Genetic Variation at Transcription Factor Binding Sites Largely Explains Phenotypic Heritability in Maize

Authors

Julia Engelhorn, Heinrich-Heine-Universitat Dusseldorf and University of Montpellier
Samantha J. Snodgrass, Iowa State University
Amelie Kok, Heinrich-Heine-Universitat Dusseldorf
Arun S. Seetharam, Iowa State University
Michael Schneider, Heinrich-Heine-Universitat Dusseldorf
Tatjana Kiwit, Heinrich-Heine-Universitat Dusseldorf
Ayush Singh, South Florida State College
Michael Banf, Perelyn, Munich, Germany
Duong Thi Hai Doan, Heinrich-Heine-Universitat Dusseldorf
Merritt Khaipho-Burch, Cornell University
Daniel E. Runcie, University of California, Davis
Victor A, Sánchez-Camargo, University of Amsterdam
Rechien Bader, University of Amsterdam
J. Vladimir Torres-Rodriguez, University of Nebraska-Lincoln
Guangchao Sun, Sichuan Agricultural University
Maike Stam, University of Amsterdam
Fabio Fiorani, Forschungszentrum Jülich
Sebastian Beier, Forschungszentrum Jülich
James C. Schnable, University of Nebraska-Lincoln
Hank W. Bass, Florida State University
Matthew B. Hufford, Iowa State University
Benjamin Stich, Heinrich-Heine-Universitat Dusseldorf
Wolf B. Frommer, Heinrich-Heine-Universitat Dusseldorf and Nagoya University
Jeffrey Ross-Ibarra, University of California, Davis
Thomas Hartwig, Heinrich-Heine-Universitat DusseldorfFollow

ORCID IDs

Engelhorn https://orcid.org/0000-0002-6680-3012

Snodgrass https://orcid.org/0000-0001-9209-6051

 Kok https://orcid.org/0009-0009-5930-5232

Seetharam https://orcid.org/0000-0002-6789-9298

Schneider https://orcid.org/0000-0002-6491-8852

Singh https://orcid.org/0000-0003-0184-4486

Runcie https://orcid.org/0000-0002-3008-9312

Sánchez-Camargo https://orcid.org/0000-0002-7184-0301

Bader https://orcid.org/0009-0001-4738-190X

Sun https://orcid.org/0000-0003-3942-6175

Stam https://orcid.org/0000-0003-0363-4677

Fiorani https://orcid.org/0000-0001-8775-1541

Beier https://orcid.org/0000-0002-2177-8781

Schnable https://orcid.org/0000-0001-6739-5527

Bass https://orcid.org/0000-0003-0522-0881

Hufford https://orcid.org/0000-0003-3945-1143

Stich https://orcid.org/0000-0001-6791-8068

Frommer https://orcid.org/0000-0001-6465-0115

Ross-Ibarra https://orcid.org/0000-0003-1656-4954

Hartwig https://orcid.org/0000-0002-2707-2771

Document Type

Article

Date of this Version

2025

Citation

Nature Genetics (2025) 57(9): 2313–2322

doi: 10.1038/s41588-025-02246-7

Comments

Open access

License: CC BY 4.0 International

Abstract

Comprehensive maps of functional variation at transcription factor (TF) binding sites (cis-elements) are crucial for elucidating how genotype shapes phenotype. Here, we report the construction of a pan-cistrome of the maize leaf under well-watered and drought conditions. We quantified haplotype-specific TF footprints across a pan-genome of 25 maize hybrids and mapped over 200,000 variants, genetic, epigenetic, or both (termed binding quantitative trait loci (bQTL)), linked to cis-element occupancy. Three lines of evidence support the functional significance of bQTL: (1) coincidence with causative loci that regulate traits, including vgt1, ZmTRE1 and the MITE transposon near ZmNAC111 under drought; (2) bQTL allelic bias is shared between inbred parents and matches chromatin immunoprecipitation sequencing results; and (3) partitioning genetic variation across genomic regions demonstrates that bQTL capture the majority of heritable trait variation across ~72% of 143 phenotypes. Our study provides an auspicious approach to make functional cis-variation accessible at scale for genetic studies and targeted engineering of complex traits.