title: The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism.
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 ∼4.5-Mb 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 data sets, 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 data sets, 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.
authors.affiliation: Centre for Endocrinology, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom. max.salm05@imperial.ac.uk
authors.forename: Maximilian P A
authors.initials: MP
authors.lastname: Salm
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Horswell
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hutchison
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: William O
authors.initials: WO
authors.lastname: Cookson
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Wierzbicki
authors.forename: Rossi P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
mesh_terms: D000818:Animals; D001483:Base Sequence; D007446:Chromosome Inversion; D002898:Chromosomes, Human, Pair 8; D019143:Evolution, Molecular; D015870:Gene Expression; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000235:genetics; D010802:Phylogeny; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger; D056916:Segmental Duplications, Genomic
chemical_list: D012333:RNA, Messenger