Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Abstract

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent–child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation even across complex loci. We identify 107,590 structural variants (SVs), of which 68% are not discovered by short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterize 130 of the most active mobile element source elements and find that 63% of all SVs arise by homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex

“…Out of the 26,712 SVs we detected, we observed 10,613 deletions, 16,069 insertions, and 30 inversions. These findings are consistent with the levels reported in our previous research on samples of similar ancestry 3 . We also annotated 1,818 TEs, including 172 L1Hs, 1565 Alu Ys, and 81 SVAs, projecting expected peaks in the overall length distribution at 320 bp and 6 kb for full-length Alu and L1, respectively ( Fig.…”

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex

“…Out of the 26,712 SVs we detected, we observed 10,613 deletions, 16,069 insertions, and 30 inversions. These findings are consistent with the levels reported in our previous research on samples of similar ancestry 3 . We also annotated 1,818 TEs, including 172 L1Hs, 1565 Alu Ys, and 81 SVAs, projecting expected peaks in the overall length distribution at 320 bp and 6 kb for full-length Alu and L1, respectively ( Fig.…”

Population-scale Long-read Sequencing in the All of Us Research Program

“…By contrast, there was a dramatic increase in SV discovery ranging from 60% to 290% depending on the stringency level applied to the putative SV callset before comparisons. This result is consistent with prior studies demonstrating the superior sensitivity of long-read technologies for SV detection 12,15,30 . We have therefore released two SV callsets—a lenient callset of 1,213,876 SVs maximized for sensitivity and a strict callset of 665,869 SVs optimized for high specificity.…”

A global map for introgressed structural variation and selection in humans

“…Among PNG-specific SVs, while 31% (n=1,094 out of 3,568; 12 exon-overlapped SVs) and 32% (n=1,082 out of 3,372; 57 exon-overlapped SVs) of the insertions and deletions overlap with genes (i.e., introns and/or exons), respectively, our analysis shows a significant depletion of these SVs in genes (p<0.001; 1,000 permutations). These results are consistent with the expectation of selection against large SVs in functionally constrained sequences( 17 ).…”

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex

“…Out of the 26,712 SVs we detected, we observed 10,613 deletions, 16,069 insertions, and 30 inversions. These findings are consistent with the levels reported in our previous research on samples of similar ancestry 3 . We also annotated 1,818 TEs, including 172 L1Hs, 1565 Alu Ys, and 81 SVAs, projecting expected peaks in the overall length distribution at 320 bp and 6 kb for full-length Alu and L1, respectively ( Fig.…”

Population-scale Long-read Sequencing in the All of Us Research Program

“…By contrast, there was a dramatic increase in SV discovery ranging from 60% to 290% depending on the stringency level applied to the putative SV callset before comparisons. This result is consistent with prior studies demonstrating the superior sensitivity of long-read technologies for SV detection 12,15,30 . We have therefore released two SV callsets—a lenient callset of 1,213,876 SVs maximized for sensitivity and a strict callset of 665,869 SVs optimized for high specificity.…”

A global map for introgressed structural variation and selection in humans

“…Among PNG-specific SVs, while 31% (n=1,094 out of 3,568; 12 exon-overlapped SVs) and 32% (n=1,082 out of 3,372; 57 exon-overlapped SVs) of the insertions and deletions overlap with genes (i.e., introns and/or exons), respectively, our analysis shows a significant depletion of these SVs in genes (p<0.001; 1,000 permutations). These results are consistent with the expectation of selection against large SVs in functionally constrained sequences( 17 ).…”

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex

“…Out of the 26,712 SVs we detected, we observed 10,613 deletions, 16,069 insertions, and 30 inversions. These findings are consistent with the levels reported in our previous research on samples of similar ancestry 3 . We also annotated 1,818 TEs, including 172 L1Hs, 1565 Alu Ys, and 81 SVAs, projecting expected peaks in the overall length distribution at 320 bp and 6 kb for full-length Alu and L1, respectively ( Fig.…”

Population-scale Long-read Sequencing in the All of Us Research Program

“…By contrast, there was a dramatic increase in SV discovery ranging from 60% to 290% depending on the stringency level applied to the putative SV callset before comparisons. This result is consistent with prior studies demonstrating the superior sensitivity of long-read technologies for SV detection 12,15,30 . We have therefore released two SV callsets—a lenient callset of 1,213,876 SVs maximized for sensitivity and a strict callset of 665,869 SVs optimized for high specificity.…”

A global map for introgressed structural variation and selection in humans

“…Among PNG-specific SVs, while 31% (n=1,094 out of 3,568; 12 exon-overlapped SVs) and 32% (n=1,082 out of 3,372; 57 exon-overlapped SVs) of the insertions and deletions overlap with genes (i.e., introns and/or exons), respectively, our analysis shows a significant depletion of these SVs in genes (p<0.001; 1,000 permutations). These results are consistent with the expectation of selection against large SVs in functionally constrained sequences( 17 ).…”