Déterminants génétiques du contrôle de la masse cardiaque et/ou de la taille des cardiomyocytes dans des croisements expérimentaux de rongeurs

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

A strategy for building and using a human reference pangenome

In March 2019, 45 scientists and software engineers from around the world converged at the University of California, Santa Cruz for the first pangenomics codeathon. The purpose of the meeting was to propose technical specifications and standards for a usable human pangenome as well as to build relevant tools for genome graph infrastructures. During the meeting, the group held several intense and productive discussions covering a diverse set of topics, including advantages of graph genomes over a linear reference representation, design of new methods that can leverage graph-based data structures, and novel visualization and annotation approaches for pangenomes. Additionally, the participants self-organized themselves into teams that worked intensely over a three-day period to build a set of pipelines and tools for specific pangenomic applications. A summary of the questions raised and the tools developed are reported in this manuscript

High-Resolution Analysis of Cytosine Methylation in Ancient DNA

Epigenetic changes to gene expression can result in heritable phenotypic characteristics that are not encoded in the DNA itself, but rather by biochemical modifications to the DNA or associated chromatin proteins. Interposed between genes and environment, these epigenetic modifications can be influenced by environmental factors to affect phenotype for multiple generations. This raises the possibility that epigenetic states provide a substrate for natural selection, with the potential to participate in the rapid adaptation of species to changes in environment. Any direct test of this hypothesis would require the ability to measure epigenetic states over evolutionary timescales. Here we describe the first single-base resolution of cytosine methylation patterns in an ancient mammalian genome, by bisulphite allelic sequencing of loci from late Pleistocene Bison priscus remains. Retrotransposons and the differentially methylated regions of imprinted loci displayed methylation patterns identical to those derived from fresh bovine tissue, indicating that methylation patterns are preserved in the ancient DNA. Our findings establish the biochemical stability of methylated cytosines over extensive time frames, and provide the first direct evidence that cytosine methylation patterns are retained in DNA from ancient specimens. The ability to resolve cytosine methylation in ancient DNA provides a powerful means to study the role of epigenetics in evolution

Runes from Lany (Czech Republic) - The oldest inscription among Slavs. A new standard for multidisciplinary analysis of runic bones

When Roman administration and legions gradually withdrew from the outer provinces after the fall of the Western Roman Empire, they created a power void filled by various groups. The dynamic Migration Period that followed is usually considered to have ended when the Germanic Lombards allegedly left Central Europe and were replaced by Slavs. Whether or how Slavic and Germanic tribes interacted, however, is currently disputed. Here we report the first direct archaeological find in support of a contact: a bone fragment dated to similar to 600 AD incised with Germanic runes but found in Lany, Czechia, a contemporaneous settlement associated with Slavs. We documented and authenticated this artifact using a combined approach of use-wear analysis with SEM microscopy, direct radiocarbon dating, and ancient DNA analysis of the animal bone, thereby setting a new standard for the investigation of runic bones. The find is the first older fuark inscription found in any non-Germanic context and suggests that the presumed ancestors of modern Slavic speakers encountered writing much earlier than previously thought.Když se římská správa a legie po pádu Západořímské říše postupně stáhly z vnějších provincií, vytvořilo se mocenské vakuum vyplněné různými skupinami. Dynamické období migrace, které následovalo, se obvykle považuje za ukončené v okamžiku, když germánští Longobardi údajně opustili střední Evropu a byli nahrazeni Slovany. Zda nebo jak na sebe vzájemně působily slovanské a germánské kmeny, se v současné době diskutuje. Zde publikujeme první přímý archeologický nález na podporu kontaktu: fragment kosti datovaný okolo roku 600 n.l. s vyrytými germánskými runami, který však byl nalezen v na sídlišti v Lánech (jižní Morava), na sídlišti spojeném se Slovany. Tento artefakt jsme dokumentovali a ověřili pomocí kombinace různých metod: tafonomie s mikroskopií SEM, datování radiokarbonovou metodou a analýzou aDNA zvířecí kosti, čímž jsme stanovili nový standard pro výzkum runových kostí. Nález je prvním nápisem staršího futharku nalezeným v jiném než germánském kontextu, což naznačuje, že se předkové slovansky mluvících obyvatel střední Evropy setkali s písmem mnohem dříve, než se dříve myslelo.When Roman administration and legions gradually withdrew from the outer provinces after the fall of the Western Roman Empire, they created a power void filled by various groups. The dynamic Migration Period that followed is usually considered to have ended when the Germanic Lombards allegedly left Central Europe and were replaced by Slavs. Whether or how Slavic and Germanic tribes interacted, however, is currently disputed. Here we report the first direct archaeological find in support of a contact: a bone fragment dated to similar to 600 AD incised with Germanic runes but found in Lany, Czechia, a contemporaneous settlement associated with Slavs. We documented and authenticated this artifact using a combined approach of use-wear analysis with SEM microscopy, direct radiocarbon dating, and ancient DNA analysis of the animal bone, thereby setting a new standard for the investigation of runic bones. The find is the first older fuark inscription found in any non-Germanic context and suggests that the presumed ancestors of modern Slavic speakers encountered writing much earlier than previously thought

Ancient mitochondrial genomes from the Argentinian Pampas inform the early peopling of the Southern Cone of South America

