A complete reference genome improves analysis of human genetic variation

Abstract

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 million base pairs of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for clinical and functional study. We show how this reference universally improves read mapping and variant calling for 3202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of variants per sample in previously unresolved regions, showcasing the promise of the T2T-CHM13 reference for evolutionary and biomedical discovery. Simultaneously, this reference eliminates tens of thousands of spurious variants per sample, including reduction of false positives in 269 medically relevant genes by up to a factor of 12. Because of these improvements in variant discovery coupled with population and functional genomic resources, T2T-CHM13 is positioned to replace GRCh38 as the prevailing reference for human genetics.

Nde1 is required for heterochromatin compaction and stability in neocortical neurons

“…However, the role of satellite repeats and their associated constitutive heterochromatin remains unclear, as their high repetitiveness makes them almost entirely missing from the genome assembly in the past two decades, and a lack of in vivo models to determine their functional impacts also hinders their study. Recent advances in fully sequencing the T2T-CHM13 genome now demonstrate the rich genetic and epigenetic variations hidden in the repeat elements of the human genome (Nurk et Gershman et al, 2022;Hoyt et al, 2022;Aganezov et al, 2022). Our finding of hyper-variability of heterochromatin landscape in human neocortical neurons as well as their physical and functional regulation by NDE1/Nde1 aligns fully with the new human genome information.…”

Chasing perfection: validation and polishing strategies for telomere-to-telomere genome assemblies

“…4a). Additionally, we found that CHM13v1.0 had 33× fewer false or rare collapses than GRCh38 (~185 loci covering 6.84 Mb) 6 . We identified five regions (160 kb) with rare duplications in CHM13v1.0.…”

“…In summary, we found 7.5× fewer rare or falsely duplicated bases in CHM13v1.0 relative to the 12 likely falsely duplicated regions affecting 1.2 Mb and 74 genes in GRCh38 (ref. 6 ), including the medically relevant CBS, CRYAA and KCNE1 genes 46 .…”

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enome assembly is a foundational practice of quantitative biological research with increasing utility. By representing the genomic sequence of a sample of interest, genome assemblies enable researchers to annotate important features, quantify functional data and discover/genotype genetic variants in a population [1][2][3][4][5][6] . Modern draft eukaryotic genome assembly graphs are typically built from a subset of four whole-genome shotgun (WGS) sequencing data types: Illumina short reads 7,8 , Oxford Nanopore Technologies (ONT) long reads 9,10 , PacBio continuous long reads (CLRs) and PacBio high-fidelity (HiFi) long reads 9,11 , all of which have been extensively described [7][8][9]11 .

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Population-scale genotyping of structural variation in the era of long-read sequencing

“…Notably, most recent population-scale studies of SVs have used pan-genomic models to eliminate reference bias and successfully scaled up the population size for genotyping from a few hundred to thousands of samples [4] , [32] , [63] , [64] , [65] , facilitating other genotype-based downstream analyses. Recently, the Telomer-to-Telomere (T2T) Consortium and the Human Pangenome Reference Consortium have successively announced their exciting progress in constructing complete and error-free T2T assemblies of all chromosomes as well as full-spectrum genomic variant collections [116] , [117] , [118] , which will further promote the application of pan-genomic approaches in population genetic studies.…”