您的 DNA 包含 30 億個字母。一個字母的變異可能會導致癌症或使藥物失效。人工智慧現在可以在幾個小時內讀取整個基因組。
1. 基因組學 AI — 概述
Sequencing data (FASTQ)
↓
Alignment (BWA, STAR)
↓
Variant Calling (GATK, DeepVariant)
↓
Annotation (ANNOVAR, VEP)
↓
Interpretation (AI + clinical knowledge)
↓
Clinical Decision (pharmacogenomics, cancer typing)
人工智慧在基因組學中的 3 個主要應用：
- 變體調用：DeepVariant (Google) — 基於 CNN，優於 GATK
- 功能註釋：預測變異對蛋白質功能的影響
- 癌症基因組學：腫瘤突變負荷、MSI、HRD 評分
2. 使用深度學習處理 DNA 序列
import torch
import torch.nn as nn
import numpy as np
# One-hot encode DNA sequences
DNA_VOCAB = {'A': 0, 'T': 1, 'G': 2, 'C': 3, 'N': 4} # N = unknown
def encode_dna(sequence: str, max_len: int = 1000) -> torch.Tensor:
"""
One-hot encode DNA sequence.
'ATGC' → (4, L) tensor (4 nucleotides × sequence length)
"""
seq = sequence.upper()[:max_len]
# Pad if shorter
seq = seq.ljust(max_len, 'N')
encoding = torch.zeros(5, max_len, dtype=torch.float32)
for i, base in enumerate(seq):
idx = DNA_VOCAB.get(base, 4) # N for unknown
encoding[idx, i] = 1.0
return encoding[:4] # Remove N channel (model handles it as 0)
class DNAConvNet(nn.Module):
"""
CNN cho DNA sequence classification.
Ứng dụng: promoter region prediction, splice site detection,
transcription factor binding site prediction.
ENCODE project: annotate 80% của human genome với regulatory elements.
"""
def __init__(self, n_classes: int = 2, seq_len: int = 1000):
super().__init__()
# First conv: detect short motifs (k-mers ~6-10 bp)
self.conv1 = nn.Conv1d(4, 320, kernel_size=8, padding=4)
self.pool1 = nn.MaxPool1d(4)
# Second conv: combine motifs → patterns
self.conv2 = nn.Conv1d(320, 480, kernel_size=8, padding=4)
self.pool2 = nn.MaxPool1d(4)
# Third conv: higher-order structure
self.conv3 = nn.Conv1d(480, 960, kernel_size=8, padding=4)
self.dropout1 = nn.Dropout(0.2)
self.dropout2 = nn.Dropout(0.5)
self.global_pool = nn.AdaptiveAvgPool1d(1)
self.classifier = nn.Sequential(
nn.Linear(960, 925),
nn.ReLU(),
nn.Dropout(0.5),
nn.Linear(925, n_classes)
)
def forward(self, x: torch.Tensor) -> torch.Tensor:
"""x: (batch, 4, seq_len)"""
x = torch.relu(self.conv1(x))
x = self.pool1(x)
x = self.dropout1(x)
x = torch.relu(self.conv2(x))
x = self.pool2(x)
x = self.dropout1(x)
x = torch.relu(self.conv3(x))
x = self.dropout2(x)
x = self.global_pool(x).squeeze(-1)
return self.classifier(x)
3. 變異效應預測
def predict_variant_effect(
wild_type_seq: str,
mutant_seq: str,
model: DNAConvNet,
context_window: int = 500
) -> dict:
"""
Predict functional effect của SNP/indel.
So sánh model score của wild-type vs mutant sequence.
Inspired by: DeepSEA, Enformer (DeepMind)
"""
wt_encoded = encode_dna(wild_type_seq, max_len=context_window).unsqueeze(0)
mt_encoded = encode_dna(mutant_seq, max_len=context_window).unsqueeze(0)
model.eval()
with torch.no_grad():
wt_score = torch.softmax(model(wt_encoded), dim=-1)
mt_score = torch.softmax(model(mt_encoded), dim=-1)
# Delta score: ΔTF-binding = model(mutant) - model(WT)
delta = (mt_score - wt_score).squeeze()
return {
"wt_score": wt_score.squeeze().tolist(),
"mt_score": mt_score.squeeze().tolist(),
"delta_score": delta.tolist(),
"predicted_impact": "HIGH" if abs(delta.max().item()) > 0.2 else "LOW"
}
4. AlphaFold2 — 蛋白質結構預測
# AlphaFold2 predict 3D structure từ amino acid sequence
# Không cần viết lại model — dùng ColabFold API hoặc LocalColabFold
import subprocess
import json
from pathlib import Path
def predict_protein_structure(
sequence: str,
output_dir: str,
model_type: str = "alphafold2_multimer_v3"
) -> dict:
"""
Wrapper cho ColabFold (AlphaFold2-based, nhanh hơn original 40-60x).
