardinians: a Genetic Window onto an Island's Past, Molecular Biology and Evolution (2017). DOI: 10.1093/molbev/msx082


Castaldi A.,Institute of Genetic and Biomedical Research | Castaldi A.,University of Milan Bicocca | Zaglia T.,Venetian Institute of Molecular Medicine | Zaglia T.,University of Padua | And 21 more authors.
Circulation Research | Year: 2014

RATIONALE:: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. OBJECTIVE:: To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS:: Based on bioinformatic analysis, β1-adrenergic receptor (β1AR) and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. CONCLUSIONS:: miR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure. © 2014 American Heart Association, Inc.


Bang M.-L.,Institute of Genetic and Biomedical Research | Gu Y.,University of California at San Diego | Dalton N.D.,University of California at San Diego | Peterson K.L.,University of California at San Diego | And 3 more authors.
PLoS ONE | Year: 2014

Ankrd1/CARP, Ankrd2/Arpp, and Ankrd23/DARP belong to a family of stress inducible ankyrin repeat proteins expressed in striated muscle (MARPs). The MARPs are homologous in structure and localized in the nucleus where they negatively regulate gene expression as well as in the sarcomeric I-band, where they are thought to be involved in mechanosensing. Together with their strong induction during cardiac disease and the identification of causative Ankrd1 gene mutations in cardiomyopathy patients, this suggests their important roles in cardiac development, function, and disease. To determine the functional role of MARPs in vivo, we studied knockout (KO) mice of each of the three family members. Single KO mice were viable and had no apparent cardiac phenotype. We therefore hypothesized that the three highly homologous MARP proteins may have redundant functions in the heart and studied double and triple MARP KO mice. Unexpectedly, MARP triple KO mice were viable and had normal cardiac function both at basal levels and in response to mechanical pressure overload induced by transverse aortic constriction as assessed by echocardiography and hemodynamic studies. Thus, CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to mechanical pressure overload. © 2014 Bang et al.


Elia L.,Humanitas Clinical and Research Center | Elia L.,Institute of Genetic and Biomedical Research | Condorelli G.,Humanitas Clinical and Research Center | Condorelli G.,Institute of Genetic and Biomedical Research | Condorelli G.,University of Milan
Journal of Molecular and Cellular Cardiology | Year: 2015

Next-generation sequencing has greatly improved our knowledge of the mammalian transcriptome, identifying thousands of non-coding RNAs (ncRNAs), which are RNAs that rather than translate for proteins, have regulatory functions. Perhaps unsurprisingly, dysregulation of individual ncRNAs has been associated with the development of pathologies, including of the cardiovascular system. The best-characterized group of ncRNAs is represented by the short, highly conserved RNAs named microRNAs (miRNAs). This ncRNA species, which principally exerts an inhibitory action on gene expression, has been implicated in many cardiovascular diseases. Unfortunately, the complexity of action of other types of ncRNA, such as long ncRNAs, has somewhat hampered the study of their role in cardiovascular pathologies. A detailed characterization of the mechanism of action of these different ncRNA species would be conducive to a better understanding of the cellular processes underlying cardiovascular disease and may lead to the development of innovative therapeutic strategies. Here, we give an overview of the current knowledge on the function of ncRNAs and their roles in cardiovascular disease development, concentrating mainly on microRNAs and long ncRNAs. © 2015 Elsevier Ltd.


Marrella V.,Institute of Genetic and Biomedical Research | Marrella V.,Instituto Clinico Humanitas IRCCS | Maina V.,Institute of Genetic and Biomedical Research | Maina V.,Instituto Clinico Humanitas IRCCS | And 2 more authors.
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of Review: During the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we describe the expanding clinical and immunological spectrum associated with Omenn syndrome phenotype. In particular, we review the cellular and molecular mechanisms involved in the pathophysiology of classical Omenn syndrome due to the recombination activating gene (RAG) defects and of a new subgroup of Omenn-like disorders. Recent Findings: Different types of mutations are associated with the Omenn phenotype characterized by skin erythroderma, oligoclonal-activated T cells and elevated IgE in the absence of circulating B cells. Extensive studies conducted over the last few years have allowed the definition of the classical form of Omenn syndrome due to hypomorphic defects in genes involved in V(D)J recombination, mainly RAG genes, and Omenn-like features associated with mutations in genes involved in the maturation steps of lymphoid cells other than V(D)J recombination. Moreover, an increasing number of diseases other than those due to V(D)J recombination defects develop Omenn signs. Summary: Impaired but not abolished V(D)J recombination process leads to the generation of a few T cells which expand in the periphery, infiltrate target organs such as skin and gut, resulting in severe erythroderma and colitis, both typical signs of Omenn syndrome. Extensive molecular studies now demonstrate that genes other than V(D)J molecules have a role in the pathogenesis of this disease, supporting the evidence that Omenn defines an inflammatory condition associated with various genetic defects. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


PubMed | Institute of Genetic and Biomedical Research
Type: Journal Article | Journal: Circulation journal : official journal of the Japanese Circulation Society | Year: 2015

