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

Cechova, M.; Potapova, T. A.; Rechtsteiner, A.; Hickey, G.; Mari, R. S.; Mastoras, M.; Menendez, J.; Polakova, N.; Hebbar, P.; Ryabov, F.; Loucks, H.; Groot, A.; Pavlik, T.; Asri, M.; Dong, S.; Yan, S. M.; Lucas, J. K.; Solar, S. J.; Borchers, M.; Mattingly, M.; McKinney, S.; Kratka, M.; Mikhailova, C.; Hanak, O.; Saha, S. T.; Xu, E.; Antipov, D.; Koren, S.; Eizenga, J. M.; McNulty, B.; Gardner, J. M. V.; Hillaker, T.; Violich, I.; Markovic, C.; Kruglyak, S.; Levy, S.; Wolf, T. H.; Mitchell, M. W.; Scheinfeldt, L.; Cheng, H.; Alexandrov, I. A.; McCoy, R. C.; Paten, B.; Phillippy, A. M.; Zook,

doi:10.64898/2025.12.14.693655

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bioRxiv · 10.64898/2025.12.14.693655

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

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Abstract

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.

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Cechova, M., Potapova, T. A., Rechtsteiner, A., Hickey, G., Mari, R. S., Mastoras, M., Menendez, J., Polakova, N., Hebbar, P., Ryabov, F., Loucks, H., Groot, A., Pavlik, T., Asri, M., Dong, S., Yan, S. M., Lucas, J. K., Solar, S. J., Borchers, M., Mattingly, M., McKinney, S., Kratka, M., Mikhailova, C., Hanak, O., Saha, S. T., Xu, E., Antipov, D., Koren, S., Eizenga, J. M., McNulty, B., Gardner, J. M. V., Hillaker, T., Violich, I., Markovic, C., Kruglyak, S., Levy, S., Wolf, T. H., Mitchell, M. W., Scheinfeldt, L., Cheng, H., Alexandrov, I. A., McCoy, R. C., Paten, B., Phillippy, A. M., Zook,. 2025-12-16. Complete genomes of a multi-generational pedigree to expand studies of genetic and epigenetic inheritance. https://doi.org/10.64898/2025.12.14.693655

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