Régulation de la fonction du récepteur dopaminergique D2 dans les neurones dopaminergiques

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

L’apport des données génétiques à la mesure généalogique des origines amérindiennes des Canadiens français

Dans le cadre d’un programme de recherche sur la diversité génétique des populations régionales du Québec, nous avons mesuré la contribution des ancêtres amérindiens au pool génique de 794 participants résidant dans les régions de Montréal, du Saguenay—Lac-Saint-Jean (SLSJ), de la Gaspésie et de la Côte-Nord. Les ancêtres amérindiens ont été identifiés à partir de reconstructions généalogiques (fichier BALSAC) et de données génétiques (ADN mitochondrial) à l’aide d’une approche qui repose sur l’exploitation conjointe de ces deux types de données. Les résultats indiquent que plus de la moitié des participants ont au moins un ancêtre amérindien dans leur généalogie. Ceci veut dire que la majorité des participants sont porteurs de gènes reçus de fondateurs amérindiens. Cependant la contribution génétique totale de ces ancêtres aux quatre groupes régionaux demeure faible. En effet, elle est de moins de 1 % au SLSJ et à Montréal alors qu’elle dépasse à peine 1 % sur la Côte-Nord et en Gaspésie

When genetics and genealogies tell different stories-maternal lineages in Gaspesia

Data from uniparentally inherited genetic systems were used to trace evolution of human populations. Reconstruction of the past primarily relies on variation in present-day populations, limiting historical inference to lineages that are found among living subjects. Our analysis of four population groups in the Gaspé Peninsula, demonstrates how this may occasionally lead to erroneous interpretations. Mitochondrial DNA analysis of Gaspesians revealed an important admixture with Native Americans. The most likely scenario links this admixture to French-Canadians from the St. Lawrence Valley who moved to Gaspesia in the 19th century. However, in contrast to genetic data, analysis of genealogical record shows that Native American maternal lineages were brought to Gaspesia in the 18th century by Acadians who settled on the south-western coast of the peninsula. Intriguingly, within three generations, virtually all Métis Acadian families separated from their nonadmixed relatives and moved eastward mixing in with other Gaspesian groups, in which Native American maternal lines are present in relatively high frequencies. Over time, the carriers of these lines eventually lost memory of their mixed Amerindian-Acadian origin. Our results show that a reliable reconstruction of population history requires cross-verification of different data sources for consistency, thus favouring multidisciplinary approaches

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain

<p>Abstract</p> <p>Background</p> <p>The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, <it>in vitro </it>and <it>in vivo </it>pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.</p> <p>Results</p> <p>We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889.</p> <p>Conclusions</p> <p>Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.</p

Deep Human Genealogies Reveal a Selective Advantage to Be on an Expanding Wave Front

Since their origin, human populations have colonized the whole planet, but the demographic processes governing range expansions are mostly unknown. We analyzed the genealogy of more than one million individuals resulting from a range expansion in Quebec between 1686 and 1960 and reconstructed the spatial dynamics of the expansion. We find that a majority of the present Saguenay Lac-Saint-Jean population can be traced back to ancestors having lived directly on or close to the wave front. Ancestors located on the front contributed significantly more to the current gene pool than those from the range core, likely due to a 20% larger effective fertility of women on the wave front. This fitness component is heritable on the wave front and not in the core, implying that this life-history trait evolves during range expansions

Native American Admixture in the Quebec Founder Population

<div><p>For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders’ origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play.</p></div

Native American ancestry proportions in the Quebec regions.

<p>Here Quebec regional/ethnocultural groups are presented with (number of individuals with genotype data; number of individuals with genealogical data). For each population, expected Native American genetic contribution was estimated using genealogical data. The Native American ancestry proportions in the Quebec subpopulations was estimated with 1) the ADMIXTURE software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Alexander1" target="_blank">[43]</a> 2) the HAPMIX software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Price1" target="_blank">[39]</a>, and 3) IBD sharing analysis using the fastIBD software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Browning1" target="_blank">[41]</a>. For each measure, we tested for differences among subpopulations using a Kruskal-Wallis test (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507.s008" target="_blank">Table S3</a>).</p

Scatter plots of correlations.

<p>Scatter plots showing the correlations between different Native American genetic ancestry estimates in the Quebec subpopulations (upper) and between genetic ancestry estimates and genealogical genetic contribution of Native American founders to the Quebec individuals (lower). The Pearson correlation coefficient (r) is shown on each plot.</p

Map of Quebec subpopulations.

<p>In colors are the 10 regions/subpopulations included in the analyses.</p