Gene Essentiality Analysis
Single Gene Knockouts
import cobra
from cobra.flux_analysis import single_gene_deletion
model = cobra.io.load_model('textbook')
# Perform all single gene deletions
# Returns growth rate with each gene knocked out
deletion_results = single_gene_deletion(model)
# deletion_results is a DataFrame with:
# - ids: gene IDs (frozenset)
# - growth: growth rate after deletion
# - status: solver status
# Find essential genes (no growth when deleted)
# Essential: growth < 0.01 (allowing for numerical tolerance)
essential = deletion_results[deletion_results['growth'] < 0.01]
print(f'Essential genes: {len(essential)}')
Classify Gene Essentiality
def classify_gene_essentiality(model, growth_threshold=0.1):
'''Classify genes by their impact on growth
Categories:
- Essential: Growth < 1% of WT (lethal)
- Growth-reducing: 1-50% of WT
- Non-essential: >50% of WT
'''
from cobra.flux_analysis import single_gene_deletion
# Get wild-type growth
wt_growth = model.optimize().objective_value
# Run deletions
results = single_gene_deletion(model)
results['relative_growth'] = results['growth'] / wt_growth
# Classify
results['classification'] = 'non-essential'
results.loc[results['relative_growth'] < 0.5, 'classification'] = 'growth-reducing'
results.loc[results['relative_growth'] < 0.01, 'classification'] = 'essential'
classification_counts = results['classification'].value_counts()
return results, classification_counts
Synthetic Lethality
from cobra.flux_analysis import double_gene_deletion
# Warning: O(n^2) complexity - can be slow for large models
# For full E. coli (~1500 genes), this is ~1M combinations
# Subset to genes of interest
genes_of_interest = [g.id for g in model.genes[:50]]
# Run double deletions
double_results = double_gene_deletion(
model,
gene_list1=genes_of_interest,
gene_list2=genes_of_interest
)
# Find synthetic lethal pairs
# Synthetic lethal: double KO is lethal when singles are viable
# Get single deletion results first
single_results = single_gene_deletion(model, gene_list=genes_of_interest)
single_dict = {list(ids)[0]: growth for ids, growth in
zip(single_results['ids'], single_results['growth'])}
Identify Synthetic Lethal Pairs
def find_synthetic_lethal_pairs(model, genes=None, growth_threshold=0.01):
'''Find synthetic lethal gene pairs
Synthetic lethality criteria:
- Single KO of gene A: viable (growth > threshold)
- Single KO of gene B: viable (growth > threshold)
- Double KO of A+B: lethal (growth < threshold)
Useful for:
- Drug combination targets
- Genetic interaction networks
- Backup pathway identification
'''
from cobra.flux_analysis import single_gene_deletion, double_gene_deletion
if genes is None:
genes = [g.id for g in model.genes]
# Single deletions
single = single_gene_deletion(model, gene_list=genes)
viable_singles = single[single['growth'] > growth_threshold]
viable_genes = [list(ids)[0] for ids in viable_singles['ids']]
# Double deletions (only for viable single KOs)
double = double_gene_deletion(model, gene_list1=viable_genes,
gene_list2=viable_genes)
# Find synthetic lethal pairs
sl_pairs = []
for _, row in double.iterrows():
genes_in_pair = list(row['ids'])
if len(genes_in_pair) == 2 and row['growth'] < growth_threshold:
sl_pairs.append({
'gene1': genes_in_pair[0],
'gene2': genes_in_pair[1],
'double_ko_growth': row['growth']
})
return sl_pairs
Condition-Specific Essentiality
def compare_essentiality_conditions(model, conditions):
'''Compare gene essentiality across conditions
Args:
conditions: dict mapping condition name to media setup function
Example:
conditions = {
'aerobic': lambda m: m.reactions.EX_o2_e.lower_bound = -20,
'anaerobic': lambda m: m.reactions.EX_o2_e.lower_bound = 0
}
'''
from cobra.flux_analysis import single_gene_deletion
essentiality_by_condition = {}
for condition_name, setup_func in conditions.items():
with model:
setup_func(model)
results = single_gene_deletion(model)
essential = set(list(ids)[0] for ids in
results[results['growth'] < 0.01]['ids'])
essentiality_by_condition[condition_name] = essential
# Find condition-specific essential genes
all_essential = set.union(*essentiality_by_condition.values())
core_essential = set.intersection(*essentiality_by_condition.values())
condition_specific = {cond: ess - core_essential
for cond, ess in essentiality_by_condition.items()}
return {
'core_essential': core_essential,
'condition_specific': condition_specific,
'total_essential': len(all_essential)
}
Robustness Analysis
def gene_robustness_analysis(model, gene_id, flux_levels=10):
'''Analyze growth as function of gene expression level
Instead of complete knockout, simulate reduced expression
by constraining reactions associated with the gene.
'''
from cobra.flux_analysis import flux_variability_analysis
gene = model.genes.get_by_id(gene_id)
# Get reactions associated with this gene
rxns = list(gene.reactions)
results = []
for level in [i/flux_levels for i in range(flux_levels + 1)]:
with model:
for rxn in rxns:
# Get FVA bounds at wild-type
fva = flux_variability_analysis(model, reaction_list=[rxn])
max_flux = fva.loc[rxn.id, 'maximum']
min_flux = fva.loc[rxn.id, 'minimum']
# Constrain to fraction of wild-type
rxn.upper_bound = max_flux * level
rxn.lower_bound = min_flux * level
sol = model.optimize()
results.append({
'expression_level': level,
'growth': sol.objective_value
})
return results
Related Skills
- systems-biology/flux-balance-analysis - Base FBA methods
- pathway-analysis/go-enrichment - Enrich essential gene sets
- clinical-databases/variant-prioritization - Link to disease genes
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