Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity

Danzi, M. C.; Xu, I. R. L.; Fazal, S.; Dolzhenko, E.; Pellerin, D.; Weisburd, B.; Reuter, C.; Sampson, J.; Folland, C.; Wheeler, M. T.; O'Donnell-Luria, A.; Wuchty, S.; Ravenscroft, G.; Eberle, M. A.; All of Us Research Program Long Read Working Group,; Zuchner, S.

doi:10.1101/2025.01.06.631535

bioRxiv · 10.1101/2025.01.06.631535

Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity

Danzi, M. C.·Xu, I. R. L.·Fazal, S.·Dolzhenko, E.·Pellerin, D.·Weisburd, B.·Reuter, C.·Sampson, J.·Folland, C.·Wheeler, M. T.·O'Donnell-Luria, A.·Wuchty, S.·Ravenscroft, G.·Eberle, M. A.·All of Us Research Program Long Read Working Group,·Zuchner, S.

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Abstract

Short tandem repeat (STR) instability is a major cause of disease association, yet their full length-distributions and sequence content have been difficult to resolve with short-read sequencing. By analyzing long-read sequencing genomes from 2,645 participants of the All of Us Research Program, we establish a comprehensive STR resource of 23 billion alleles covering a catalog of 4.4 million loci. We find that known disease-associated STR loci exhibit markedly elevated allelic variability relative to genome-wide distributions, which is most pronounced when based on the length of uninterrupted, pure repeat motifs (Odds Ratio: 244, p=1.62e-29). We establish the Pure Length Variability Index (PLVI) as a measure of this instability, which is robust across ancestries and replicated in 500 samples from the 1000 Genomes Project (Odds Ratio: 84, p=2.72e-28). To illustrate, we identify 55 unstable coding CAG and 5-UTR CGG STR loci with this metric, 60% of which have not been associated with disease. From this set, we document potential pathogenic repeat expansions for FAM193B and EP400 by integrating PLVI with single-genome length outlier analysis. These data establish a population-scale framework for STR discovery in rare and common diseases using long-read sequencing cohorts.

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Danzi, M. C., Xu, I. R. L., Fazal, S., Dolzhenko, E., Pellerin, D., Weisburd, B., Reuter, C., Sampson, J., Folland, C., Wheeler, M. T., O'Donnell-Luria, A., Wuchty, S., Ravenscroft, G., Eberle, M. A., All of Us Research Program Long Read Working Group,, Zuchner, S.. 2025-01-07. Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity. https://doi.org/10.1101/2025.01.06.631535

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