Chromosome inversions in human populations Maria Bellet Coll

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1 Chromosome inversions in human populations Maria Bellet Coll Universitat Autònoma de Barcelona - Genomics

2 Table of contents Structural variation Inversions Methods for inversions analysis Pair-end mapping Disorders associated to inversions Article: Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics.

3 Structural Variation Genome structural variation encompasses polymorphic rearrangements 50 base pairs to hundreds of kilobases in size and affects about 0.5% of the genome of an individual. (Monya Baker, Structural variation: the genome's hidden architecture, Nature Methods 9, (2012))

4 Structural Variation Database of Genomic Variants, which posts curated data from peer-reviewed studies on human samples. (Monya Baker, Structural variation: the genome's hidden architecture, Nature Methods 9, (2012))

5 Structural Variation Unbalanced: Deletions Duplications Copy-Number Variations Balanced: Inversions Translocations

6 Inversions Generate by two different mechanisms: Homologous (NAHR). Repetitive sequence at break points. Non-homologous (NHEJ, FoSTeS). Simple break points.

7 Inversions InvFEST database. Example

8 Methods for inversion analysis G-banding karyotyping FISH Southern blot hybridization Pulsed-field gel electrophoresis

9 Methods for inversion analysis G-banding karyotyping FISH Southern blot hybridization Pulsed-field gel electrophoresis But with developed sequencing techniques it is possible to identify inversions at genome-wide level: Sequence comparison Paired-end sequencing and mapping (PEM)

10 Methods for inversion analysis G-banding karyotyping FISH Southern blot hybridization Pulsed-field gel electrophoresis But with developed sequencing techniques it is possible to identify inversions at genome-wide level: Sequence comparison Paired-end sequencing and mapping (PEM)

11 Inversion discovery by paired-end mapping Feuk L. (2010) Inversion variants in the human genome: role in disease and genome architecture. Genome Med.

12 Disorders associated to inversions Feuk L. (2010) Inversion variants in the human genome: role in disease and genome architecture. Genome Med.

13 Disorders associated to inversions Feuk L. (2010) Inversion variants in the human genome: role in disease and genome architecture. Genome Med.

14 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Its locus represents one of the most dynamic and complex regions of the human genome. It exists either as direct (H1) or inverted (H2) haplotypes (different orientations) with differential predispositions to disease and selection. It does not recombine over nearly 2 Mbp resulting in extended linkage disequilibrium.

15 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Frequency of haplotypes (H1D and H2D) carrying duplications (CNP155 and CNP205) in 620 individuals using NGS. Population stratification of duplicated alleles.

16 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. FISH co-hybridization experiments using probes mapping to CNP155/CNP205 in green, CNP210 duplication in red and at the single-copy region in blue. Confirm different structures.

17 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Using BAC pool sequencing and FISH, eight alternate structural configurations of the 17q21.31 region were characterized, which differ dramatically in their organization and duplication content.

18 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Haplotype frequency of 17q21.31 inversion in Africa. Frequency of direct (H1), inverted (H2 ), and inverted with duplication (H2D) haplotypes in 818 individuals (1636 chromosomes) from 23 African populations.

19 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Build a maximum likelihood tree for each haplotype and ethnic group in the HapMap Project. H1 and H2 haplotype clades are completely distinct. Hypothesis that the H1 haplotype is ancestral to the H1D haplotype. H2 and H2D show little to no variation. The topology of the tree, as well as the lack of diversity on the H2 haplotypes, is suggestive of a recent bottleneck followed by population expansion.

20 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Phylogenetic relationship between H1 and H2 haplotypes. In general, inversions are predicted to result in complete suppression of recombination, so sequence divergence is expected to be higher than in normal recombining chromosomal segments.

21 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Conclusions: 1.- H2 haplotype represents the ancestral configuration of the 17q21.31 region in humans.

22 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Conclusions: 2.- Approximately 2.3 mya, the inversion toggled back to the direct orientation (H1) and spread to South Africa.

23 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Conclusions: 3.- The H2D duplication arose in Africa 1.3 mya, and the H1D duplication independently arose approximately 250,000 years ago.

24 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Conclusions: 4.- The H1 haplotype spread throughout Western Africa, and all haplotypes spread to the Middle East and Europe.

25 Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism Nature Genetics. Are duplications quickly increased in Europe related with the increase of fertility??

26 Thank you for your attention! Maria Bellet Coll Universitat Autònoma de Barcelona - Genomics