Tandem repeat variation within and between species reveals signatures of selection in humans and chimpanzees

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Abstract
Tandem repeats (TRs) are highly mutable DNA elements that influence gene regulation 1 , protein structure 2 , and disease 3 . Until recently, their repetitive nature has hindered accurate TR sequencing and genotyping, resulting in sparse comparative data across species. In addition, we lack population-aware approaches to analyze TR conservation, divergence, and mutational dynamics. Here, leveraging telomere-to-telomere primate genomes and long-read data from 46 humans and 23 chimpanzees, we constructed a catalog of homologous TR loci, and developed an analytical framework to jointly analyze TR variation within- and between-species. Across primates, TR diversity and conservation vary strongly with genomic context, with coding and 5’ UTR TRs exhibiting reduced polymorphism and constraint across species, consistent with stabilizing selection. Yet, while TRs are depleted in coding sequence, they are enriched in 5’ UTRs, suggesting functional roles that outweighs mutational risks. TR heterozygosity varies across motif lengths and is concordant with both evolutionary and trio-based mutation rate estimates 4 . Introducing an HKA-like approach to control for locus-specific mutation rates, we identified TRs with signatures of directional and balancing selection. These candidates are significantly enriched in genes involved in nervous system development and synaptic function, highlighting TRs as potential contributors to neural evolution. Further, TR divergence correlates with gene expression divergence, particularly for promoter-related TRs and expression in organoids related to neurodevelopment, implicating a subset of regulatory TRs as candidates for adaptive expression evolution. Finally, trait-associated TRs display longer alleles and higher diversity in humans compared to chimpanzees, consistent with lineage-specific runaway mutations and/or directional selection 5 . Together, our results establish a comparative framework for TR evolutionary analyses, revealing how mutational processes and selection jointly shape repeat variation, and supporting their role as both conserved functional elements and as drivers of evolutionary innovation.

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