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Nikolaev S.I.,University of Geneva | Rimoldi D.,University of Lausanne | Iseli C.,University of Lausanne | Iseli C.,Swiss Institute of Bioinformatics | And 22 more authors.
Nature Genetics | Year: 2012

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1. © 2012 Nature America, Inc. All rights reserved. Source

Dermitzakis E.T.,University of Geneva | Dermitzakis E.T.,Institute of Genetics and Genomics in Geneva iGE3
Nature Reviews Genetics | Year: 2012

Recent developments in the collection and analysis of cellular multilayered data in large cohorts with extensive organismal phenotyping promise to reveal links between genetic variation and biological processes. The use of these cellular resources as models for human biology-known as 'cellular phenotyping'-is likely to transform our understanding of the genetic and long-term environmental influences on complex traits. I discuss the advantages and caveats of a deeper analysis of cellular phenotypes in large cohorts and assess the methodological advances, resource needs and prospects of this new approach. © 2012 Macmillan Publishers Limited. All rights reserved. Source

Kubik S.,Institute of Genetics and Genomics in Geneva iGE3 | Bruzzone M.J.,Institute of Genetics and Genomics in Geneva iGE3 | Jacquet P.,Ecole Polytechnique Federale de Lausanne | Falcone J.-L.,University of Geneva | And 2 more authors.
Molecular Cell | Year: 2015

Previous studies indicate that eukaryotic promoters display a stereotypical chromatin landscape characterized by a well-positioned +1 nucleosome near the transcription start site and an upstream -1 nucleosome that together demarcate a nucleosome-free (or -depleted) region. Here we present evidence that there are two distinct types of promoters distinguished by the resistance of the -1 nucleosome to micrococcal nuclease digestion. These different architectures are characterized by two sequence motifs that are broadly deployed at one set of promoters where a nuclease-sensitive ("fragile") nucleosome forms, but concentrated in a narrower, nucleosome-free region at all other promoters. The RSC nucleosome remodeler acts through the motifs to establish stable +1 and -1 nucleosome positions, while binding of a small set of general regulatory (pioneer) factors at fragile nucleosome promoters plays a key role in their destabilization. We propose that the fragile nucleosome promoter architecture is adapted for regulation of highly expressed, growth-related genes. © 2015 Elsevier Inc. Source

dos Santos Francisco R.,University of Sao Paulo | dos Santos Francisco R.,University of Geneva | Buhler S.,University of Geneva | Nunes J.M.,University of Geneva | And 7 more authors.
Immunogenetics | Year: 2015

Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions—the B and F pockets—of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (GST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and GST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens. © 2015, The Author(s). Source

Rivera-Rivera C.J.,University of Geneva | Rivera-Rivera C.J.,Institute of Genetics and Genomics in Geneva iGE3 | Montoya-Burgos J.I.,University of Geneva | Montoya-Burgos J.I.,Institute of Genetics and Genomics in Geneva iGE3
Molecular Biology and Evolution | Year: 2016

Phylogenetic inference artifacts can occur when sequence evolution deviates from assumptions made by the models used to analyze them. The combination of strong model assumption violations and highly heterogeneous lineage evolutionary rates can become problematic in phylogenetic inference, and lead to the well-described long-branch attraction (LBA) artifact. Here, we define an objective criterion for assessing lineage evolutionary rate heterogeneity among predefined lineages: the result of a likelihood ratio test between a model in which the lineages evolve at the same rate (homogeneous model) and a model in which different lineage rates are allowed (heterogeneous model). We implement this criterion in the algorithm Locus Specific Sequence Subsampling (LS3), aimed at reducing the effects of LBA in multi-gene datasets. For each gene, LS3 sequentially removes the fastest-evolving taxon of the ingroup and tests for lineage rate homogeneity until all lineages have uniform evolutionary rates. The sequences excluded from the homogeneously evolving taxon subset are flagged as potentially problematic. The software implementation provides the user with the possibility to remove the flagged sequences for generating a new concatenated alignment. We tested LS3 with simulations and two real datasets containing LBA artifacts: a nucleotide dataset regarding the position of Glires within mammals and an amino-acid dataset concerning the position of nematodes within bilaterians. The initially incorrect phylogenies were corrected in all cases upon removing data flagged by LS3. © 2016 The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. Source

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