The origin, global distribution and functional impact of the human 8p23 inversion polymorphism
- Maximilian PA Salm1,
- Stuart D Horswell1,
- Claire E Hutchison2,
- Helen E Speedy2,
- Xia Yang3,
- Liming Liang4,
- Eric E Schadt3,
- William O Cookson5,
- Anthony S Wierzbicki6,
- Rossi P Naoumova7 and
- Carol C Shoulders2,8
- 1 Cancer Research UK London Research Institute;
- 2 William Harvey Research Institute;
- 3 Sage Bionetworks;
- 4 Harvard School of Public Health;
- 5 National Heart and Lung Institute, Imperial College London;
- 6 Guys & St Thomas Hospital, King's College London;
- 7 Institute of Clinical Science, Imperial College London
- ↵* Corresponding author; email: c.shoulders{at}qmul.ac.uk
Abstract
Genomic inversions are an increasingly recognized source of genetic variation. However, a lack of reliable high-throughput genotyping assays for these structures has precluded a full understanding of an inversion’s phylogenetic, phenotypic and population genetic properties. We characterize these properties for one of the largest polymorphic inversions in man (the ~4.5Mb 8p23.1 inversion), a structure that encompasses numerous signals of natural selection and disease association. We developed and validated a flexible bioinformatics tool that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion. This tool was applied retrospectively to diverse genome-wide datasets revealing significant population stratification that largely follows a clinal "serial founder effect" distribution model. Phylogenetic analyses establish the inversion's ancestral origin within the Homo lineage, indicating that 8p23.1 inversion has occurred independently in the Pan lineage. The human inversion breakpoint was localized to an inverted pair of Human Endogenous Retrovirus elements within the large, flanking low copy repeats; experimental validation of this breakpoint confirmed these elements as the likely intermediary substrates that sponsored inversion formation. In five datasets, mRNA levels of disease-associated genes were robustly associated with inversion genotype. Moreover, a haplotype associated with Systemic Lupus Erythematosus was restricted to the derived inversion state. We conclude that the 8p23.1 inversion is an evolutionarily dynamic structure that can now be accommodated into the understanding of human genetic and phenotypic diversity.
- Received May 9, 2011.
- Accepted March 6, 2012.
- Copyright © 2012, Cold Spring Harbor Laboratory Press
