1. GENOMICS OF STRUCTURAL VARIATION
Irene Hernández Pérez
GENOMICS

2. 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

3. 99.9% similarity among individuals
Genetic variation between individuals
Phenotypic variation
Disease susceptibility

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

5. 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

6. 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

7. Prototypic structural-variant-associated human diseases

8. 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

9. 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

10. 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

11. 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.

12. Bibliography
-Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A. and Korenberg, J. (1999). Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome. Trends in Neurosciences, 22(5), pp Burgio, G. (1981). Trisomy 21. Berlin: Springer. -Donnai, D. and Karmiloff-Smith, A. (2000). Williams syndrome: From genotype through to the cognitive phenotype. American Journal of Medical Genetics, 97(2), pp Feuk, L., Carson, A. and Scherer, S. (2006). Structural variation in the human genome. Nature Reviews Genetics, 7(2), pp Mabb, A., Judson, M., Zylka, M. and Philpot, B. (2011). Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends in Neurosciences, 34(6), pp Patterson, D. and Costa, A. (2005). History of genetic disease: Down syndrome and genetics - a case of linked histories. Nature Reviews Genetics, 6(2), pp Rarediseases.info.nih.gov. (2017). Angelman syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. [online] Available at: [Accessed 9 Dec. 2017]. -Reference, G. (2017). Williams syndrome. [online] Genetics Home Reference. Available at: [Accessed 9 Dec. 2017]. -Weischenfeldt, J., Symmons, O., Spitz, F. and Korbel, J. (2013). Phenotypic impact of genomic structural variation: insights from and for human disease. Nature Reviews Genetics, 14(2), pp Yao, G., Chen, X., Flores-Sarnat, L., Barlow, G., Palka, G., Moeschler, J., McGillivray, B., Morse, R. and Korenberg, J. (2006). Deletion of chromosome 21 disturbs human brain morphogenesis. Genetics in Medicine, 8(1), pp.1-7.