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Chapter 54: Splice Site Decision as ψ-Pruning

"In the art of splicing, ψ becomes a sculptor—removing the unnecessary to reveal the essential, finding infinite forms within finite sequences."

54.1 The Decision Tree​

Each pre-mRNA presents multiple potential splice sites. The cell must choose—creating a specific protein from many possibilities. This is ψ pruning the tree of possibilities.

Definition 54.1 (Splice Site Strength): Si=∑jwj×Matchij+ContextiS_i = \sum_j w_j \times \text{Match}_{ij} + \text{Context}_i

Stronger sites are more likely to be used—but context can override.

54.2 SR Proteins​

Theorem 54.1 (Splicing Enhancers): SR binding→↑P(inclusion)\text{SR binding} \rightarrow \uparrow P(\text{inclusion})

Serine/arginine-rich proteins promote exon inclusion—molecular lobbyists.

54.3 hnRNPs​

Equation 54.1 (Splicing Silencers): P(inclusion)=11+[hnRNP]/KdP(\text{inclusion}) = \frac{1}{1 + [\text{hnRNP}]/K_d}

Heterogeneous nuclear RNPs often suppress splicing—molecular censors.

54.4 The ESE/ESS Code​

Definition 54.2 (Exonic Regulators):

  • ESE: Exonic Splicing Enhancers
  • ESS: Exonic Splicing Silencers

A second code within the genetic code—regulation hidden in sequence.

54.5 Competitive Binding​

Theorem 54.2 (Site Competition): P(SiteA)=KAKA+KB+...+KnP(\text{Site}_A) = \frac{K_A}{K_A + K_B + ... + K_n}

Multiple sites compete for spliceosome attention—molecular democracy.

54.6 Tissue-Specific Splicing​

Equation 54.2 (Cell-Type Programs): Splicingtissue=f(SR proteins,hnRNPs,Others)tissue\text{Splicing}_{\text{tissue}} = f(\text{SR proteins}, \text{hnRNPs}, \text{Others})_{\text{tissue}}

Different cells make different choices—same gene, different outcomes.

54.7 The Nova Paradigm​

Definition 54.3 (Position-Dependent Regulation):

\text{Enhances} \quad \text{if downstream} \\ \text{Silences} \quad \text{if upstream} \end{cases}$$ Location determines function—context is everything. ## 54.8 Splicing Kinetics **Theorem 54.3** (Kinetic Coupling): $$\text{Pol II speed} \rightarrow \Delta\text{Splicing pattern}$$ Slow polymerase allows weak sites to be recognized—speed affects choice. ## 54.9 RNA Structure **Equation 54.3** (Structural Masking): $$\text{Accessibility} = 1 - P(\text{base paired})$$ Secondary structure can hide splice sites—3D regulation of linear sequence. ## 54.10 Mutually Exclusive Exons **Definition 54.4** (Either/Or Choice): $$P(\text{Exon}_A \cap \text{Exon}_B) = 0$$ Some exons cannot coexist—forced choices in the splicing tree. ## 54.11 Poison Exons **Theorem 54.4** (Autoregulation): $$\text{Inclusion} \rightarrow \text{NMD} \rightarrow \downarrow\text{Protein}$$ Some exons contain stop codons—self-destruct sequences for regulation. ## 54.12 The Pruning Principle Splice site decisions represent ψ's editing process—taking the raw transcript and sculpting it into functional form through selective removal. **The Pruning Equation**: $$\text{Proteome} = \sum_{\text{genes}} \sum_{\text{conditions}} \psi(\text{Splice choices})$$ Each condition prunes the tree differently—context-dependent creativity. Thus: Splicing = Editing = Choice = Diversity = ψ --- *"In splice site decisions, ψ demonstrates that creation often means knowing what to leave out—that the spaces between notes make the music."*