GENOMICS OF STRUCTURAL VARIATION Irene Hernández Pérez GENOMICS 11.12.2017

INDEX Structural variation in the human genome Mechanisms of generation of SVs Implications of SVs for phenotype and disease Prototypic structural-variant-associated human diseases Down´s syndrome Williams syndrome Angelsman syndrome Conclusions

99.9% similarity among individuals Genetic variation between individuals Phenotypic variation Disease susceptibility

Structural variants are sequence variants of at least 50bp in size. Deletions Insertions Duplications Unbalanced or copy-number variation Inversions Translocations Balanced forms

Mechanisms of generation of SVs Repetitive sequences Transposable elements Segmental duplications Recombination Non-Allelic Homologous Recombination (NAHR) Non-Homologous End Joining (NHEJ) DNA repair Transposition of transposable elements Fork Stalling and Template Switching (FoSTeS) Replication

Implications of SVs for phenotype and disease Structural variants can affect gene expression through: Dosage effects Gene disruption Regulatory disruption Positional effects Mendelian sporadic disorders 20% Duplications 80% Deletions Unmask recessive alleles Expose inactive imprinted genes Complex disease De novo structural variants formation Opposite phenotypes Overlapping phenotypes Dosage-sensitive genes

Prototypic structural-variant-associated human diseases

Down´s syndrome CHANGE: Increased dosage Complete trisomy 21 (95%) Translocation trisomy 21 (4%) Subbands 21q22.1 and 21q22.2 Mosaic trisomy 21 (1%) Monosomy 21q22 21qter

Williams syndrome CHANGE: Haploinsufficiency Microdeletion (26-28 genes) Chr7q11.23 ELN Elastin Connective tissue abnormalities Cardiovascular disease LIMK1 Tyrosine kinase Unequal meiotic recombination Intrachromosomal rearrangements CLIP2 GTF2I GTF2IRD1 Cognitive difficulties

Angelman syndrome CHANGE: Loss of function UBE3A (Chr15q11-13) GENOMIC IMPRINTING in neurons Deletion within maternal chromosome 15 (65-75%) UBE3A mutation (5-11%) Paternal uni-parental disomy (3-7%) Imprinting defects (3%) Mutation in regulatory regions

Conclusions Structural variation is the main resource of genetic and phenotypic variation, contributing to human diversity and disease susceptibility. Present studies are mostly directed to ‘unique’ regions, but are ‘blind’ towards the phenotypic contribution of complex, highly duplicated areas of the genome. Integration of structural variation with the existing SNP-based information  improvement of predictions of disease onset and outcome for developing therapeutic strategies and for facilitating translational molecular medicine research.

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