Biomedical subjects

Andrea Guarracino

Publications and source records attributed to Andrea Guarracino.

5 recordsLinked to original sources

PubMed2026

COSIGT: population-scalable genotyping of complex loci from low-coverage sequencing data using pangenome graphs.

Pangenome graphs capture extensive structural diversity, but resolving complex loci from shallow sequencing remains challenging, particularly when samples are of low quality such as in ancient DNA. We introduce COSIGT (COsine SImilarity-based GenoTyper), which assigns diploid genotypes by matching read-depth distributions to haplotype paths via cosine similarity. Because this metric evaluates relative coverage profiles rather than absolute read counts, COSIGT substantially outperforms existing likelihood-based tools at low coverage (1-2X). We demonstrate scalability to thousands of modern and ancient genomes, enabling robust, population-scale analyses of complex variation directly from low-coverage datasets.

Humans↗

PubMed2026

HPRC2: A human pangenome reference with near-complete coverage of common genetic variation.

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortium's (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

Journal Article↗

PubMed2025

Chromosome-specific epigenetic control and transmission of ribosomal DNA arrays in Hominidae genomes.

Ribosomal RNA (rRNA) genes are organized in tandem arrays known as ribosomal DNA (rDNA) on multiple chromosomes in Hominidae genomes. We measured copy number and transcriptional activity status of rRNA gene arrays across multiple individual genomes, revealing an identifiable fingerprint of rDNA copy number and activity. In some cases, entire arrays were transcriptionally silent, characterized by high DNA methylation across the rRNA gene, inaccessible chromatin, and the absence of transcription factors and transcripts. Silent arrays showed reduced association with the nucleolus and decreased interchromosomal interactions, consistent with the model that nucleolar organizer function depends on transcriptional activity. Removing rDNA methylation activated silent arrays. Array activity status remained stable through induced pluripotent stem cell reprogramming and differentiation into cerebral and intestinal organoids. Haplotype tracing in two unrelated family trios showed paternal transmission of silent arrays. We propose that the epigenetic state buffers rRNA gene dosage, specifies nucleolar organizer function, and can propagate transgenerationally.

Epigenesis, Genetic↗

PubMed2025

A complete diploid human genome benchmark for personalized genomics.

Human genome resequencing typically involves mapping reads to a reference genome to call variants; however, this approach suffers from both technical and reference biases, leaving many duplicated and structurally polymorphic regions of the genome unmapped. Consequently, existing variant benchmarks, generated by the same methods, fail to assess these complex regions. To address this limitation, we present a telomere-to-telomere genome benchmark that achieves near-perfect accuracy (i.e. no detectable errors) across 99.4% of the complete, diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), totaling 15.3% of the genome that was absent from prior benchmarks. We also provide a diploid annotation of genes, transposable elements, segmental duplications, and satellite repeats, including 39,144 protein-coding genes across both haplotypes. To facilitate application of the benchmark, we developed tools for measuring the accuracy of sequencing reads, phased variant call sets, and genome assemblies against a diploid reference. Genome-wide analyses show that state-of-the-art de novo assembly methods resolve 2-7% more sequence and outperform variant calling accuracy by an order of magnitude, yielding just one error per 100 kb across 99.9% of the benchmark regions. Adoption of genome-based benchmarking is expected to accelerate the development of cost-effective methods for complete genome sequencing, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.

Journal Article↗

PubMed2025

The reference genome of the human diploid cell line RPE-1.

Recent technological advances have facilitated the assembly of telomere-to-telomere (T2T) genomes. The current T2T CHM13 showcases the complete architecture of the human genome, yet its use in functional experiments is limited by discrepancies with the actual genome of the specific biological system under study. Access to reference assemblies for experimentally relevant cell lines is therefore essential in advancing sequencing-based analyses and precise manipulation, particularly in highly variable regions such as centromeres. Here, we present RPE1v1.1, the near-complete diploid genome assembly of the hTERT RPE-1 cell line, a non-cancerous human retinal epithelial model with a stable karyotype. Using high-coverage Pacific Biosciences and Oxford Nanopore Technologies long-read sequencing, we generate a high-quality de novo assembly, validate it through multiple methods, and phase it by integrating high-throughput chromosome conformation capture (Hi-C) data. Our assembly includes chromosome-level scaffolds that span centromeres for all chromosomes. Comparing both haplotypes with the CHM13 genome, we detect haplotype-specific genomic variations, including the translocation between chromosome 10 and chromosome X t(X;10)(Xq28;10q21.2) characteristic of RPE-1 cells, and divergence peaking at centromeres. Altogether, the RPE1v1.1 genome provides a reference-quality diploid assembly of a widely used cell line, supporting high-precision genetic and epigenetic studies in this model system.

Humans↗