Characterization of large-scale genomic differences in the first complete human genome

Abstract

Background The first telomere-to-telomere (T2T) human genome assembly (T2T-CHM13) release is a milestone in human genomics. The T2T-CHM13 genome assembly extends our understanding of telomeres, centromeres, segmental duplication, and other complex regions. The current human genome reference (GRCh38) has been widely used in various human genomic studies. However, the large-scale genomic differences between these two important genome assemblies are not characterized in detail yet. Results Here, in addition to the previously reported “non-syntenic” regions, we find 67 additional large-scale discrepant regions and precisely categorize them into four structural types with a newly developed website tool called SynPlotter. The discrepant regions (~ 21.6 Mbp) excluding telomeric and centromeric regions are highly structurally polymorphic in humans, where the deletions or duplications are likely associated with various human diseases, such as immune and neurodevelopmental disorders. The analyses of a newly identified discrepant region—the KLRC gene cluster—show that the depletion of KLRC2 by a single-deletion event is associated with natural killer cell differentiation in ~ 20% of humans. Meanwhile, the rapid amino acid replacements observed within KLRC3 are probably a result of natural selection in primate evolution. Conclusion Our study provides a foundation for understanding the large-scale structural genomic differences between the two crucial human reference genomes, and is thereby important for future human genomics studies.

Comparative genomics of macaques and integrated insights into genetic variation and population history

“…With the rapid advancement of long-read sequencing techniques and hybrid assembly strategies, we have entered an era where we can generate complete telomere-to-telomere (T2T) genome assemblies 7,12,15 . These efforts enable the study of complex genomic regions, including centromeres, segmental duplications (SDs), and structurally divergent regions (SDRs, or complex regions) 10,[16][17][18][19][20] . Currently, haplotype-resolved genome assemblies can be generated with trio-based, Hi-C-based, or Strand-seq-based approaches [21][22][23] .…”

Natural variation in oxytocin receptor signaling causes widespread changes in brain transcription: a link to the natural killer gene complex

“…Using a systemic OXTR KO prairie vole, we show that parts of the transcriptional differences associated with genotype are directly modulated by OXTR signaling. In particular, OXTR signaling controls the gene expression of C-type lectin-like receptors (CTLRs) located in the natural killer gene complex (NKC), a genomic region that is primarily known to govern innate immune responses 33 , although a central function has been suggested recently 34 . Our results give surprising clues to the cellular processes that are under control of OXT signaling and thereby provide hypotheses on the origins of diversity in social phenotypes.…”

The complete diploid reference genome of RPE-1 identifies human phased epigenetic landscapes

“…These, and others that have since been added [4][5][6] , represent an important step toward a more equitable and fair representation of human genomic diversity 3,7 . Comparative analyses of the currently available complete assemblies have revealed an unexpected level of sequence variation 3,8 . Complete understanding of the divergence between individuals 3 and population-level variants [9][10][11] , including their functional significance, is ongoing.…”

“…We reasoned that the analysis of multi-omics sequencing data generated from laboratory cell lines presents challenges when using a non-matched reference, the so-called 'reference bias' 18 . These challenges are particularly important for faithful studies of our most polymorphic and divergent regions including centromeres 8 . Human centromeres consist of repetitive monomers of alphasatellite DNA hierarchically organized into reiterating higher order repeats (HORs) arrays [19][20][21] that span from 0.3 up to 5 Mb in size (in CHM13) 1,22 .…”

“…These and others that have since been added 4–6 represent an important step toward a more equitable representation of human genomic diversity 3,7 . Comparative analyses of the currently available assemblies have revealed an unexpected level of sequence variation 3,8 , including inter-individuals divergence 3 and population-level variants 9–11 . Differences within an individual genome pertaining to the parental alleles are largely unexplored 2,12 due to lack of high-quality human diploid genomes with fully phased haplotypes.…”