# SoftGene: Protein Language Model-Enhanced Soft Prompting for Interpretable Gene Set Annotation

arXiv: https://arxiv.org/abs/2610.03029 · HTML: https://mlsanity.com/paper/2610.03029/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 18 of its 72 references that are in the map.
- First posted on arXiv 2 Oct 2026.

## Builds on (most cited first, 18 of 18)

- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
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- [DistilBERT, a distilled version of BERT: smaller, faster, cheaper and lighter](https://mlsanity.com/paper/1910.01108/) (2019)
- [Prefix-Tuning: Optimizing Continuous Prompts for Generation](https://mlsanity.com/paper/2101.00190/) (2021)
- [The Power of Scale for Parameter-Efficient Prompt Tuning](https://mlsanity.com/paper/2104.08691/) (2021)
- [HuggingFace's Transformers: State-of-the-art Natural Language Processing](https://mlsanity.com/paper/1910.03771/) (2019)
- [Gemma 3 Technical Report](https://mlsanity.com/paper/2503.19786/) (2025)
- [Domain-Specific Language Model Pretraining for Biomedical Natural Language Processing](https://mlsanity.com/paper/2007.15779/) (2020)
- [P-Tuning v2: Prompt Tuning Can Be Comparable to Fine-tuning Universally Across Scales and Tasks](https://mlsanity.com/paper/2110.07602/) (2021)
- [BioGPT: Generative Pre-trained Transformer for Biomedical Text Generation and Mining](https://mlsanity.com/paper/2210.10341/) (2022)
- [GeneGPT: Augmenting Large Language Models with Domain Tools for Improved Access to Biomedical Information](https://mlsanity.com/paper/2304.09667/) (2023)
- [InterPLM: Discovering Interpretable Features in Protein Language Models via Sparse Autoencoders](https://mlsanity.com/paper/2412.12101/) (2024)
- [BioReason: Incentivizing Multimodal Biological Reasoning within a DNA-LLM Model](https://mlsanity.com/paper/2505.23579/) (2025)
- [Evaluate & Evaluation on the Hub: Better Best Practices for Data and Model Measurements](https://mlsanity.com/paper/2210.01970/) (2022)
- [Evaluation of large language models for discovery of gene set function](https://mlsanity.com/paper/2309.04019/) (2023)
- [GeneAgent: Self-verification Language Agent for Gene Set Knowledge Discovery using Domain Databases](https://mlsanity.com/paper/2405.16205/) (2024)
- [Gene-R1: Reasoning with Data-Augmented Lightweight LLMs for Gene Set Analysis](https://mlsanity.com/paper/2509.10575/) (2025)

## Abstract (arXiv)

Gene set analysis is a cornerstone of functional genomics, yet it remains labor-intensive and heavily dependent on manual curation and expert biological interpretation. While Large Language Models (LLMs) have emerged as powerful tools for genomic reasoning and annotation, most existing approaches rely on symbolic gene names and fail to capture domain-specific biological structure, particularly protein sequence information that governs molecular activity, interactions, and downstream gene function. In this work, we propose SoftGene, a novel framework for LLM-based gene set annotation that leverages the hierarchical structure of gene sets. First, we use a hierarchical attention-based encoder built on ESM, a protein language model, to represent each gene set using protein-level amino acid sequence information. Second, we construct a hybrid prompting scheme that combines soft prompts derived from gene set embeddings with hard prompts containing auxiliary context generated by an LLM, and feed the resulting prompt into a local LLM for annotation. We evaluate our framework on two benchmark datasets: Gene Ontology (GO) and the Molecular Signatures Database (MSigDB). Our results show that integrating protein-sequence representations with textual context improves gene set annotation overall, while per-domain analyses reveal that the contribution of protein embeddings varies across biological domains.