The members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, and N-RAP, contain various numbers of nebulin repeats and bind to actin, but are otherwise heterogeneous with regard to size, expression pattern, and function. This review focuses on the roles of nebulin family members in the heart. Nebulin is the largest member predominantly expressed in skeletal muscle, where it stretches along the thin filament. In heart, nebulin is detectable only at low levels and its absence has no apparent effects. Nebulette is similar in structure to the nebulin C-terminal Z-line region and specifically expressed in heart. Nebulette gene mutations have been identified in dilated cardiomyopathy patients and transgenic mice overexpressing nebulette mutants partially recapitulate the human pathology. In contrast, nebulette knockout mice show no functional phenotype, but exhibit Z-line widening. LASP-2 is an isoform of nebulette expressed in multiple tissues, including the heart. It is present in the Z-line and intercalated disc and able to bind and cross-link filamentous actin. LASP-1 is similar in structure to LASP-2, but expressed only in non-muscle tissue. N-RAP is present in myofibril precursors during myofibrillogenesis and thought to be involved in myofibril assembly, while it is localized at the intercalated disc in adult heart. Additional in vivo models are required to provide further insights into the functions of nebulin family members in the heart.


PubMed | Institute of Genetic and Biomedical Research and University of Milan
Type: Journal Article | Journal: Journal of molecular and cellular cardiology | Year: 2015

Next-generation sequencing has greatly improved our knowledge of the mammalian transcriptome, identifying thousands of non-coding RNAs (ncRNAs), which are RNAs that rather than translate for proteins, have regulatory functions. Perhaps unsurprisingly, dysregulation of individual ncRNAs has been associated with the development of pathologies, including of the cardiovascular system. The best-characterized group of ncRNAs is represented by the short, highly conserved RNAs named microRNAs (miRNAs). This ncRNA species, which principally exerts an inhibitory action on gene expression, has been implicated in many cardiovascular diseases. Unfortunately, the complexity of action of other types of ncRNA, such as long ncRNAs, has somewhat hampered the study of their role in cardiovascular pathologies. A detailed characterization of the mechanism of action of these different ncRNA species would be conducive to a better understanding of the cellular processes underlying cardiovascular disease and may lead to the development of innovative therapeutic strategies. Here, we give an overview of the current knowledge on the function of ncRNAs and their roles in cardiovascular disease development, concentrating mainly on microRNAs and long ncRNAs.


News Article | February 15, 2017
Site: www.eurekalert.org

Sardinia sits at a crossroads in the Mediterranean Sea, the second largest island next to Sicily. Surrounded by sparkling turquoise waters, this Mediterranean jewel lies northwest of the toe of the Italian peninsula boot, about 350 kilometers due west of Rome. For evolutionary biologists, islands are often intriguing, geographically isolated pockets with unique populations that can be ripe for exploration. Now, in a new study appearing in the advanced online edition of Molecular Biology and Evolution an international team led by geneticist Anna Olivieri from the University of Pavia tackles a highly interesting question: what were the origins of the Sardinian population in the context of European prehistory and ancient human migrations? The authors analyzed 3,491 modern, whole mitochondrial DNA genomes from Sardinia (which are only passed down maternally). These were compared with 21 samples of ancient mitogenomes from the island, a large panel of non-Sardinian mitogenomes ---and even Ötzi (the nickname of Europe's oldest natural mummy, the 3,300 BCE-year old "Tyrolean Iceman") ---to better understand their origins. Their findings show Sardinia as an outlier in the general European genetic landscape. Almost 80 percent of modern Sardinian mitogenomes belong to branches that cannot be found anywhere else outside the island. Thus, they were defined as Sardinian-Specific Haplogroups (SSHs) that most likely arose in the island after its initial occupation. Almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. However, some rare SSHs display age estimates older than 7,800 years ago, the postulated archeologically-based starting time of the Neolithic in Sardinia. "Our analyses raise the possibility that several SSHs may have already been present on the island prior to the Neolithic," said prof. Francesco Cucca, from the Institute of Genetic and Biomedical Research (IRGB), at the CNR in Cagliari (Sardinia). The most plausible candidates would include haplogroups K1a2d and U5b1i1, which together comprise almost 3 percent of modern Sardinians, and possibly others. Such a scenario would not only support archaeological evidence of a Mesolithic occupation of Sardinia, but could also suggest a dual ancestral origin of its first inhabitants. K1a2d is of Late Paleolithic Near Eastern ancestry, whereas U5b1i1 harbours deep ancestral roots in Paleolithic Western Europe. This work provides evidence that contemporary Sardinians harbour a unique genetic heritage, as a result of their distinct history and relative isolation from the demographic upheavals of continental Europe. Anna Olivieri stresses: "It now seems plausible that human mobility, inter-communication and gene flow around the Mediterranean from Late Glacial times onwards may well have left signatures that survive to this day. Some of these signals are still retained in modern Sardinians." "Although in the past the stress has often been on the spread of the Neolithic, genetic studies too are beginning to emphasize the complexity and mosaic nature of human ancestry in the Mediterranean, and indeed in Europe more widely," concludes prof. Antonio Torroni, from the University of Pavia. "Future work on ancient DNA should be able to test directly to what extent this more complex model is supported by genetic evidence, and whether our predictions of Mesolithic ancestry in contemporary Sardinians can be sustained."

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