Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tanudisastro, H. A.; Cuomo, A. S. E.; Weisburd, B.; Welland, M.; Spenceley, E.; Franklin, M.; Xue, A.; Bowen, B.; Wing, K.; Tang, O.; Gray, M.; Reis, A. L. M.; Margoliash, J.; Kurtas, E. N.; Pullin, J.; Lee, A. S.; Brand, H.; Harper, M.; Bobowik, K.; Silk, M.; Marshall, J.; Bakiris, V.; Swapna Madala, B.; Uren, C.; Bartie, C.; Senabouth, A.; Dashnow, H.; Fearnley, L.; Dolzhenko, E.; Qiao, Z.; Grieve, S.; Nguyen, T.; Talkowski, M.; Alexander, S. I.; Siggs, O. M.; Gruenschloss, L.; Nicholas, H. R.; Piscionere, J.; Simons, C.; Wallace, C.; Gymrek, M.; Deveson, I. W.; Hewitt, A. W.; Figtree, G. A.

doi:10.1101/2024.11.02.621562

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bioRxiv · 10.1101/2024.11.02.621562

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

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Abstract

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

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Tanudisastro, H. A., Cuomo, A. S. E., Weisburd, B., Welland, M., Spenceley, E., Franklin, M., Xue, A., Bowen, B., Wing, K., Tang, O., Gray, M., Reis, A. L. M., Margoliash, J., Kurtas, E. N., Pullin, J., Lee, A. S., Brand, H., Harper, M., Bobowik, K., Silk, M., Marshall, J., Bakiris, V., Swapna Madala, B., Uren, C., Bartie, C., Senabouth, A., Dashnow, H., Fearnley, L., Dolzhenko, E., Qiao, Z., Grieve, S., Nguyen, T., Talkowski, M., Alexander, S. I., Siggs, O. M., Gruenschloss, L., Nicholas, H. R., Piscionere, J., Simons, C., Wallace, C., Gymrek, M., Deveson, I. W., Hewitt, A. W., Figtree, G. A.. 2024-11-04. Polymorphic tandem repeats shape single-cell gene expression across the immune landscape. https://doi.org/10.1101/2024.11.02.621562

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