Ancestral genomic submicroscopic inversions of human genome and their relation with multifactorial human diseases

• Autores: Armand Gutierrez Arumi
• Directores de la Tesis: L. A. Pérez Jurado (dir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2016
• Idioma: español
• Tribunal Calificador de la Tesis: Tomàs Marques-Bonet (presid.), Abel González Pérez (secret.), Cinta Pegueroles Queralt (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Matemáticas
    • Análisis numérico
      • Construcción de algoritmos
  • Ciencias de la vida
    • Biología humana
      • Genética humana
    • Biología vegetal (botánica)
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • There has been significant advance in the definition, mapping and characterization of different sources of variation in the human genome, including single nucleotide and small changes, medium and large insertions, deletions, and other structural and complex genomic variants. Many of these variants have been involved in rare and common diseases. Nevertheless, there is still an important genetic component of multifactorial diseases that remains unsolved. Inversions are chromosome mutations with balanced genetic material (neutral copy number) in which a given fragment changes its orientation respect to a reference and present. Recombination is inhibited between inverted intervals leading to the selection of genetic variation within inversions. Based on this feature, our group has developed tools to infer or predict ancestral submicroscopic inversions (0.5 Mb – 5Mb) using computational methods and single nucleotide variants (SNPs), and documented that inversions correlate with gene expression. Therefore, submicroscopic inversions not properly studied so far, if common in the population can have a contributive effect to multifactorial diseases.

    Our goal was to improve the genotyping and determine the contribution of those inversions to the phenotype of model complex diseases (neuropsychiatric and autoimmune): Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), Rheumatoid Arthritis (RA) and Ulcerative Colitis (UC). Our results using available datasets of genome-wide SNPs (~27,000 samples) have determined that:

    The inversions at 17q21.31 and 8p23.1 are associated with ASD and SSD risk. The inverted allele at 17q21.31 is associated with increased risk for high-functioning ASD while it protects against SSD (OR=0.86 p-value 0.007). The inverted allele at 8p23.1 is over-transmitted in ASD but also in the population indicating meiotic drive.

    There are three inversion-related haplotypes at 15q24.2 (NI, Ia and Ib). Homozygous haplotypes correlate with over-expression of MAN2C1 in many brain areas and are associated with differences in cognitive skills in children.

    In a search for additional genetic variation related to RA and UC, we found a few chromosomal rearrangements in mosaicism, shared regions of homozygosity, and novel putative inversion haplotypes. Replication in additional cohorts will be required to confirm the involvement of these variants in the disorders.