Genomic foundation models

genomic-foundation-models

When to Use

• Deciding which DNA/RNA foundation model fits a task: embeddings vs. regulatory-track prediction vs. splice scoring vs. sequence design.
• Extracting sequence embeddings (Nucleotide Transformer, DNABERT-2, HyenaDNA) for downstream classifiers (promoter/enhancer/splice-site).
• Fine-tuning a genomic LLM for a binary/multi-class sequence classification task.
• Running Enformer for multi-track regulatory prediction or in-silico mutagenesis (ISM) variant-effect scoring.
• Routing a coding variant onward to a protein structure model (AlphaFold2/3, RoseTTAFold) once sequence-level scoring is done.

Version Compatibility

transformers >=4.40, torch >=2.1, enformer-pytorch >=0.8, Python >=3.10. Nucleotide Transformer checkpoints live under InstaDeepAI/ on the HF Hub; Enformer via the community PyTorch port EleutherAI/enformer-official-rough (DeepMind's original is TensorFlow/Sonnet, on GitHub). HyenaDNA and Evo ship their own HF-compatible repos (LongSafari/hyenadna-*, togethercomputer/evo-1-*).

Prerequisites

pip install transformers torch enformer-pytorch accelerate

GPU guidance: T4 (16 GB) is enough for NT-500M or DNABERT-2; NT-2.5B and Evo-7B need an A100-class GPU (~40 GB) or model.half() + gradient checkpointing. Enformer/SpliceAI inference on short windows runs fine on CPU. Familiarity with the HF AutoModel/Trainer API is assumed.

Model Landscape

Model	Context	Best For
DNABERT-2	~3 kbp (BPE tokens)	Short-window classification (promoter/enhancer/splice)
Nucleotide Transformer	kb-scale (6-mer tokens)	Transfer learning across species
HyenaDNA	up to 1M bp	Distal regulatory context
Evo	~100 kb+	Prokaryotic sequence design (autoregressive)
Enformer	196,608 bp	Multi-track regulatory signal (5,313 tracks, 128 bp bins)
Borzoi	524 kb	RNA-seq coverage at 32 bp bins
SpliceAI	local window	Clinical splice variant delta scores (DS_AG/AL/DG/DL)
AlphaGenome	up to 1M bp	Unified variant effect (expression + splicing + chromatin + contacts)

Routing: general embeddings -> DNABERT-2 / NT / HyenaDNA. Regulatory track prediction -> Enformer / Borzoi / AlphaGenome. Splice-specific scoring -> SpliceAI. Sequence design -> Evo. Coding variants with a structural hypothesis -> hand off to AlphaFold2/3 or RoseTTAFold (see bio-structural-biology-modern-structure-prediction).

1. Extract Sequence Embeddings

Goal: turn raw DNA strings into fixed-length vectors for a downstream classifier or similarity search. Approach: tokenize with the model's native scheme (NT uses overlapping 6-mers), forward-pass with no grad, mean-pool over the token dimension.

from transformers import AutoTokenizer, AutoModel
import torch


def embed_sequences(sequences: list[str], model_name: str = "InstaDeepAI/nucleotide-transformer-v2-500m-multi-species",
                     max_length: int = 512) -> "torch.Tensor":
    """Mean-pooled per-sequence embeddings from a genomic foundation model.

    Returns a (n_sequences, hidden_dim) tensor, e.g. (n, 1024) for NT-500M.
    """
    tokenizer = AutoTokenizer.from_pretrained(model_name)
    model = AutoModel.from_pretrained(model_name).eval()

    inputs = tokenizer(sequences, return_tensors="pt", padding=True,
                       truncation=True, max_length=max_length)
    with torch.no_grad():
        outputs = model(**inputs)

    # Per-residue (token-level) embeddings are outputs.last_hidden_state
    # (n_sequences, seq_len_tokens, hidden_dim) -- use that instead for per-base tasks.
    return outputs.last_hidden_state.mean(dim=1)

2. Fine-Tune for Sequence Classification

Goal: adapt a pretrained genomic LLM to a labeled task (e.g. promoter vs. non-promoter, splice-site usage). Approach: swap in a classification head (AutoModelForSequenceClassification) and fine-tune with the HF Trainer; freeze the backbone first if the label set is small (<1k examples) to avoid overfitting.

