Finite State Machine Circuit for Parallel Off-Target Site Identification
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Solution Overview
Problem
The CRISPR/Cas9 genome editing system faces inefficiencies in identifying all correct locations to edit the genome without modifying off-target sites, due to the computational expense of searching for potential off-target sites with similar DNA sequences, which can take days even with GPU assistance.
Innovation Solution
A finite state machine circuit is used to compare target sequences with a reference genome, allowing for specified differences such as Hamming distance, to quickly identify off-target sites by transitioning between states based on character mismatches, and custom circuits can be generated for each target sequence to be run in parallel, reducing search time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If local off-target search tools are used to search for potential off-target sites allowing several mis-matches, then the search can identify all correct locations to edit the genome, but the search time may take days even with GPU assistance
Solution Approach 1:
The patent replaces traditional software-based search algorithms (mechanical computing systems) with a hardware-based finite state machine circuit. This circuit uses state transitions to track character mismatches between target sequences and reference genome, enabling parallel processing that reduces search time from days to minutes while maintaining the ability to identify off-target sites with specified Hamming distances
Solution Approach 2:
The patent transitions from sequential software processing to parallel hardware processing by implementing multiple finite state machine circuits that operate simultaneously. Each circuit processes a different target sequence in parallel, adding a spatial dimension to the search process and dramatically reducing overall search time while maintaining comprehensive coverage of all potential off-target sites
2Measurement precision
If more differences (Hamming distance) are allowed from the reference sequence to find all potential off-target sites, then the completeness of off-target identification improves, but the computational expense increases
Solution Approach 1:
The patent uses finite state machine circuits where the number of states directly corresponds to the allowed Hamming distance. By configuring the circuit with a specific number of states, users can adjust the parameter of allowed differences without changing the underlying algorithm or software complexity. The circuit maintains O(n*L) time complexity regardless of the Hamming distance parameter, enabling complete off-target identification even with higher tolerance for differences
3Measurement precision
If multiple target sequences are searched simultaneously to edit the genome at multiple locations, then the genome editing comprehensiveness improves, but the search time increases
Solution Approach 1:
The patent divides the search task into independent segments, with each finite state machine circuit handling one target sequence. These segmented circuits operate in parallel rather than sequentially, so the total search time remains proportional to the time for a single sequence search. This segmentation approach maintains comprehensive genome editing coverage across multiple locations without linearly increasing total search time
Solution Approach 2:
The patent merges multiple finite state machine circuits into a single integrated hardware system that processes multiple target sequences simultaneously. By combining these parallel processing units into one unified circuit architecture, the system achieves comprehensive search coverage across all target sequences while maintaining efficient parallel execution, reducing total search time compared to sequential software processing
Data Source
AI summary
A method of operating a finite state machine circuit can be provided by determining if a target sequence of characters included in a string of reference characters occurs within a specified difference distance using states indicated by the finite state machine circuit to indicate a number of character mis-matches between the target sequence of characters and a respective sequence of characters within the string of reference characters.