DNA Replication Fidelity and Proofreading

DNA polymerase achieves an error rate of approximately 10⁻⁸ per base pair per replication. (a) Explain the three levels of fidelity: base selection, proofreading, and mismatch repair. (b) Calculate the expected number of errors per replication in the human genome (3 × 10⁹ bp) without mismatch repair (error rate 10⁻⁶ after proofreading). (c) How does the 3'→5' exonuclease activity of DNA polymerase contribute to proofreading? (d) Explain the thermodynamic basis for base selection fidelity. (e) What diseases are associated with defects in mismatch repair genes?