Local adaptation and archaic introgression shape global diversity at human structural variant loci

Abstract

Large genomic insertions, deletions, and inversions are a potent source of functional and fitness-altering variation, but are challenging to resolve with short-read DNA sequencing alone. While recent long-read sequencing technologies have greatly expanded the catalog of structural variants (SVs), their costs have so far precluded their application at population scales. Given these limitations, the role of SVs in human adaptation remains poorly characterized. Here, we used a graph-based approach to genotype 107,866 long-read-discovered SVs in short-read sequencing data from diverse human populations. We then applied an admixture-aware method to scan these SVs for patterns of population-specific frequency differentiation—a signature of local adaptation. We identified 220 SVs exhibiting extreme frequency differentiation, including several SVs that were among the lead variants at their corresponding loci. The top two signatures traced to separate insertion and deletion polymorphisms at the immunoglobulin heavy chain locus, together tagging a 325 Kbp haplotype that swept to high frequency and was subsequently fragmented by recombination. Alleles defining this haplotype are nearly fixed (60-95%) in certain Southeast Asian populations, but are rare or absent from other global populations composing the 1000 Genomes Project. Further investigation revealed that the haplotype closely matches with sequences observed in two of three high-coverage Neanderthal genomes, providing strong evidence of a Neanderthal-introgressed origin. This extraordinary episode of positive selection, which we infer to have occurred between 1700 and 8400 years ago, corroborates the role of immune-related genes as prominent targets of adaptive archaic introgression. Our study demonstrates how combining recent advances in genome sequencing, genotyping algorithms, and population genetic methods can reveal signatures of key evolutionary events that remained hidden within poorly resolved regions of the genome.

A complete reference genome improves analysis of human genetic variation

“…These successful lift overs allowed us to make direct comparisons to selection results, generated with identical methods, based on 1KGP Phase 3 data aligned to GRCh38 (see Supplemental Methods ; Fig. S4.6 ) [52]. For 41.3% of the lifted over variants, we found GRCh38 variants within a 2 kbp window that possessed similar or higher likelihood ratio statistics for the same ancestry component, indicating that these loci were possible to identify in previous scans based on GRCh38 ( Fig.…”

The first sheep graph-based pan-genome reveals the spectrum of structural variations and their effects on tail phenotypes

“…Only the insertions and deletions from autosomes were genotyped. Paragraph represent SVs as diverging paths in a graph and could achieve high rate of genotyping accuracy [29]. The samples included 644 domestic sheep from Europe, East Asia Middle East and Africa, 33 Asiatic mouflons and 8 argali with an average coverage of 18.1× (Fig.…”

“…To ensure a high-quality set of genotyped SVs for population genetics analysis, we filtered genotyping results based on genotyping rates and adherence to Hardy Weinberg equilibrium [29]. We excluded 12,705 SVs that failed to be genotyped in >90% of the samples and another 2011 displaying deviation from Hardy Weinberg equilibrium by displaying excess of heterozygotes, leaving 121,258 (89.2%) reliably genotyped SVs for downstream analysis (Supplementary data 4).…”

“…2a, see Methods for the assignment of the breeds and populations. Paragraph represent SVs as diverging paths in a graph and achieves a high rate of genotyping accuracy 33 .…”

“…To obtain a high-confidence call set of SVs, the resulting genotypes were filtered based on overall genotyping rates and Hardy-Weinberg equilibrium 33 . Those variants 90% of all samples were retained using ≥ vcftools 67 for further analysis.…”