Method for constructing a genomic hybridization array for precision genetic diagnosis

Abstract

Methods and apparatuses for selecting and arranging clinically relevant chromosomal loci allow an exemplary diagnostic array to simultaneously test for numerous genetic alterations that occur in many different parts of the human genome. Clinically irrelevant or ineffective loci are eliminated. One implementation increases reliability and accuracy by dividing the base-pair sequence of each chromosomal locus into segments and then assigning nucleic acid clones for comparative genomic hybridization to each different segment. The segments may overlap for increased resolution and control. Clones representing segments that are adjacent on a native chromosome are placed in non-adjacent target areas of the array to avoid interfering hybridization reactions. Arrangement motifs within an array may be redundantly repeated for high availability and increased reliability and accuracy of results. Techniques, hardware, software, logic engines, loci collections, and diagnostic arrays are described.

1 . A method of constructing a comparative genomic hybridization array for precision genetic diagnosis, comprising:
 selecting chromosomal loci for diagnosing clinically significant genetic alterations;   for a base-pair sequence of each chromosomal locus, assigning nucleic acid clones to represent logically overlapping segments of the base-pair sequence; and   distributing the clones for adjacent overlapping segments in non-adjacent target areas of the comparative genomic hybridization array.   
   
   
       2 . The method as recited in  claim 1 , further comprising combining the clones assigned to the segments of multiple chromosomal loci into a single target on the array to compress the array, while distributing the clones representing the adjacent overlapping segments in non-adjacent target areas. 
   
   
       3 . The method as recited in  claim 1 , further comprising distributing multiple copies of the comparative genomic hybridization array on a single comparative genomic hybridization substrate. 
   
   
       4 . The method as recited in  claim 3 , further comprising comparing comparative genomic hybridization results from one copy of the array with another copy of the array. 
   
   
       5 . The method as recited in  claim 3 , further comprising comparing comparative genomic hybridization results from a first sub-array within one copy of the array with comparative genomic hybridization results from a second sub-array within the one copy of the array. 
   
   
       6 . The method as recited in  claim 3 , further comprising comparing a first target area that resides in a first sub-array with a second target area that resides in a second sub-array, wherein the first target area and the second target area represent the same segment of the base-pair sequence. 
   
   
       7 . A system, comprising:
 means for selecting clinically relevant chromosomal loci capable of genetic alteration;   means for assigning multiple nucleic acid clones to represent a base-pair sequence of each chromosomal locus, wherein each clone represents a segment of the base-pair sequence; and   means for arranging the multiple clones assigned to each chromosomal locus on a comparative genomic hybridization array, wherein clones representing segments that are adjacent on a native chromosome are placed in non-adjacent target areas of the array.   
   
   
       8 . An array for comparative genomic hybridization, comprising:
 multiple redundant sub-arrays secured to a substrate, wherein each sub-array includes multiple test areas;   a nucleic acid clone in each test area;   wherein at least some of the clones in some of the test areas represent segments of base-pair sequences of clinically relevant chromosomal loci, each chromosomal locus capable of a genetic alteration indicating a disease, and   wherein clones representing segments that are adjacent on a native chromosome are placed in non-adjacent target areas of the array to avoid hybridization interactions.