Methods of increasing the effective probe densities of arrays
First Claim
1. A compound probe, comprising:
- at least a first oligonucleotide probe comprising a first nucleotide sequence capable of hybridizing to a first target nucleotide sequence in a nucleic acid molecule of interest;
at least a second oligonucleotide probe comprising a second nucleotide sequence capable of hybridizing to a second target nucleotide sequence in the nucleic acid molecule of interest; and
an oligonucleotide linker segment linking the first oligonucleotide probe to the second oligonucleotide probe, and separating the probes from each other,wherein the linker segment is selected to minimize homology noise associated with hybridization of the first nucleotide sequence of the first oligonucleotide probe to the first target nucleotide sequence, and hybridization of the second nucleotide sequence of the second oligonucleotide probe to the second target nucleotide sequence.
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Abstract
Methods and articles for analyzing nucleotide sequences of nucleic acid molecules, e.g., using multiple probes per spot of an array, are described. In some embodiments, the methods and articles can reduce the numbers of arrays necessary to probe regions of interest in a biological sample, and/or increase the resolution at which biological events are probed. In some cases, these methods exploit the vertical aspect of an array in order to decrease the number of arrays or spots required for an assay. These probes may be in the form of compound probes, which comprise at least first and second probes, including first and second nucleotide sequences capable of hybridizing to first and second target nucleotide sequences, respectively, in a nucleic acid molecule of interest.
79 Citations
20 Claims
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1. A compound probe, comprising:
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at least a first oligonucleotide probe comprising a first nucleotide sequence capable of hybridizing to a first target nucleotide sequence in a nucleic acid molecule of interest; at least a second oligonucleotide probe comprising a second nucleotide sequence capable of hybridizing to a second target nucleotide sequence in the nucleic acid molecule of interest; and an oligonucleotide linker segment linking the first oligonucleotide probe to the second oligonucleotide probe, and separating the probes from each other, wherein the linker segment is selected to minimize homology noise associated with hybridization of the first nucleotide sequence of the first oligonucleotide probe to the first target nucleotide sequence, and hybridization of the second nucleotide sequence of the second oligonucleotide probe to the second target nucleotide sequence. - View Dependent Claims (2, 3, 4, 5, 6, 7)
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8. A method of designing a compound probe, comprising:
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selecting candidate probes for a compound probe, the candidate probes comprising at least a first oligonucleotide probe comprising a first nucleotide sequence capable of hybridizing to a first target nucleotide sequence in a nucleic acid molecule of interest, and at least a second oligonucleotide probe comprising a second nucleotide sequence capable of hybridizing to a second target nucleotide sequence in the nucleic acid molecule of interest; estimating the boundary homology noise of at least two possible arrangements of the first and second oligonucleotide probes within a compound probe; and selecting the arrangement estimated to have the overall lowest boundary homology noise. - View Dependent Claims (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
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20. An array or array set for determining a location of a biological phenomenon in terms of chromosomal coordinates in a nucleic acid molecule of interest, comprising:
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at least a first oligonucleotide probe comprising a first nucleotide sequence capable of hybridizing to a first target nucleotide sequence in a nucleic acid molecule of interest; at least a second oligonucleotide probe comprising a second nucleotide sequence capable of hybridizing to a second target nucleotide sequence in the nucleic acid molecule of interest; and an oligonucleotide linker segment linking the first oligonucleotide probe to the second oligonucleotide probe, and separating the probes from each other, wherein the linker segment is selected to minimize homology noise associated with hybridization of the first nucleotide sequence of the first oligonucleotide probe to the first target nucleotide sequence, and hybridization of the second nucleotide sequence of the second oligonucleotide probe to the second target nucleotide sequence.
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Specification