The Southern Cone of South America (SCSA) is a key region for investigations about the peopling of the Americas. However, little is known about the eastern sector, the Argentinian Pampas. We analyzed 18 mitochondrial genomes?7 of which are novel?from human skeletal remains from 3 Early to Late Holocene archaeological sites. The Pampas present a distinctive genetic makeup compared to other Middle to Late Holocene pre-Columbian SCSA populations. We also report the earliest individuals carrying SCSA-specific mitochondrial haplogroups D1j and D1g fromEarly andMiddle Holocene, respectively. Using these deep calibration time points in Bayesian phylogenetic reconstructions, we suggest that the first settlers of the Pampas were part of a single and rapid dispersal 15,600 years ago. Finally, we propose that present-day genetic differences between the Pampas and the rest of the SCSA are due to founder effects, genetic drift, and a partial population replacement 9,000 years ago.Fil: Roca Rada, Xavier. Centre For Ancient Dna, University Of Adelaide; AustraliaFil: Politis, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Messineo, Pablo Geronimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Scheifler, Nahuel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Scabuzzo, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Entre Ríos. Universidad Nacional de Entre Ríos. Centro de Investigaciones y Transferencia de Entre Ríos; ArgentinaFil: Gonzalez, Mariela Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Harkins, Kelly M.. University of California; Estados UnidosFil: Reich, David. Harvard Medical School; Estados UnidosFil: Souilmi, Yassine. University of Adelaide; AustraliaFil: Teixeira, Joao C. T.. University of Adelaide; AustraliaFil: Llamas, Bastien. University of Adelaide; AustraliaFil: Fehren Schmitz, Lars. University of California; Estados Unido

Differential Gene Expression Profiling of Orbital Adipose Tissue in Thyroid Orbitopathy

Published under a Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/legalcode)PURPOSE. We aimed to determine differentially expressed genes relevant to orbital inflammation and orbital fat expansion in thyroid orbitopathy (TO) using microarray gene profiling in a case-control study. METHODS. Human orbital adipose samples were obtained from individuals with active TO (n ¼ 12), inactive TO (n ¼ 21), and normal controls (n ¼ 21). Gene expression profiles were examined using microarray analysis and were compared between active and inactive TO, and between active TO and normal controls. Top ranked differentially expressed genes were validated by real-time RT-PCR in an additional eight active TO, 13 inactive TO, and 11 normal controls and correlated with gene set enrichment analysis (GSEA) and molecular pathways analysis. RESULTS. Seven hundred twenty-one probes (683 genes) and 806 probes (735 genes) were significantly differentially expressed in comparing active to inactive TO and in comparing active TO to healthy controls, respectively. All selected genes were confirmed to be differentially expressed by real-time RT-PCR. Multiple top ranked genes in active versus inactive TO comparison are overrepresented by immune and inflammatory response genes. They include defensins (DEFA1, DEFA1B, DEFA3), which were overexpressed by 3.05- to 4.14-fold and TIMD4 by 4.20-fold. Markers for adipogenesis were overexpressed including SCD, FADS1, and SCDP1. Gene set enrichment analysis revealed dysregulation of epigenetic signatures, T-cell activation, Th1 differentiation, defensin pathway, cell adhesion, cytoskeleton organization, apoptosis, cell cycling, and lipid metabolism in active TO. CONCLUSIONS. Active TO is characterized by upregulation of genes involved in cell-mediated immune, innate immune, and inflammatory response and enhanced orbital adipogenesis. TIMD4, DEFA1, DEFA1B, and DEFA3 genes may be involved in the innate immune-mediated orbital inflammation in TO. Epigenetic mechanisms may play a role in the pathogenesis of TO

Ancient mitochondrial genomes from the Argentinian Pampas inform the early peopling of the Southern Cone of South America

The Southern Cone of South America (SCSA) is a key region for investigations about the peopling of the Americas. However, little is known about the eastern sector, the Argentinian Pampas. We analyzed 18 mitochondrial genomes-7 of which are novel-from human skeletal remains from 3 Early to Late Holocene archaeological sites. The Pampas present a distinctive genetic makeup compared to other Middle to Late Holocene pre-Columbian SCSA populations. We also report the earliest individuals carrying SCSA-specific mitochondrial haplogroups D1j and D1g from Early and Middle Holocene, respectively. Using these deep calibration time points in Bayesian phylogenetic reconstructions, we suggest that the first settlers of the Pampas were part of a single and rapid dispersal ∼15,600 years ago. Finally, we propose that present-day genetic differences between the Pampas and the rest of the SCSA are due to founder effects, genetic drift, and a partial population replacement ∼9,000 years ago.Facultad de Ciencias Naturales y Muse

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics

We thank the Municipality of Bragança, the University of Coimbra, the University of Adelaide, the Max Planck Society, and the Calouste Gulbenkian Foundation for the support provided. ST is supported by the Fundação para a Ciência e a Tecnologia (SFRH/BD/116363/2016). BL (FT170100448) and JCT (DE210101235) are supported by the Australian Research Council. ABR is supported by the European Research Council (771234-PALEoRIDER)

Cases of trisomy 21 and trisomy 18 among historic and prehistoric individuals discovered from ancient DNA

Aneuploidies, and in particular, trisomies represent the most common genetic aberrations observed in human genetics today. To explore the presence of trisomies in historic and prehistoric populations we screen nearly 10,000 ancient human individuals for the presence of three copies of any of the target autosomes. We find clear genetic evidence for six cases of trisomy 21 (Down syndrome) and one case of trisomy 18 (Edwards syndrome), and all cases are present in infant or perinatal burials. We perform comparative osteological examinations of the skeletal remains and find overlapping skeletal markers, many of which are consistent with these syndromes. Interestingly, three cases of trisomy 21, and the case of trisomy 18 were detected in two contemporaneous sites in early Iron Age Spain (800-400 BCE), potentially suggesting a higher frequency of burials of trisomy carriers in those societies. Notably, the care with which the burials were conducted, and the items found with these individuals indicate that ancient societies likely acknowledged these individuals with trisomy 18 and 21 as members of their communities, from the perspective of burial practice