Week 1 HW: Principles and Practices
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Prompts were directly based on the homework questions provided.
Homework Questions from Professor Jacobson
1. What is the error rate of polymerase? How does this compare to the human genome length, and how does biology address the discrepancy?
Polymerase error rate:
~10⁻⁵ per base without proofreading; ~10⁻⁷–10⁻⁸ with proofreading; ~10⁻⁹–10⁻¹⁰ with mismatch repair.
Human genome size:
~3 × 10⁹ base pairs.
Biological solutions:
Proofreading, mismatch repair, diploidy, and natural selection.
2. How many different DNA codes can encode an average human protein? Why don’t all of them work in practice?
Theoretical number of encodings:
Due to codon degeneracy, typically 10³–10⁶+ possible sequences.
Practical constraints:
- Codon bias and tRNA availability
- mRNA secondary structure
- GC content and sequence stability
- Regulatory motifs (e.g., splicing, translation signals)
- Error accumulation during synthesis and replication
Homework Questions from Dr. LeProust
3. What is the most commonly used method for oligo synthesis today?
Phosphoramidite solid-phase synthesis.
4. Why is it difficult to synthesize oligos longer than ~200 nt directly?
- Each coupling step is less than 100% efficient
- Errors accumulate linearly with length
- Yield and purity drop exponentially
5. Why can’t a 2000 bp gene be made by direct oligo synthesis?
- Error rates become prohibitive
- Full-length product yield approaches zero
- Long genes must be assembled from shorter oligos (e.g., Gibson assembly, PCA)
Homework Question from George Church
What are the 10 essential amino acids in all animals?
The ten essential amino acids that animals cannot synthesize de novo and must obtain from diet are:
Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine, and Arginine
(Arginine is conditionally essential in adults but universally essential during growth.)
How does this affect the “Lysine Contingency”?
Lysine’s essentiality reflects a deep evolutionary constraint: animals universally lost lysine biosynthesis pathways, making them metabolically dependent on external sources. This supports the “lysine contingency” as a system-level lock-in rather than an arbitrary biochemical choice. Once lysine synthesis was abandoned, translational machinery, diet, and ecological dependencies co-evolved around its availability, making reversal highly unlikely. Thus, lysine exemplifies how early metabolic decisions constrain future evolutionary trajectories.