Biology subjects

Santos, C.

Publications and source records attributed to Santos, C..

4 recordsLinked to original sources

bioRxiv2018

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DNA (mtDNA) defects, mainly driven by the central role of mitochondria in cellular metabolism. Considering the importance of the control region (CR) on the regulation of the mtDNA gene expression, the aim of the present study was to investigate the role of the mtDNA CR mutations in two CVDs: stroke and myocardial infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two population samples of demographically-matched case and controls, were analysed using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found between cases and controls, reporting the m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, m.73A>G and m.16356T>C could act as possible beneficial genetic factors for MI (conditional logistic regression: p=0.001, p=0.009 and p=0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in MI controls (logistic regression: p=0.046; OR= 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and MI, and show the importance of including this regulatory region in genetic association studies.\n\nAuthor SummaryGiven the association between cardiovascular disease and specific mitochondrial DNA (mtDNA) defects and considering the importance of the control region of this genome on the regulation of mtDNA gene expression, here, we investigate the role of mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke and myocardial infarction. In this study we found five mitochondrial genetic variants related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), which are located in the control region of mtDNA. Despite the abundance of work on the role of mitochondrial DNA in relation to cardiovascular disease, little literature has been published on the variation that this genome expresses in relation to this disease. For this reason, our study provides significant insight of the genetic variability that determines normality or pathology in relation to the genetic risk of cardiovascular disease. The results obtained demonstrate the possible role of mtDNA mutations in the control region on the pathogenesis of stroke and myocardial infarction, and show the importance of including this regulatory region in genetic association studies.

genetics↗

bioRxiv2018

matchSCore: Matching Single-Cell Phenotypes Across Tools and Experiments

Single-cell transcriptomics allows the identification of cellular types, subtypes and states through cell clustering. In this process, similar cells are grouped before determining co-expressed marker genes for phenotype inference. The performance of computational tools is directly associated to their marker identification accuracy, but the lack of an optimal solution challenges a systematic method comparison. Moreover, phenotypes from different studies are challenging to integrate, due to varying resolution, methodology and experimental design. In this work we introduce matchSCore (https://github.com/elimereu/matchSCore), an approach to match cell populations fast across tools, experiments and technologies. We compared 14 computational methods and evaluated their accuracy in clustering and gene marker identification in simulated data sets. We further used matchSCore to project cell type identities across mouse and human cell atlas projects. Despite originating from different technologies, cell populations could be matched across data sets, allowing the assignment of clusters to reference maps and their annotation.

bioinformatics↗

bioRxiv2018

Reappraising the human mitochondrial DNA recombination dogma

With the \"mitochondrial Eve\" theory proposed by Rebecca Cann in the eighties, human mitochondrial DNA (mtDNA) has been used as a tool in studying human variation and evolution. Although the existence of recombination in human mtDNA has been previously advocated, studies dealing with human variation and evolution have assumed that human mtDNA does not recombine and should be considered as pathological or very infrequent. Using both direct and indirect approaches, we provide consistent evidence of mtDNA recombination in humans. We applied the single molecule PCR procedure to directly test for recombination in multiheteroplasmic individuals without any overt pathology. Moreover, we searched for past recombination events in the whole mitochondrial genomes of more than 15,000 individuals. Results from our study update and expand both the seminal indirect findings and the scarce direct evidence observed to date, paving the way for the definitive rejection of the non-recombination dogma for human mtDNA. Acknowledgment of recombination as a frequent event in mtDNA will require the description of the population recombination rate(s) and to apply it to past and future studies involving mtDNA. MtDNA recombination affects our knowledge of human evolutionary history, regarding haplogroup divergence times, as well as the time to the mitochondrial most recent common ancestor. Finally, mtDNA recombination will have a substantial impact on our understanding of the etiology and transmission of mitochondrial diseases.

molecular biology↗

bioRxiv2017

Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development

BackgroundMC1R, a G-protein coupled receptor with high affinity for alpha-melanocyte stimulating hormone (MSH), modulates pigment production in melanocytes from many species and is associated with human melanoma risk. MC1R mutations affecting human skin and hair color also have pleiotropic effects on the immune response and analgesia. Variants affecting human pigmentation in utero alter the congenital phenotype of both oculocutaneous albinism and congenital melanocytic naevi, and have a possible effect on birthweight.\n\nMethods and ResultsBy in situ hybridization, RT-PCR and immunohistochemistry, we show that MC1R is widely expressed during human, chick and mouse embryonic and fetal stages in many somatic tissues, particularly in the musculoskeletal and nervous systems, and conserved across evolution in these three amniotes. Its dynamic pattern differs from that of TUBB3, a gene overlapping the same locus in humans and encoding class III {beta}-tubulin. The MSH peptide and the transcript for its precursor, pro-opiomelanocortin (POMC), are similarly present in numerous extra-cutaneous tissues. MC1R genotyping of variants p.(V60M) and p.(R151C) was undertaken for 867 healthy children from the Avon Longitudinal Study of Parent and Children (ALSPAC) cohort, and birthweight modelled using multiple logistic regression analysis. A significant positive association initially found between R151C and birth weight, independent of known birth weight modifiers, was not reproduced when combined with data from an independent genome-wide association study of 6,459 additional members of the same cohort.\n\nConclusionsThese data clearly show a new and hitherto unsuspected role for MC1R in non-cutaneous solid tissues before birth.

developmental biology↗