Mendel, a foundation model of human genetic variation, prioritizes regulatory variants and improves gene expression prediction
- 1The University of Texas MD Anderson Cancer Center
Abstract
Human genome-wide association studies have identified hundreds of thousands of variant trait associations, but interpreting their mechanistic consequences at allele resolution remains a central bottleneck. DNA foundation models pretrained on genomic sequence corpora learn features predictive of regulatory activity, yet their training objectives are dominated by the conserved background common to all individuals, rather than the sparse variant sites at which human genetic variation is concentrated. Here we introduce Mendel, a DNA foundation model trained from scratch on human whole genome sequences using a variant-centric objective that concentrates supervision on allelic events within reference aligned sequence context. On held-out individuals, Mendel attains 0.984 micro-averaged SNV allele-prediction accuracy, compared with 0.311 for Evo 2. Mendel residual difficulty is selectively enriched at cis-eQTL variants, prioritizes fine-mapped causal variants (AUROC 0.731), where Evo 2 residuals performed near chance, and when converted into a cis-expression prior for modelling, improves prediction relative to an unweighted baseline in all 50 GTEx tissues.
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BibTeX
@misc{salman2026mendel,
title = {{Mendel, a foundation model of human genetic variation, prioritizes regulatory variants and improves gene expression prediction}},
author = {A. Salman and H. Feng and P. Wei and R. Sun and L. Wu and W. Pan and C. Wu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755183},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755183v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mendel, a foundation model of human genetic variation, prioritizes regulatory variants and improves gene expression prediction
AU - A. Salman
AU - H. Feng
AU - P. Wei
AU - R. Sun
AU - L. Wu
AU - W. Pan
AU - C. Wu
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755183
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755183v1
AB - Human genome-wide association studies have identified hundreds of thousands of variant trait associations, but interpreting their mechanistic consequences at allele resolution remains a central bottleneck. DNA foundation models pretrained on genomic sequence corpora learn features predictive of regulatory activity, yet their training objectives are dominated by the conserved background common to all individuals, rather than the sparse variant sites at which human genetic variation is concentrated. Here we introduce Mendel, a DNA foundation model trained from scratch on human whole genome sequences using a variant-centric objective that concentrates supervision on allelic events within reference aligned sequence context. On held-out individuals, Mendel attains 0.984 micro-averaged SNV allele-prediction accuracy, compared with 0.311 for Evo 2. Mendel residual difficulty is selectively enriched at cis-eQTL variants, prioritizes fine-mapped causal variants (AUROC 0.731), where Evo 2 residuals performed near chance, and when converted into a cis-expression prior for modelling, improves prediction relative to an unweighted baseline in all 50 GTEx tissues.
ER -