Structural variations, environment and disease

J. Aigner, L. Bassaganyas, M. Bustamante, G. Escaramís, J. González, C. Hor-Henrichsen, M. Morell, R. Rabionet, C. Tornador, N. Vilahur

We characterize SVs as genomic regions potentially involved in phenotype variation, including disease. Some of the targeted regions contain CNVs, inversions, segmental duplications or transposable se- quences. The group is part of the chronic lymphocytic leukaemia (CLL) International Cancer Genomics Consortium (ICGC), with the aim to fully characterize the genome of CLL cells.

We have already characterized the genome and transcriptome of the first ten cases of CLL and have developed new tools for the bioinformatic characterization of SV in this common type of leukaemia. We have performed a deep characterization of one case of chromotripsis by carrying out a longitudinal analysis of SVs and point mutations over a period of eleven years of disease evolution, including the analysis of pre-treatment samples, post-treatment and relapsed samples. To identify SVs from whole genome sequencing data, we have developed the PeSV-Fisher pipeline, which includes paired-end mapping (PEM) and depth of coverage (DOC) strategies to identify SVs.

In collaboration with the group of Stephan Ossowski, we are also developing a method for CNVs detection from multi-sample exome sequencing data to detect hete- rozygous deletions and duplications as well as higher order genome amplifications, even if more than two alleles exist in the population. We are also working in the identification of germ line mutations (SNVs and SVs) in the CLL project with the aim identify genetic factors that drive the development of several cancer types at their early stages of development. The project will provide gold standard information on the spectrum of SV of the human genome of importance for many human diseases and phenotypic traits.

The group had made specific progress in the dissection of genetics of psoriasis-related phenotypes. We have identified a common CNV that involves the deletion of two genes (LCE3B and LCE3C) in a significant fraction of patients with psoriasis. We have found that patients with rheumatoid arthritis and psoriatic arthritis also have a higher frequency of deletions of LCE3B and LCE3C. Our group has evaluated the effect of CNVs in two broader phenotypes, fibromyalgia and reproductive outcomes, identifying the association of a specific CNV with adverse reproductive outcomes and with fibromyalgia, in which we have identified an association with a CNV in a subset of samples showing highest levels of pain and lower levels of comorbidities.

We have identified a common 45-kb deletion that affects two genes of the same family, BTNL8 and BTNL3, and leads to the formation of a novel fusion transcript and the subsequent down-regulation of the expression level of the neighbouring gene BTNL9. We have found that over-expression of BTNL9 inhibits glucocorticoid-induced apoptosis, suggesting that it has a pro-survival function.

The group collaborates with investigators of the CREAL (Centre for Research in Environmental Epi- demiology) to study gene-environment interaction in several phenotypes. The INMA (Infancia y Medio Ambiente) is a network of birth cohorts in Spain with more than 2000 children-mother pairs having DNA available. Approximately 1000 child samples have been genome-wide genotyped. Within the Early Grow Genetics Consortium (EGG) and The Early Genetics and Lifecourse Epidemiology (EAGLE) consortia, INMA has participated in more than 10 GWAS metaanalysis. The group is performing whole-exome sequencing of individuals from families that segregate Mendelian diseases. Several disorders (cardiac electric conduction, idiopathic juvenile arthritis, cystic fibrosis, mitral valve prolapse, Parkinson diasese, dominant ataxia and essential tremor) are currently under investigation. The group is also implementing whole-exome sequencing as a diagnostic tool in the clinical setting.