Computer-aided engineering system for design of sequence arrays and lithographic masks

• US 5,593,839 A
• Filed: 06/02/1995
• Issued: 01/14/1997
• Est. Priority Date: 05/24/1994
• Status: Expired due to Term

• Current Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Morris, Macdonald S., Lipshutz, Robert J., Hubbell, Earl A., Winkler, James L.
• Primary Examiner(s): Elliott, George C.
• Assistant Examiner(s): Brusca, John S.
• Application Number:
  US08/460,411
• Time in Patent Office: 592 Days
• Field of Search: 435/6, 435/287.2, 536/24.3, 536/25.3, 935/88, 430/5
• US Class Current: 435/6.18
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00432 Photolithographic masks
• CPC Class Codes: B01J 2219/00529 DNA chips
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00608 DNA chips
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00693 Means for quality control
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00711 Light-directed synthesis
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07K 1/04 on carriers C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/045 using devices to improve synthesis, e.g. reactors, special vessels
• CPC Class Codes: C40B 40/06 Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries

Abstract

An improved set of computer tools for forming arrays. According to one aspect of the invention, a computer system is used to select probes and design the layout of an array of DNA or other polymers with certain beneficial characteristics. According to another aspect of the invention, a computer system uses chip design files to design and/or generate lithographic masks.

Claims

1. A method of designing a synthesis method for an array of materials to be synthesized on a substrate, said array formed from groups of diverse biological materials, comprising the steps of:

inputting genetic sequences to a design computer system;

determining a sequence of monomer additions used to form said genetic sequences in said computer by the steps of;

identifying a monomer addition template; and

for monomer additions in said template, determining if said monomer additions are needed in formation of said genetic sequence and, if not, removing said monomer additions from said template;

generating an output file comprising a series of desired monomer additions not removed from said template; and

providing said series of monomer additions as an input file to a synthesizer.

2. The method as recited in claim 1 wherein said monomer addition template comprises repeated additions of A, C, T, and G.

3. The method as recited in claim 1 wherein said step of determining a series of monomer additions further comprises a step of optimizing said series of monomer additions, said step of optimizing further comprising the steps of:

removing a monomer addition from said template to generate a test template; and

determining if said genetic sequence can be formed using said test template as said monomer addition template.

4. The method as recited in claim 3 wherein said step of removing a monomer addition is repeated for a plurality of monomer additions in said template.

5. The method as recited in claim 4 wherein said step of removing monomer additions is repeated from left to right in said template, and right to left.

6. A method of designing and using a synthesis sequence for a biological polymer comprising the steps of:

in a programmed digital computer, identifying a series of monomer additions for adjacent synthesis regions on a substrate;

adjusting said series of monomer additions to reduce the number of monomer additions that differ between at least two adjacent synthesis regions; and

using said adjusted series of monomer additions to form said substrate.

7. The method as recited in claim 6 wherein differences between adjacent synthesis regions are preferentially allowed on ends of said biological polymers.

8. The method as recited in claim 6 wherein said step of adjusting said series of monomer additions comprises the steps of:

identifying at least one common monomer addition step in two adjacent synthesis regions; and

shifting monomer addition steps in one of said synthesis regions such that said common monomer addition steps are performed at the same time.

9. The method as recited in claim 8 wherein said step of shifting monomer addition steps shifts all monomer addition steps in said one of said synthesis regions.

10. The method as recited in claim 8 wherein said step of shifting shifts a selected part of said monomer addition steps in said one of said synthesis regions.

11. The method as recited in claim 10 wherein said step of shifting is performed in said selected part of said monomer addition steps and a remaining part of said monomer addition steps.

12. A method of designing an array and its method of synthesis comprising the steps of:

in a computer system;

inputting a genetic sequence file;

identifying locations in said array for formation of genetic probes corresponding to said genetic sequence and selected mutations thereof;

determining a sequence of monomer additions for formation of said probes and said selected mutations thereof;

outputting at least one computer file representing said locations and said sequence of monomer additions; and

using said at least one computer file to form said array.

13. The method as recited in claim 12 further comprising the step of minimizing differences between monomer addition steps in adjacent positions on said array.

14. The method as recited in claim 12 wherein said step of outputting at least one computer file provides a record for each synthesis region in said array comprising at least probe location, probe sequence, substitution location, and substitution base.

15. The method as recited in claim 12 wherein said step of outputting also outputs position with respect to an exon.

16. The method as recited in claim 12 wherein said step of using said at least one computer file further comprises the steps of using said computer file to design a series of reticles for synthesizing said array;

using said series of reticles to selectively expose a surface of a substrate to light, exposing reactive groups; and

exposing said surface to selected monomers.