Abstract
Abstract
Human centromeres harbor extensive structural variation that has remained largely inaccessible to human genetics because their repetitive
α
-satellite arrays are absent from standard reference and imputation panels. Here we catalog 188,589 centromeric structural variants (SVs) from haplotype-resolved long-read assemblies of 196 Human Pangenome Reference Consortium individuals aligned to the telomere-to-telomere CHM13 reference. Resolving recurrent SVs into monophyletic components along centromeric haplotype phylogenies makes them imputable from pericentromeric SNPs (
= 0.407 vs. 0.065 unresolved). In 124 individuals with haplotype-resolved nanopore methylation, we identify 418 same-chromosome SV–CpG associations that form local hypomethylation-enriched domains in the centromeric region, most strongly for deletions. We also show that a truncated 113-bp monomer on chromosome 8 is associated with the position of the CENP-A-associated centromere dip region (CDR) at
n
= 151, independent of array length. Imputed into 630 individuals with expression and splicing data, centromeric SVs are associated with 141 genes, 14 of them new relative to the SNP-based cis-QTL analysis, including the H3K9 methyltransferase
SUV39H1
. In 315,204 All of Us participants, we identify 170 associations between 61 SV predictors and 27 clinical phenotypes, including substance-related disorders and breast cancer. Our study brings a previously inaccessible class of variation into population-scale genetics and links centromeric SVs to centromere organization, gene expression, splicing and complex traits.