Biology subjects

Belter, E. A.

Publications and source records attributed to Belter, E. A..

5 recordsLinked to original sources

bioRxiv2026

The genetic architecture of human DNA methylome variation

Population DNA methylome analyses remain largely confined to reference-defined genomic space despite extensive human genetic diversity. A central challenge is therefore to define comparable methylation phenotypes across diverse genomes and map the genetic architecture of methylome variation. Here, using 460 haplotypes from the Human Pangenome Reference Consortium Release 2, we develop two complementary pangenome-based frameworks: one compares methylation within homologous regions while retaining haplotype-specific structural configuration and CpG content; the other represents CpG island (CGI) variation at homologous loci as sequence-resolved alleles. We identified 47,039 CGI alleles, including 8,040 absent from CHM13; 62% were attributable to structural variants and 31% to small variants. Through local genealogies, we reconstructed CGI gain, loss and turnover, revealing how present-day methylation differences align with CGI evolutionary trajectories. We found that genome-wide, methylation variability was buffered against genetic diversity across more than 90% of the genome, with exceptions at extreme nucleotide diversity and locally around structural variants. Our methylation framework enabled population-scale allele-aware methylation quantitative trait locus (mQTL) mapping into non-reference and structurally complex sequence, where mQTL-associated intervals were enriched. mQTLs linked methylation to transcriptomic phenotypes, population differentiation and complex traits, supporting 8% of population differentially methylated regions and colocalizing with more than half of genome-wide association study loci. Together, our study redefines human methylome analysis and our findings reveal a genome-wide architecture of genetic-epigenetic coupling, reshaping how methylation variation is interpreted across human development and disease.

genetics↗

bioRxiv2026

Human panepigenome represents epigenomic diversity

The human pangenome captures genetic diversity beyond a single linear reference, yet conventional DNA methylome maps largely assume that the underlying CpG substrate is fixed. Here we present a first draft of the human panepigenome on DNA methylation, generated from 440 haplotype-resolved long-read methylomes spanning 26 globally distributed populations. This map jointly captures CpG presence, absence and methylation across diverse human haplotypes, revealing 12.8 million CpGs absent from GRCh38 and an average of 1.2 million variant-associated CpGs (var-CpGs) per methylome. Var-CpGs captured population-associated epigenomic variation beyond that represented by shared reference CpGs, and structural variants could create or remove entire CpG islands, frequently through mobile element insertions. Promoter var-CpG methylation was associated with transcript expression, with most associations persisting after adjustment for the underlying CpG-altering variant, whereas a subset showed evidence of mediation or variant-by-methylation interactions. CpG-altering variants were also enriched among molecular QTLs in HPRC2 and across GTEx tissues, and among clinically and pharmacogenomically annotated loci. Together, these results establish a haplotype-resolved framework in which human epigenomic diversity reflects not only variation in methylation level but also genetic variation in presence or absence of CpG substrates, providing a foundation for panepigenomic studies across tissues, populations and disease contexts.

genomics↗

bioRxiv2026

Fully T2T pedigree assemblies reveal genetic stability and epigenetic plasticity of human centromeres across inheritance and cell-fate transitions

Centromeres are essential chromosome components yet remain poorly understood due to their highly repetitive sequence architecture. Using fully-phased telomere-to-telomere diploid assemblies from a three-generation pedigree integrated with long-read epigenomes from matched peripheral blood mononuclear cells, induced pluripotent stem cells, and neural progenitor cells, we generate allele-resolved single basepair resolution maps of centromere genetic and epigenetic dynamics across inheritance, reprogramming, and differentiation. We show that centromeric dip regions (CDRs), which define the functional core of centromeres, are positionally stable across generations and cell-fate transitions. In contrast, CDR epigenetic architecture is highly dynamic. Reprogramming markedly attenuates CDR hypomethylation, which is partially restored during differentiation in parallel with global hypomethylation of active alpha-satellite arrays and coordinated changes in nucleosome organization and protein occupancy. Centromeric remodeling is insulated from X-chromosome status, including Xa, Xi, and erosion. Finally, de novo mutations arising during reprogramming are enriched in centromeric regions but depleted within functional centromeric cores.

genomics↗

bioRxiv2026

Leveraging Human Pangenome for Improved Somatic Variant Detection

Somatic variant detection is technically challenging due to low variant allele fractions, the confounding presence of germline variation, and reference bias. Linear references such as GRCh38 miss sample-specific variation, causing misalignments and incorrect variant calls. Although telomere-to-telomere donor-specific assemblies (DSAs) accurately represent individual genomes, their application is limited by cost and technical barriers. Alternatively, the graph-based human pangenome provides a scalable framework to improve read alignment and perform genome inference. Here, we benchmarked somatic variant detection using GRCh38, graph-based pangenomes, and pangenome-inferred DSAs with a HapMap mixture dataset and the COLO829 melanoma cell line. Pangenome-guided alignment improves read mapping and somatic variant calling accuracy. Furthermore, personalized pangenomes partially reconstruct donor-specific genomic content, improving accuracy, reducing germline contamination, and enabling detection of events in loci absent or poorly represented in GRCh38. These findings demonstrate that graph-based and personalized pangenomes are effective strategies for enhancing somatic variant detection compared with GRCh38.

genomics↗

bioRxiv2024

Characterizing cytosine methylation of polymorphic human transposable element insertions using human pangenome resources

Cytosine methylation, a crucial epigenetic modification, plays a vital role in genomic regulation. Leveraging the advancements in third-generation sequencing, we investigated the methylation patterns of non-reference insertions of human lymphoblastoid cell lines (LCLs), particularly polymorphic transposable elements (TEs). We validated the high concordance between long-read methylation calls and conventional whole genome bisulfite sequencing (WGBS) method. By characterizing thousands of polymorphic TE insertions genome-wide using long reads from the draft Human Pangenome Reference, we aimed to establish general rules of TE methylation by addressing three key questions: 1) what is the methylation profile of each insertion? 2) do newly inserted TEs adopt the methylation pattern of their genomic context? and 3) do new TE insertions affect the methylation of their flanking regions? While most non-TE insertions exhibit DNA methylation patterns consistent with their genomic context, TE insertions are generally highly methylated, exhibiting distinct, class-specific patterns, and with profound variation within TE bodies. A small percentage of Alu insertions are hypomethylated, particularly those inserted within hypomethylated CpG islands. By comparing DNA methylation of flanking regions of TE insertions between individuals with and without the TE insertions, we revealed that majority of TEs exhibited minimal impact on nearby regions, although numerous exceptions exist where the methylation status of both L1 and Alu insertions "leak" into nearby regions, leading to either methylation spreading or hypomethylation sloping shores. In conclusion, we demonstrated the methylation calling capability of third-generation sequencing and its unique advantage in characterizing epigenomic features within non-reference positions. While TE insertions primarily exhibit methylation patterns restricted within their boundaries, some TEs are able to engage in context-dependent complex interactions with genomic neighborhood.

bioinformatics↗