{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"contact_person":["Joaquin Dopazo"],"full_dataset_link":["https://ega-archive.org/dacs/EGAC00001000222"],"host":["EGA"],"description":["EGA DAC EGAC00001000222"],"repository":["EGA"],"email":["joaquin.dopazo@juntadeandalucia.es"],"pubmed_abstract":["Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms.","Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins."],"pubmed_title":["267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.","The role of the interactome in the maintenance of deleterious variability in human populations."],"pubmed_authors":["Garcia-Alonso Luz L, Jiménez-Almazán Jorge J, Carbonell-Caballero Jose J, Vela-Boza Alicia A, Santoyo-López Javier J, Antiñolo Guillermo G, Dopazo Joaquin J","Dopazo Joaquín J, Amadoz Alicia A, Bleda Marta M, Garcia-Alonso Luz L, Alemán Alejandro A, García-García Francisco F, Rodriguez Juan A JA, Daub Josephine T JT, Muntané Gerard G, Rueda Antonio A, Vela-Boza Alicia A, López-Domingo Francisco J FJ, Florido Javier P JP, Arce Pablo P, Ruiz-Ferrer Macarena M, Méndez-Vidal Cristina C, Arnold Todd E TE, Spleiss Olivia O, Alvarez-Tejado Miguel M, Navarro Arcadi A, Bhattacharya Shomi S SS, Borrego Salud S, Santoyo-López Javier J, Antiñolo Guillermo G"],"additional_accession":[]},"is_claimable":false,"name":"MGP Spanish controls","description":"Data Access Committee EGAC00001000222","dates":{"output":"2025-1-9"},"accession":"EGAC00001000222","cross_references":{"TAXONOMY":["9606"],"pubmed":["26764160","25261458"],"EGA":["EGAS00001000938","EGAD00001003101","EGAD00001001012"]}}