from transformers import AutoModelForSequenceClassification, AutoTokenizer, TrainingArguments, Trainer


def build_classifier_trainer(model_name: str, tokenized_dataset, num_labels: int = 2,
                              output_dir: str = "./finetuned") -> Trainer:
    """Configure a Trainer for fine-tuning a genomic LLM classification head.

    tokenized_dataset must already contain input_ids/attention_mask/labels
    (produced by AutoTokenizer(...) over your sequences).
    """
    model = AutoModelForSequenceClassification.from_pretrained(model_name, num_labels=num_labels)
    args = TrainingArguments(
        output_dir=output_dir,
        per_device_train_batch_size=8,
        num_train_epochs=3,
        learning_rate=1e-4,
        eval_strategy="epoch",
        fp16=True,
    )
    return Trainer(model=model, args=args, train_dataset=tokenized_dataset)

3. Enformer: Regulatory Tracks + In-Silico Mutagenesis

Goal: predict 5,313 regulatory tracks (CAGE, DNase, ChIP-seq) from a 196,608 bp window and score a single-base variant's effect on one track. Approach: one-hot encode the exact-length window, run reference vs. mutated sequence, take the delta at the track/bin of interest (bin 448 is the window center at 128 bp resolution).

from enformer_pytorch import from_pretrained
import torch


def one_hot_encode(seq: str) -> torch.Tensor:
    """One-hot encode an ACGT string to shape (1, len(seq), 4); ambiguous bases -> 0.25 each."""
    mapping = {"A": [1, 0, 0, 0], "C": [0, 1, 0, 0], "G": [0, 0, 1, 0], "T": [0, 0, 0, 1]}
    return torch.tensor([[mapping.get(b, [0.25] * 4) for b in seq.upper()]], dtype=torch.float32)


def ism_score(model, ref_one_hot: torch.Tensor, center_pos: int = 196608 // 2,
              target_track: int = 4799) -> list[float]:
    """In-silico mutagenesis: delta of a target track for each possible base at center_pos.

    Returns [delta_A, delta_C, delta_G, delta_T] relative to the reference prediction.
    """
    with torch.no_grad():
        baseline = model(ref_one_hot)["human"][0, 448, target_track].item()
        deltas = []
        for alt_idx in range(4):
            mut = ref_one_hot.clone()
            mut[0, center_pos, :] = 0
            mut[0, center_pos, alt_idx] = 1
            pred = model(mut)["human"][0, 448, target_track].item()
            deltas.append(pred - baseline)
    return deltas


model = from_pretrained("EleutherAI/enformer-official-rough", target_length=-1).eval()
#NB: window must be exactly 196,608 bp; pad/extract from a reference genome with pysam.FastaFile.

Pitfalls

• Context length: NT 6-mers with 512 tokens covers only ~3 kbp; use HyenaDNA/Borzoi/AlphaGenome for distal regulatory interactions beyond that.
• Tokenization mismatch: DNABERT-2 uses BPE, NT uses overlapping 6-mers — embeddings from different models are not directly comparable.
• Enformer input: requires exactly 196,608 bp; a mismatched window silently reshapes or errors depending on the port.
• GPU memory: NT-2.5B/Evo-7B need ~40 GB; use model.half() or a smaller checkpoint before assuming OOM means "add more data."
• Species/checkpoint fit: NT-multi-species (850 species) vs. NT-human — pick the checkpoint matching your organism.
• Gain vs. loss splice deltas: SpliceAI's DS_AG/DS_DG (new site) are harder to interpret than DS_AL/DS_DL (weakened known site) — don't treat all four scores as equivalent.
• Modality confusion: Enformer/Borzoi/AlphaGenome are regulatory-genomics models; AlphaFold/RoseTTAFold predict protein structure — a high ISM delta does not imply anything about protein folding.
• eQTL validation: correlating model output with GTEx-style eQTLs only tests population-level directionality, not per-individual expression prediction (Sasse et al. 2023).

See Also

• ai-science-genomic-llms — deeper NT/HyenaDNA/Evo embedding and k-mer tokenization walkthrough.
• ai-science-epigenomic-sequence-models — Borzoi vs. Epiformer vs. AlphaGenome selection for RNA-seq/accessibility.
• ai-science-variant-to-structure-models — triage variant scores into AlphaFold2/3 or RoseTTAFold structural follow-up.
• bio-structural-biology-modern-structure-prediction — run AlphaFold2/3/RoseTTAFold once a coding variant needs structural interpretation.