Semidefinite optimization in discrepancy theory

Recently, there have been several new developments in discrepancy theory based on connections to semidefinite programming. This connection has been useful in several ways. It gives efficient polynomial time algorithms for several problems for which only non-constructive results were previously known. It also leads to several new structural results in discrepancy itself, such as tightness of the so-called determinant lower bound, improved bounds on the discrepancy of the union of set systems and so on. We will give a brief survey of these results, focussing on the main ideas and the techniques involved

Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2 : In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants

The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvement

Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants

Endofenotip; Prediccions de patogenicitat; Predictor específic de proteïnaEndofenotipo; Predicciones de patogenicidad; Predictor específico de proteínaEndophenotype; Pathogenicity predictions; Protein-specific predictorThe present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.This research was funded by the EU European Regional Development Fund (ERDF) through the Program Interreg V-A Spain-France-Andorra (POCTEFA), grant number EFA086/15-PIREPRED, by the Spanish Ministerio de Ciencia e Innovación, grant number PID2019-111217RB-I00, and by the Spanish Ministerio de Economía y Competitividad, grant number SAF2016-80255-R

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

BACKGROUND: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. RESULTS: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes) are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. CONCLUSION: An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin) also have a substantial impact on the formation of co-expression islands in colorectal carcinoma

Genetic studies of familial myeloproliferative disorders

Hereditary thrombocythemia (HT) is an autosomal dominant disorder with clinical features resembling sporadic essential thrombocythemia. HT families share similar clinical symptoms caused by heterogeneous genetic alterations. Inherited germ-line mutations in the thrombopoietin (TPO) gene and its receptor MPL have been found causing thrombocytosis in a number of HT families. Five reported mutations in the thrombopoietin gene are all located in the 5 prime untranslated region (5’UTR) and cause overproduction of Tpo protein by the same mechanism: increased translation efficiency for the mutant mRNAs. One mutation identified in the MPL gene is located at the transmembrane domain and results in a hyperactive receptor, thereby leading to thrombocytosis. All these germ-line mutations have not been found in sporadic patients and are only responsible for the etiology of some HT families, indicating that the occurrence of these germ-line mutations is a rare event. The disease-causing genes for many HT families remain unknown. Identifying genetic lesions in these families will increase our knowledge of the physiology of thrombopoiesis and some of these unknown genetic components may contribute to the pathogenesis in sporadic MPD patients. In the first part of the project for genetic studies of HT families, the TPO and MPL genes were analyzed by genomic DNA exon sequencing and linkage analysis. A splice donor mutation in the TPO gene was identified in a Polish family. This mutation was previously identified in a Dutch family and the reoccurrence of this rare mutation has not been reported to date. In order to determine whether the 6 mutation mutation in these two families arose de novo or from a founder effect, haplotype analysis was performed to examine polymorphic DNA sequences in the vicinity of the mutation using microsatellites and single nucleotide polymorphism (SNP) in these two families. Six microsatellite markers on the affected allele showed different sizes in PCR products and 3 SNPs close to the mutation differed in their sequences between the two families. We therefore concluded that the mutation in these two families occurred de novo. The previously reported MPL mutation at the transmembrane domain of MPL protein was identified in one of the HT families studied here. Recently, 5 additional HT families were found carrying this mutation. We conducted haplotype analysis using microsatellite markers in the MPL gene locus for the 6 HT families. Four microsatellite markers surrounding the MPL mutation showed identical sizes in the PCR products on the affected allele, suggesting that the MPL mutation occurred from a single founder event. This may explain the high frequency of this mutation in HT families. In a large US family with HT, where the TPO and MPL genes were excluded as disease causes, genome-wide linkage analysis was performed aiming to identify novel genetic component for the thrombocytosis phenotype. Two genetic regions with significant logarithm of odds (LOD) score values have been located using microsatellites and SNP chip arrays. Candidate gene sequencing revealed one novel polymorphism in the gelsolin gene, which encodes an actin-binding protein abundant in platelets. Gelsolin has multiple biological functions in addition to cytoskeletal actin modulation. Functional studies in cell proliferation assays and mouse bone marrow transplantation did not validate this polymorphism as an active disease causing mutation. Further studies on this polymorphism in platelet biogenesis are planned for the future. In addition, sequencing of all the candidate genes in the segregating regions is in progress. In a second project, genome-wide linkage analyses were performed using microsatellites and SNP chip arrays in a family with secondary polycythemia inherited in an autosomal recessive mode. Both parametric and nonparametric linkage analysis were conducted for this family. Five genetic regions were found linked to the disease phenotype. A few candidate genes were sequenced and studied, however no genetic variation was found so far. Additionally, no mutations were found in several genes involved in erythropoiesis and oxygen sensing pathway. Burst forming units-Erythroid cultures in hypoxia condition showed high expression of the EPO gene in 3 out of 4 affected family members, suggesting a potential unknown defect in the oxygen-sensing pathway