Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly

Abstract

The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health.

Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes

“…Although the genome-wide increased nucleotide divergence in the Muridae lineage was previously known (Mouse Genome Sequencing Consortium 2002; Rat Genome Sequencing Project Consortium 2004), our analysis shows that all categories of genomic annotation and function have similar relative acceleration when compared to Hominidae. Indeed, our results are likely to be more precise due to the progressive increase in genome assembly quality for human and mouse over the last 10-15 yr, especially within the repetitive regions (Church et al 2009;Schneider et al 2017). The rate change between the two clades is similar, regardless of whether the genomic region is under evolutionary constraint (e.g., coding exons) or apparently evolving neutrally (e.g., ancestral repeats).…”

Single-molecule sequencing and chromatin conformation capture enable de novo reference assembly of the domestic goat genome

“…3) that will require further investigation to confirm. Considering that ARS1 comprises just 31 scaffolds and 649 gaps covering 30 of the 31 haploid, acrocentric goat chromosomes 38 (excluding only the Y chromosome), our assembly compares favorably with the current human reference (GRCh38), which has 24 scaffolds, 169 unplaced/unlocalized scaffolds, and 832 gaps in the primary assembly 39 .…”

Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer

“…The average consensus genome map is 1.7 Mb in length with the longest map reaching 6.5 Mb. More than 97% of the genome maps could be aligned to the human reference GRCh38 (Schneider et al 2017), achieving a breadth of coverage of 90%, which is a theoretical limit given the lack of reference genomic information at and around low complexity regions (Fig. 2).…”

“…SVs were identified relative to the human reference genome, GRCh38 (Schneider et al 2017), whose genome maps were bioinformatically deduced based on predicted Nt.BspQI motif sites. SV detection was performed using the Bionano custom SV caller (Bionano Genomics).…”