Andrew B. Stergachis

Detecting low-allele-fraction mosaic mutations: A multi-institution benchmarking with cell-line mixtures.

Mosaic mutations in normal tissues occur at low variant allele fractions (VAFs), complicating detection. To benchmark variant-calling strategies, the SMaHT Network created a cell-line mixture (1:49) and produced ultra-deep short- and long-read whole-genome sequencing data across five centers (170×-470× per center). We...

A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer.

Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their...

A practical guide to studying genome function using single-molecule genomics.

Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes

Approximately 8% of the human genome is derived from ancient retroviral infections. The most recently integrated of these endogenous retroviruses is the HERV-K(HML-2) clade, whose expression has been associated with cancer, amyotrophic lateral sclerosis, and embryogenesis. Studies of HERV expression, particularly HML-2...

Enhancer Tuning by Sequence-Specific Repressors

It is proposed that SNAI1/2 function as a molecular dimmer switch—modulating nucleosome dynamics to calibrate enhancer output to achieve precise spatiotemporal control of transcript dosage.

CHROMATIN SEQUENCING Single-molecule regulatory architectures captured by chromatin fiber sequencing

Fiber-seq exposed widespread plasticity in the linear organization of individual chromatin fibers and illuminated principles guiding regulatory DNA actuation, the coordinated actuation of neighboring regulatory elements, single-molecule nucleosome positioning, and single-molecule transcription factor occupancy.

Inverted logic of ecDNA localization converts nuclear periphery into oncogenic transcription hubs in cancer

It is shown that ecDNAs, in contrast to chromosomal DNA, preferentially localize to the nuclear periphery yet resist peripheral gene silencing, and single-molecule multi-omic sequencing and imaging-based CRISPR screening demonstrate enhanced ecDNA hub formation, H3K27ac and H3K9me3 bivalency, late DNA replication, long...

Integrated map of somatic mosaicism across human tissues in 25 individuals

The first integrated analysis of the Somatic Mosaicism across Human Tissues (SMaHT) Network’s production resource is presented, profiling up to 20 tissues from 25 donors using short- and long-read, duplex, single-cell, transcriptomic, and epigenomic sequencing, alongside donor-specific near-telomere-to-telomere assembl...

A complete diploid human genome benchmark for personalized genomics

A telomere-to-telomere genome benchmark with near-perfect accuracy across 99.4% of the diploid HG002 genome is presented, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.

Abstract B011: Single-molecule protein footprinting with Fiber-seq resolves coordinated chromatin states across regulatory domain

An integrated single-molecule view of regulatory remodeling may support identification of adaptive resistance mechanisms, compensatory regulatory programs, pharmacodynamic biomarkers, and candidate synthetic lethal interactions relevant to epigenetic drug development.

Pangenome discovery and characterization of human protein-coding duplicated genes

The pangenome provides unparalleled specificity to understand genetic variation in SD genes allowing us to distinguish functional genes from pseudogenes and highlighting potential gene innovations that arose most recently in human evolution.