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  1. Free, publicly-accessible full text available June 1, 2023
  2. INTRODUCTION One of the central applications of the human reference genome has been to serve as a baseline for comparison in nearly all human genomic studies. Unfortunately, many difficult regions of the reference genome have remained unresolved for decades and are affected by collapsed duplications, missing sequences, and other issues. Relative to the current human reference genome, GRCh38, the Telomere-to-Telomere CHM13 (T2T-CHM13) genome closes all remaining gaps, adds nearly 200 million base pairs (Mbp) of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for scientific inquiry. RATIONALE We demonstrate how the T2T-CHM13 reference genome universally improves read mapping and variant identification in a globally diverse cohort. This cohort includes all 3202 samples from the expanded 1000 Genomes Project (1KGP), sequenced with short reads, as well as 17 globally diverse samples sequenced with long reads. By applying state-of-the-art methods for calling single-nucleotide variants (SNVs) and structural variants (SVs), we document the strengths and limitations of T2T-CHM13 relative to its predecessors and highlight its promise for revealing new biological insights within technically challenging regions of the genome. RESULTS Across the 1KGP samples, we found more than 1 million additional high-quality variants genome-wide using T2T-CHM13more »than with GRCh38. Within previously unresolved regions of the genome, we identified hundreds of thousands of variants per sample—a promising opportunity for evolutionary and biomedical discovery. T2T-CHM13 improves the Mendelian concordance rate among trios and eliminates tens of thousands of spurious SNVs per sample, including a reduction of false positives in 269 challenging, medically relevant genes by up to a factor of 12. These corrections are in large part due to improvements to 70 protein-coding genes in >9 Mbp of inaccurate sequence caused by falsely collapsed or duplicated regions in GRCh38. Using the T2T-CHM13 genome also yields a more comprehensive view of SVs genome-wide, with a greatly improved balance of insertions and deletions. Finally, by providing numerous resources for T2T-CHM13 (including 1KGP genotypes, accessibility masks, and prominent annotation databases), our work will facilitate the transition to T2T-CHM13 from the current reference genome. CONCLUSION The vast improvements in variant discovery across samples of diverse ancestries position T2T-CHM13 to succeed as the next prevailing reference for human genetics. T2T-CHM13 thus offers a model for the construction and study of high-quality reference genomes from globally diverse individuals, such as is now being pursued through collaboration with the Human Pangenome Reference Consortium. As a foundation, our work underscores the benefits of an accurate and complete reference genome for revealing diversity across human populations. Genomic features and resources available for T2T-CHM13. Comparisons to GRCh38 reveal broad improvements in SNVs, indels, and SVs discovered across diverse human populations by means of short-read (1KGP) and long-read sequencing (LRS). These improvements are due to resolution of complex genomic loci (nonsyntenic and previously unresolved), duplication errors, and discordant haplotypes, including those in medically relevant genes.« less
    Free, publicly-accessible full text available April 1, 2023
  3. Bread wheat (Triticum aestivum) is a major food crop and an important plant system for agricultural genetics research. However, due to the complexity and size of its allohexaploid genome, genomic resources are limited compared to other major crops. The IWGSC recently published a reference genome and associated annotation (IWGSC CS v1.0, Chinese Spring) that has been widely adopted and utilized by the wheat community. Although this reference assembly represents all three wheat subgenomes at chromosome-scale, it was derived from short reads, and thus is missing a substantial portion of the expected 16 Gbp of genomic sequence. We earlier published an independent wheat assembly (Triticum_aestivum_3.1, Chinese Spring) that came much closer in length to the expected genome size, although it was only a contig-level assembly lacking gene annotations. Here, we describe a reference-guided effort to scaffold those contigs into chromosome-length pseudomolecules, add in any missing sequence that was unique to the IWGSC CS v1.0 assembly, and annotate the resulting pseudomolecules with genes. Our updated assembly, Triticum_aestivum_4.0, contains 15.07 Gbp of non-gap sequence anchored to chromosomes, which is 1.2 Gbps more than the previous reference assembly. It includes 108,639 genes unambiguously localized to chromosomes, including over 2,000 genes that were previously unplaced.more »We also discovered more than 5,700 additional gene copies, facilitating the accurate annotation of functional gene duplications including at the Ppd-B1 photoperiod response locus.« less
  4. Valencia, Alfonso (Ed.)
    Abstract Motivation Improvements in DNA sequencing technology and computational methods have led to a substantial increase in the creation of high-quality genome assemblies of many species. To understand the biology of these genomes, annotation of gene features and other functional elements is essential; however, for most species, only the reference genome is well-annotated. Results One strategy to annotate new or improved genome assemblies is to map or ‘lift over’ the genes from a previously annotated reference genome. Here, we describe Liftoff, a new genome annotation lift-over tool capable of mapping genes between two assemblies of the same or closely related species. Liftoff aligns genes from a reference genome to a target genome and finds the mapping that maximizes sequence identity while preserving the structure of each exon, transcript and gene. We show that Liftoff can accurately map 99.9% of genes between two versions of the human reference genome with an average sequence identity >99.9%. We also show that Liftoff can map genes across species by successfully lifting over 98.3% of human protein-coding genes to a chimpanzee genome assembly with 98.2% sequence identity. Availability and implementation Liftoff can be installed via bioconda and PyPI. In addition, the source code for Liftoffmore »is available at Supplementary information Supplementary data are available at Bioinformatics online.« less
  5. We sequenced the genome of the North American groundhog, Marmota monax , also known as the woodchuck. Our sequencing strategy included a combination of short, high-quality Illumina reads plus long reads generated by both Pacific Biosciences and Oxford Nanopore instruments. Assembly of the combined data produced a genome of 2.74 Gbp in total length, with an N50 contig size of 1,094,236 bp. To annotate the genome, we mapped the genes from another M. monax genome and from the closely related Alpine marmot, Marmota marmota , onto our assembly, resulting in 20,559 annotated protein-coding genes and 28,135 transcripts. The genome assembly and annotation are available in GenBank under BioProject PRJNA587092 .
  6. Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.
    Free, publicly-accessible full text available April 1, 2023