Non-adaptive evolutionary forces predominantly shape nucleotide composition near human transcription start sites
- 1Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- 2Laboratoire Interdisciplinaire des Sciences du Numérique, Université Paris-Saclay, Gif-sur-Yvette, France
- 3Institut Agro, Rennes Angers, Rennes, France
Abstract
In the human genome, mutation rates vary along genes, yet how their fine-scale structure contributes to gene evolution has remained largely unexplored. Here, we map inherited mutations at single-nucleotide resolution and uncover a striking hypermutation peak at transcription start sites (TSSs) of human protein-coding genes. This pattern is observed both in population polymorphisms and in de novo mutations from parent-offspring trios, and is dependent on transcriptional activity in testes. We also find similar hypermutation peaks at TSSs used to produce long noncoding RNAs and at intergenic RNA Polymerase II pause sites. In addition, we identify distinct mutational signatures at exon-intron boundaries and in introns. By comparing the current nucleotide content to predicted equilibrium levels, inferred from mutation and fixation rates, and by analyzing derived ancestral frequency spectrums, we detect signals that are compatible with a low level of ongoing background GC-biased gene conversion (gBGC) throughout the region and ancestral elevated gBGC activity that is centered right downstream from the TSS. Using a forward-in-time simulation algorithm, we show that the current nucleotide composition surrounding the TSS of protein-coding genes is best explained by local mutation biases coupled to ongoing and ancestral patterns of gene conversions. Our simulations allow us to infer several features of these gBGC events. Overall, these findings indicate that the nucleotide composition around TSSs is largely shaped by non-adaptive forces, particularly mutation bias and gBGC.
Mutation rates vary across human genes, but how fine scale mutational patterns influence gene evolution is poorly understood. This study shows that hypermutation at transcription start sites, together with mutation bias and GC-biased gene conversion, largely shapes nucleotide composition through nonadaptive evolutionary processes.
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BibTeX
@article{qiu2026nonadaptive,
title = {{Non-adaptive evolutionary forces predominantly shape nucleotide composition near human transcription start sites}},
author = {Yi Qiu and Emilie Hebraud and Fanny Pouyet and Alexander F. Palazzo},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3004063},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004063},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Non-adaptive evolutionary forces predominantly shape nucleotide composition near human transcription start sites
AU - Yi Qiu
AU - Emilie Hebraud
AU - Fanny Pouyet
AU - Alexander F. Palazzo
PY - 2026
DA - 2026/10/21
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004063
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004063
AB - In the human genome, mutation rates vary along genes, yet how their fine-scale structure contributes to gene evolution has remained largely unexplored. Here, we map inherited mutations at single-nucleotide resolution and uncover a striking hypermutation peak at transcription start sites (TSSs) of human protein-coding genes. This pattern is observed both in population polymorphisms and in de novo mutations from parent-offspring trios, and is dependent on transcriptional activity in testes. We also find similar hypermutation peaks at TSSs used to produce long noncoding RNAs and at intergenic RNA Polymerase II pause sites. In addition, we identify distinct mutational signatures at exon-intron boundaries and in introns. By comparing the current nucleotide content to predicted equilibrium levels, inferred from mutation and fixation rates, and by analyzing derived ancestral frequency spectrums, we detect signals that are compatible with a low level of ongoing background GC-biased gene conversion (gBGC) throughout the region and ancestral elevated gBGC activity that is centered right downstream from the TSS. Using a forward-in-time simulation algorithm, we show that the current nucleotide composition surrounding the TSS of protein-coding genes is best explained by local mutation biases coupled to ongoing and ancestral patterns of gene conversions. Our simulations allow us to infer several features of these gBGC events. Overall, these findings indicate that the nucleotide composition around TSSs is largely shaped by non-adaptive forces, particularly mutation bias and gBGC. Mutation rates vary across human genes, but how fine scale mutational patterns influence gene evolution is poorly understood. This study shows that hypermutation at transcription start sites, together with mutation bias and GC-biased gene conversion, largely shapes nucleotide composition through nonadaptive evolutionary processes.
SN - 1545-7885
SN - 1544-9173
ER -