Cài đặt: pip install colabfold[alphafold]
Hoặc dùng ColabFold notebook: https://colab.research.google.com/...
"""
os.makedirs(output_dir, exist_ok=True)
# Tạo FASTA file
fasta_path = os.path.join(output_dir, "query.fasta")
with open(fasta_path, 'w') as f:
f.write(f">protein\n{sequence}\n")
# Run ColabFold (command line)
cmd = [
"colabfold_batch",
fasta_path,
output_dir,
"--model-type", model_type,
"--num-recycle", "3",
"--use-gpu-relax",
]
result = subprocess.run(cmd, capture_output=True, text=True)
if result.returncode != 0:
raise RuntimeError(f"ColabFold failed: {result.stderr}")
# Parse pLDDT scores (per-residue confidence, 0-100)
pdb_files = list(Path(output_dir).glob("*.pdb"))
plddts = parse_plddt_from_pdb(str(pdb_files[0])) if pdb_files else None
return {
"pdb_file": str(pdb_files[0]) if pdb_files else None,
"mean_plddt": float(np.mean(plddts)) if plddts else None,
"output_dir": output_dir
}
def parse_plddt_from_pdb(pdb_path: str) -> list[float]:
"""Extract pLDDT scores từ B-factor column của PDB file."""
plddts = []
with open(pdb_path) as f:
for line in f:
if line.startswith("ATOM"):
try:
plddt = float(line[60:66].strip())
plddts.append(plddt)
except ValueError:
pass
return plddts
def interpret_plddt(mean_plddt: float) -> str:
"""
pLDDT confidence categories theo AlphaFold documentation:
> 90: Very high confidence (correct within experimental error)
70-90: High confidence
50-70: Low confidence (backbone might be correct, side chains unreliable)
< 50: Disordered region (intrinsically disordered proteins)
"""
if mean_plddt > 90:
return "Very high confidence — suitable for drug docking"
elif mean_plddt > 70:
return "High confidence — backbone reliable"
elif mean_plddt > 50:
return "Low confidence — use with caution"
else:
return "Likely intrinsically disordered region"
5. 癌症基因體學：突變特徵分析
def analyze_mutation_signatures(somatic_variants: list[dict]) -> dict:
"""
Mutational signatures: pattern của DNA mutations đặc trưng cho từng mutagenic process.
SBS1: Age (clock-like) — C>T at CpG
SBS4: Tobacco smoking — C>A transversions
SBS6/15: Mismatch repair deficiency (MSI) — many small indels
SBS3: BRCA1/2 deficiency (HRD) — deletions at microhomologies
Dataset: COSMIC v3.4 mutational signatures
"""
from collections import defaultdict
# Count mutation types (96 trinucleotide contexts)
mutation_counts = defaultdict(int)
for variant in somatic_variants:
chrom = variant["chrom"]
pos = variant["pos"]
ref = variant["ref"]
alt = variant["alt"]
if len(ref) == 1 and len(alt) == 1: # SNV only
# Get trinucleotide context from reference genome
# context = get_trinucleotide_context(chrom, pos)
mutation_type = f"{ref}>{alt}"
mutation_counts[mutation_type] += 1
# Classify by Tumor Mutation Burden (TMB)
tmb = len(somatic_variants) / 38.0 # mutations per Mb (38 Mb exome)
tmb_category = (
"TMB-High (≥10 mut/Mb)" if tmb >= 10 else
"TMB-Low (<10 mut/Mb)"
)
return {
"total_somatic_mutations": len(somatic_variants),
"tmb_per_mb": round(tmb, 2),
"tmb_category": tmb_category,
"mutation_counts": dict(mutation_counts),
}
6. 練習
1.下載ClinVar資料庫。根據變異註釋+蛋白質特徵訓練二元分類器（良性與致病性）。目標 AUC > 0.85。
-
可視化 UniProt 中 3 種蛋白質（1 種無序蛋白質、1 種酵素、1 種膜蛋白）的 AlphaFold2 結構。比較 pLDDT 分佈。
-
實現突變特徵反捲積：下載TCGA肺腺癌MAF文件，擷取三核苷酸計數，以NMF擬合COSMIC特徵。
第11課：聯邦學習－多醫院AI，絕對安全。