Integrative analysis of the functional consequences of inversions in the human genome
- Autores: Ion Lerga Jaso
- Directores de la Tesis: Mario Cáceres Aguilar (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Xavier Estivill Palleja (presid.), David Torrents Arenales (secret.), Juan Manuel Vaquerizas Erdocia (voc.)
- Programa de doctorado: Programa de Doctorado en Genética por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Structural variation contributes substantially to the genetic diversity, but its association with complex traits and diseases is not well understood and deserves detailed characterisation. This is particularly true for chromosomal inversions, whose functional consequences have remained elusive in humans, with very few notable exceptions. Despite the rising interest in identifying all types of genomic variants, inversions have been often set aside due to the presence of repetitive regions in their breakpoints along with their balanced nature. The InvFEST Project has tried to overcome this technical challenge by developing unique methods for inversion genotyping. Thanks to this effort, a total of 111 polymorphic human inversions have been accurately genotyped in a large number of individuals from diverse populations, becoming the most complete and reliable resource of this type of variation available to date. In the current era of precision medicine, quantitative trait loci (QTL) analysis has emerged as a key approach to determine how genetic polymorphisms influence gene expression and, in turn, phenotypic traits. Thus, this thesis makes the most of the great amount of data generated to perform for the first time a systematic quantification of the functional impact of human polymorphic inversions. The results show that inversions can affect gene expression by maintaining differentiated haplotypes, disrupting or reorganizing gene structures, creating novel fusion transcripts or acting through changes in epigenetic patterns. Strikingly, half of the inversions analysed act as lead QTLs or are in high linkage disequilibrium (LD) with top QTLs for gene expression and epigenetic changes across different tissues and cell lines, which suggests that inversions are enriched for functional effects. In particular, this influence on molecular phenotypes is even stronger for long inversions (>100kb), which are involved in 80% of the QTL associations. Although structural variants are known to have a higher chance to be associated with expression levels and complex traits, the detected inversion effects may reflect a trade-off between beneficial expression changes and potential negative costs on fertility due to production of unbalanced gametes by recombination. Furthermore, inversions present an enrichment of genome-wide association studies (GWAS) signals in their surrounding area, and 14 of them are in high LD with trait-associated variants, supporting their potential implication in human phenotypes. Finally, the phenotypic consequences of two interesting inversions have been investigated in detail. HsInv0102 inverts an alternative non-coding exon from the RHOH gene. Interestingly, this inversion is also associated with RhoH protein levels and the inverted allele could act as a moderate protective locus on blood cancer susceptibility. On the other hand, HsInv0124 regulates the expression of several genes in the IFITM region, including IFITM2 and IFITM3, through changes in histone modification patterns. Moreover, under infection conditions, this inversion has a pervasive effect on the expression of genes related with immune response, indicating that it may play an important role in defense against viral infections. All together, these findings illustrate the potential functional impact of inversions on the human genome and help to uncover previously missing variants related to phenotype variability.
