The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

DNA hypermethylation/boundary control loss identified in retinoblastomas associated with genetic and epigenetic inactivation of the RB1 gene promoter

DNA hypermethylation events occur frequently in human cancers, but less is known of the mechanisms leading to their initiation. Retinoblastoma, an intraocular cancer affecting young children, involves bi-allelic inactivation of the RB1 gene (RB−/-). RB1 encodes a tumour suppressing, cell cycle regulating transcription factor (pRB) that binds and regulates the RB1 core and other E2F responsive promoters with epigenetic functions that include recruitment of histone deacetylases (HDACs). Evidence suggests that bi-allelic epigenetic inactivation/hypermethylation of the RB1 core promoter (PrE-/E-), is specific to sporadic retinoblastomas (frequency~10%), whereas heritable RB1 promoter variants (Pr−/+, frequency~1-2%) are not associated with known epigenetic phenomena. We report heritable Pr−/- retinoblastomas with the expected loss of pRB expression, in which hypermethylation consistent with distal boundary displacement (BD) relative to normal peripheral blood DNAs was detected in 4/4 cases. In contrast, proximal BD was identified in 16/16 RB−/- retinoblastomas while multiple boundaries distal of the core promoter was further identified in PrE-/E-and PrE-/E+ retinoblastomas. However, weak or no DNA hypermethylation/BD in peripheral blood DNA was detected in 8/9 Pr−/+ patients, with the exception, a carrier of a microdeletion encompassing several RB1 promoter elements. These findings suggest that loss of boundary control may be a critical step leading to epigenetic inactivation of the RB1 gene and that novel DNA methylation boundaries/profiles identified in the RB1 promoter of Pr−/- retinoblastomas, may be the result of epigenetic phenomena associated with epimutation in conjunction with loss of pRB expression/binding and/or RB1 promoter interactions with boundary control elements

DNA hypermethylation/boundary control loss identified in retinoblastomas associated with genetic and epigenetic inactivation of the <i>RB1</i> gene promoter

DNA hypermethylation events occur frequently in human cancers, but less is known of the mechanisms leading to their initiation. Retinoblastoma, an intraocular cancer affecting young children, involves bi-allelic inactivation of the RB1 gene (RB−/-). RB1 encodes a tumour suppressing, cell cycle regulating transcription factor (pRB) that binds and regulates the RB1 core and other E2F responsive promoters with epigenetic functions that include recruitment of histone deacetylases (HDACs). Evidence suggests that bi-allelic epigenetic inactivation/hypermethylation of the RB1 core promoter (PrE-/E-), is specific to sporadic retinoblastomas (frequency~10%), whereas heritable RB1 promoter variants (Pr−/+, frequency~1-2%) are not associated with known epigenetic phenomena. We report heritable Pr−/- retinoblastomas with the expected loss of pRB expression, in which hypermethylation consistent with distal boundary displacement (BD) relative to normal peripheral blood DNAs was detected in 4/4 cases. In contrast, proximal BD was identified in 16/16 RB−/- retinoblastomas while multiple boundaries distal of the core promoter was further identified in PrE-/E-and PrE-/E+ retinoblastomas. However, weak or no DNA hypermethylation/BD in peripheral blood DNA was detected in 8/9 Pr−/+ patients, with the exception, a carrier of a microdeletion encompassing several RB1 promoter elements. These findings suggest that loss of boundary control may be a critical step leading to epigenetic inactivation of the RB1 gene and that novel DNA methylation boundaries/profiles identified in the RB1 promoter of Pr−/- retinoblastomas, may be the result of epigenetic phenomena associated with epimutation in conjunction with loss of pRB expression/binding and/or RB1 promoter interactions with boundary control elements.</p

Relaxed selection during a recent human expansion

AbstractHumans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that i) both new and low frequency variants are significantly more deleterious in front than in core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past 6-9 generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection on the wave front. Modeling the evolution of rare variants allowed us to estimate their associated selection coefficients as well as front and core effective sizes. Even though range expansions had a limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions. Since we show that modern human populations are experiencing differential strength of purifying selection, similar processes might have happened throughout human history, contributing to a higher mutation load in populations that have undergone spatial expansions.</jats:p

Molecular mechanism of a new cardiac syndrome associated with a regulatory element deletion of chromosome 4q25

Abstract Introduction We identified a large family of 53 members of whom 22 present a new cardiac syndrome characterized by electrical disorders and developmental defects following an autosomal dominant model. Among the affected family members 6 are implanted with a pacemaker, 2 experienced syncope and one a sudden death at 43yo. Linkage analysis points, with high confidence, to the chromosome 4q25 region. This region is associated with the Ankyrin syndrome (mutation in ANK2) sharing partly the electrical defects observed in the affected family members. No mutation was found in the coding region of the 4q25 region as well as in the coding and non-coding part of the ANK2. Objective Our aims are first to identity the responsible mutation present in this family and understand the molecular mechanisms leading to this new syndrome. Method Whole genome sequencing (WGS) has been employed to identify genetic variants responsible for this syndrome. ChIP-seq and ATAC-seq were used for functional annotation and genome editing (CRISPR-Cas9) to generate iPS cellular models. Results By WGS we uncovered a deleted region of 15kb in a gene desert area on 4q25, segregating in all affected relatives. Five other families (3 French and 2 Japanese) presenting the same phenotype show overlapping deletions. We generated human cardiac epigenetic data and identified among the 15kb deleted region a unique active enhancer region within the presence of a transcript factor CTCF binding site. Isogenic cell lines where the 15kb and the CTCF binding have been deleted are under investigation. Conclusion We identified a new cardiac syndrome and for the first time a mutation located within a gene desert area leading to severe and complex cardiac disorders. We demonstrated the presence of a likely gene regulatory element. Experiments are ongoing to characterize the molecular mechanisms and consequence of the deletion on gene expression. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Pays de la loire - Etoiles montantes </jats:sec

Prehistoric genomes reveal the genetic foundation and cost of horse domestication.

The domestication of the horse approximately 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4- and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place