Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence

Cristina Aguado, Magdalena Gayà-Vidal, Sergi Villatoro, Meritxell Oliva, David Izquierdo, Carla Giner-Delgado, Víctor Montalvo, Judit García-González, Alexander Martínez-Fundichely, Laia Capilla, Aurora Ruiz-Herrera, Xavier P. Estivill, Marta Puig, Mario Cáceres

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6-24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ~12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.

Original languageEnglish
Article numbere1004208
JournalPLoS Genetics
Volume10
Issue number3
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

genotyping
Single Nucleotide Polymorphism
Recurrence
Genomic Segmental Duplications
inversion polymorphism
Inverted Repeat Sequences
HapMap Project
Gorilla gorilla
Polymerase Chain Reaction
Pan troglodytes
Gorilla
fathers
Human Genome
Gene Frequency
Fathers
human population
Haplotypes
Population
Genes
gene frequency

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Aguado, C., Gayà-Vidal, M., Villatoro, S., Oliva, M., Izquierdo, D., Giner-Delgado, C., ... Cáceres, M. (2014). Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence. PLoS Genetics, 10(3), [e1004208]. https://doi.org/10.1371/journal.pgen.1004208

Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence. / Aguado, Cristina; Gayà-Vidal, Magdalena; Villatoro, Sergi; Oliva, Meritxell; Izquierdo, David; Giner-Delgado, Carla; Montalvo, Víctor; García-González, Judit; Martínez-Fundichely, Alexander; Capilla, Laia; Ruiz-Herrera, Aurora; Estivill, Xavier P.; Puig, Marta; Cáceres, Mario.

In: PLoS Genetics, Vol. 10, No. 3, e1004208, 2014.

Research output: Contribution to journalArticle

Aguado, C, Gayà-Vidal, M, Villatoro, S, Oliva, M, Izquierdo, D, Giner-Delgado, C, Montalvo, V, García-González, J, Martínez-Fundichely, A, Capilla, L, Ruiz-Herrera, A, Estivill, XP, Puig, M & Cáceres, M 2014, 'Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence', PLoS Genetics, vol. 10, no. 3, e1004208. https://doi.org/10.1371/journal.pgen.1004208
Aguado, Cristina ; Gayà-Vidal, Magdalena ; Villatoro, Sergi ; Oliva, Meritxell ; Izquierdo, David ; Giner-Delgado, Carla ; Montalvo, Víctor ; García-González, Judit ; Martínez-Fundichely, Alexander ; Capilla, Laia ; Ruiz-Herrera, Aurora ; Estivill, Xavier P. ; Puig, Marta ; Cáceres, Mario. / Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence. In: PLoS Genetics. 2014 ; Vol. 10, No. 3.
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