Chromosome inversions in human populations Marta Ruiz Fernndez Master in Advanced Genetics 17 December 2014 INTRODUCTION Inversions occur when a chromosome breaks at two points and the segment between the breakpoints is reinserted in the reverse orientation. Do not change the amount of genetic material Generally viable and show no particular abnormalities at phenotypic level TYPES OF INVERSIONS Paracentric inversion: Pericentric inversion: Problems in recombination Paracentric inversion Pericentric inversion MECHANISMS OF INVERSION Double strand break is needed for the inversion Hotspots Usually contains segmental duplications (SD) Distance between SD = kb 95 97% identity Mechanisms Non-allelic homologous recombination (NAHR) Non-homologous end joining (NHEJ) Fork stalling and template switching CONSEQUENCES OF INVERSIONS Recombination suppressed in heterozygotes Reducing cross-over within inverted regions If recombination occurs Not viable cells Inversions could lead to insertions or deletions Depending on the breakpoints position: Gene disruption Alter gene expression Generate new splicing sites Gene fusion NEUTRAL DELETERIOUS ADAPTATIVE HOW TO DETECT INVERSIONS Problems Inversions do not change genome size The genome is full of GAPs and the inversions flanked by repetitive sequences International Human Genome Sequencing Consortium (2004) Nature 409: HOW TO DETECT INVERSIONS Problems Inversions do not change genome size The genome is full of GAPs and the inversions flanked by repetitive sequences Methods Cytogenetic (conventional, FISH, FISH-based assay) Pair-end sequencing Genome assembly IMPLICATIONS OF INVERSIONS INVERSIONS Generating variability Speciation Local adaptation Human diseases HapMap project Structural Variations The role of inversions in human diversity The role of inversions in speciation Speciation Prezygotic INVERSIONS Postzygotic The role of inversions in local adaptation -Annual -Found in DRY environments in the INLAND -Flowering time BEFORE hot -Perennial -Found in WET and COOL environments in the coast -Flowering time LATER - Flowering time - Morphological differences Monkeyflower ( Mimulus guttatus) Inversions related to diseases Chr. locationConsequences X intron 22Haemophilia 4 p14q21Behavioural disorders X q11q28Klinefelter like Sd 8 p11.2q23.1Ambras Syndrome -X-linked disease -Factor VIII 26 exons and 25 introns -Inversion of the intron 22 by NAHR CONCLUSIONS Several studies have reported many inversions Way to generate variation between and within species Diversity of effects depending on: Where? (Coding/Non-coding, introns, exons) Is any gene affected? Does the inversion imply another chromosomal arrangement? REFERENCES Antonacci F, Kidd JM, Marques-Bonet T, Ventura M, Siswara P, Jiang Z, et al. Characterization of six human disease-associated inversion polymorphisms. Hum Mol Genet. 2009;18:255566. Gu W, Zhang F, Lupski JR. Mechanisms for human genomic rearrangements. Pathogenetics. 2008;1:4. Bansal V, Bashir A, Bafna V. Evidence for large inversion polymorphisms in the human genome from HapMap data 2007:21930. Lee J, Han K, Meyer TJ, Kim H-S, Batzer M a. Chromosomal inversions between human and chimpanzee lineages caused by retrotransposons. PLoS One. 2008;3:e4047. Kirkpatrick M. How and why chromosome inversions evolve. PLoS Biol. 2010;8. Lowry DB, Willis JH. A widespread chromosomal inversion polymorphism contributes to a major life-history transition, local adaptation, and reproductive isolation. PLoS Biol. 2010;8. Chromosome inversions in human populations Marta Ruiz Fernndez Master in Advanced Genetics 17 December 2014 MECHANISMS OF INVERSION 1. Non-allelic homologous recombination (NAHR) MECHANISMS OF INVERSION 1b. NAHR and Transposable Elements Some transposable elements contains LTR By homology two TE containing LTR can recombine If the TE are in opposite orientation they could cause inversions Retrotransposon recombination-mediated inversion MECHANISMS OF INVERSION 2. Fork stalling and template switching (FoSTeS) Gu W. Pathogenetics. 2008;1:4 HOW TO DETECT INVERSIONS Methods: Cytogenetic: FISH The problem of this techniques is the resolution (2Mbp) Solution FISH-based assay Antonacci F.Hum Mol Genet. 2009;18:255566 HOW TO DETECT INVERSIONS Methods: FISH Pair-end sequencing method (variants >5kb) HOW TO DETECT INVERSIONS Methods: FISH End-pair sequencing method Genome assembly