Complete genomes of a multi-generational pedigree to expand studies of genetic and epigenetic inheritance

作者：Monika Čechová, Tamara Potapova, Andreas Rechtsteiner, Glenn Hickey, Rebecca Serra Mari, Mira Mastoras, J Menéndez, Nikol Polakova, Prajna Hebbar, Fedor Ryabov, Hailey Loucks, A.C. Gittenberger-de Groot, Tomas Pavlik, Mobin Asri, Shihua Dong, Stephanie M. Yan, Julian Lucas, Steven J. Solar, Matthew Borchers, Mark Mattingly, Sean McKinney, Marie Krátká, Catherine Mikhailova, Ondrej Hanak, Sohinee Tiffany Saha, Emily Xu, Dmitry Antipov, Sergey Koren, Jordan M. Eizenga, Brandy McNulty, Joshua Gardner, Todd Hillaker, Ivo Violich, Christopher Markovic, Semyon Kruglyak, Shawn Levy, Trevor Wolf, Matthew W. Mitchell, Laura Scheinfeldt, Haoyu Cheng, Ivan A. Alexandrov, Rajiv C. McCoy, Benedict Paten, Adam M. Phillippy, Justin M. Zook, Jennifer L. Gerton, Robert S. Fulton, Nathan O. Stitziel, Ting Wang, Tobias Marschall, Carol W. Greider, Karen H. Miga · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.64898/2025.12.14.693655 · 被引用次数：4 · 研究领域：Genomic variations and chromosomal abnormalities、Chromosomal and Genetic Variations、Genomics and Phylogenetic Studies

Pedigree analysis remains the gold standard for rare disease diagnostics, yet whole genome sequencing studies typically omit critical regions like centromeres, telomeres, and acrocentric chromosome p-arms. Here, we present telomere-to-telomere (T2T) reference genomes for four self-identified African American individuals of admixed ancestry spanning three generations. Our parent-of-origin assigned, chromosome-level assemblies revealed precise meiotic recombination breakpoints in previously inaccessible regions, including recombination events across acrocentric and subtelomeric sequences. Centromeric regions were highly stable, with multi-megabase arrays inherited intact across three generations, while the position of kinetochore assembly sites remained consistent and predominantly associated with the p-arm proximal region. The relative lengths of telomeres on individual chromosomes were maintained across generations. Using a targeted rDNA assembly approach, we reconstructed a complete megabase-scale ribosomal DNA (rDNA) array corresponding to the paternal chromosome 14. This openly available pedigree provides a benchmark dataset for studying recombination and genetic and epigenetic variation across the complete genome.