The Genetic and Evolutionary Landscape of Pentanucleotide Tandem Repeats in Human Genomes
Bibliographic record
Abstract
ABSTRACT Tandem repeats are a class of genetic variation characterized by repetitions of DNA motifs of diverse sequences and lengths. Pentameric motifs, in particular, do not align with the protein-coding reading frames, often confining them to the less extensively studied non-coding portion of the genome. Intronic pentanucleotide tandem repeats are associated with 11 neurological disorders. Their pathogenic genotypes are primarily characterized by large length expansion and, unlike most repeat expansion disorders, have required a deviation from the reference motif. The population-level variability of pentameric repeats remains poorly understood due to technical limitations of short-read sequencing technologies. To address this knowledge gap, we genotyped 28,446 pentanucleotide repeat loci in 1,027 long-read PacBio HiFi samples from self-identified Black and African American participants in the All of Us Research Program. We developed new algorithms for tandem repeat decomposition, characterization, and visualization to facilitate this analysis. Our findings reveal extensive genome-wide heterogeneity in repeat length and sequence composition. Alleles with DNA sequences containing segments of distinct motifs were observed in 15% of loci. Additionally, 8% of loci exhibited multimodal repeat length distributions, in which distinct sequence compositions were often associated with distinct length ranges. Repeat loci were highly enriched in proximity to transposable elements, including 68% mapping to Alu elements, a retrotransposon specific to primates. Comparative analysis of the reference sequences from 30 species, including 27 primates, suggests that most pentanucleotide repeats fully emerged in a common ancestor of humans and other ape species, or even within more closely related hominin lineages. As an example, we describe a highly polymorphic and recently evolved repeat locus in the ABCA1 gene, a major regulator of cellular cholesterol and phospholipid homeostasis. This study provides novel and comprehensive insights into the evolutionary formation of pentamer tandem repeat loci and their extensive variability across human genomes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".