Computer method and system for correlating data

• US 6,444,422 B2
• Filed: 07/21/1998
• Issued: 09/03/2002
• Est. Priority Date: 07/22/1997
• Status: Expired due to Term

• Current Assignee: Agilent Technologies, Inc.
• Original Assignee: Qiagen Genomics, Inc.
• Inventors: Mulligan, John T., Tabone, John C., Howbert, J. Jeffry, Ness, Jeffrey Van
• Primary Examiner(s): Jones, W. Gary
• Assistant Examiner(s): Taylor, Janell E.
• Application Number:
  US09/120,686
• Publication Number:
  US 20010053516A1
• Time in Patent Office: 1,505 Days
• Field of Search: 435/6, 435/71.1, 435/287.2, 435/288.7, 436/173, 536/25.3, 536/25.4, 935/77, 935/78, 703/11, 702/20
• US Class Current: 435/6.12
• CPC Class Codes: C12Q 1/6872 involving mass spectrometry
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/10 Sequence alignment; Homology search
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/10 Signal processing, e.g. from mass spectrometry [MS] or from PCR
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

A method and system for correlating characteristics (e.g., type of nucleotide) of biomolecules (e.g., DNA) to molecular tags with unique molecular weights that are associated with the biomolecule. In one embodiment. the molecular tags are applied to primers used when synthesizing the biomolecule. The system initially receives a mapping of each characteristic of the biomolecules to the corresponding molecular weight of the molecular tag. The system also receives an indication of the molecular weights detected when analyzing the biomolecules to which the molecular tags have been associated. For each molecular weight detected, the system determines based on the received mapping the characteristic corresponding to the detected molecular weight. The system then indicates that the analyzed biomolecule has the determined characteristic.

Claims

1. A method in a computer system for correlating known characteristics of nucleic acid molecules to molecular tags with unique molecular weights that have been associated with the nucleic acid molecules or portions thereof, the method comprising:

receiving an indication of a mapping of known characteristic(s) of each nucleic acid molecule to the corresponding molecular weight of the molecular tag associated with the known characteristic(s);

receiving an indication of the molecular weights detected when analyzing the tags that have been dissociated from the nucleic acid molecules or portions thereof, wherein the tags are separated based on a determined characteristic of the associated nucleic acid molecules or portions thereof other than the sequences of the nucleic acid molecules before the dissociation of the tag from the nucleic acid molecules or portions thereof; and

for each molecular weight detected

determining based on the received mapping the known characteristic(s) of the nucleic acid molecule corresponding to the detected molecular weight; and

indicating that the nucleic acid molecule has the determined characteristic.

2. The method of claim 1 wherein the molecular tags are applied to primers used when synthesizing the nucleic acid molecules.

3. The method of claim 1 wherein the indicating further identifies a base sequence of a nucleic acid molecule.

4. The method of claim 1 wherein the known characteristic of a nucleic acid molecule identifies a primer and a base for synthesizing the nucleic acid molecule or a portion thereof, wherein the molecular weights are detected in an order corresponding to the positions of the bases in a base sequence of the nucleic acid molecule.

5. The method of claim 4 wherein the known characteristic further identifies one of multiple nucleic acid molecules which are analyzed simultaneously.

6. The method of claim 1 wherein the indicating further indicates whether one nucleic acid molecule is different from another nucleic acid molecule.

7. The method of claim 1 wherein the known characteristic identifies a primer for synthesizing a test nucleic acid molecule and a reference nucleic acid molecule, the resulting tagged test and reference nucleic acid molecules have been melted and re-annealed, and when the same molecular weight is detected at different times, the indicating indicates that the base sequences of the test nucleic acid molecule and the reference nucleic acid molecule are different.

8. The method of claim 1 wherein the indicating further identifies differences between two populations of mRNA.

9. The method of claim 1 wherein the nucleic acid molecules are cDNA molecules and the known characteristic identifies a primer that has been used to synthesize the cDNA molecules and wherein the number of peaks that the molecular tags with the same molecular weight are detected reflects the number of different cDNA molecules synthesized from the primer.

10. The method of claim 9 wherein the number of peaks a particular molecular tag detected in one population is compared to the number of peaks the same molecular tag is detected in another population of cDNA.

11. A method in a computer system for simultaneously determining the sequence of a plurality of sample oligonucleotides (ODNs), each sequence having four bases A, T, C, and G, the method comprising:

for each of the plurality of sample ODNs, receiving an indication of four molecular weights of molecular tags associated with the sample ODN, each of the four molecular weights corresponding to one of the four bases, each molecular weight being unique among all the molecular weights of all the molecular tags to be applied to all sample ODNs; and

for each of a plurality of positions corresponding to a sequence length,

receiving an indication of the molecular weights of the molecular tags that have been associated with synthesized ODNs comprising base sequences identical to portions of the sample ODNs, the tags separated based on a characteristic of the associated synthesized ODNs other than the sequence of the associated synthesized ODNs and subsequently dissociated from the synthesized ODNs, the molecular weights being detected by a mass spectrometer, wherein the mass spectrometer detects one of the four molecular weights assigned to each of the plurality of sample ODNs for each position; and

for each of the plurality of sample ODNs,

determining the base to which the detected molecular weight is assigned using the received indications for the sample ODN; and

setting the base at the position in the sequence for the sample ODN.

12. The method of claim 11 including

for each of the four bases, displaying a graph illustrating the detection of the molecular weights assigned to that base for the selected sample ODN; and

displaying the sequence for the sample ODN.

13. The method of claim 12 including receiving from a user a change to the displayed sequence.

14. A method in a computer system for determining whether a plurality of pairs of a test fragment and a reference fragment of DNA are different, the method comprising:

for each of the plurality of pairs of fragments, at various times, receiving an indication of the number of a molecular tag with a unique molecular weight that is associated with, but subsequently dissociated from, the pair of fragments, wherein the tags are separated based on a characteristic of the associated DNA fragments other than the sequences of the DNA fragments before the dissociation of the tag from the DNA fragments; and

for each of the unique molecular weights of the molecular tags,

determining whether there is more than one peak in the number of molecular tags detected for that molecular weight; and

indicating that the pair of DNA fragments are different when it is determined that there is more than one peak in the number of molecular tags detected for that molecular weight.

15. A method in a computer system for identifying whether two populations of mRNA are different, the method comprising:

for each of a plurality of primers, at various times, receiving an indication of the number of a molecular tag with a unique molecular weight, the molecular tag being associated with the cDNA derived from the mRNA using each of the primers, separated based on a characteristic of the cDNA other than the sequence of the cDNA, and subsequently dissociated from the cDNA; and

for each of the unique molecular weights of molecular tags,

comparing the presence of a peak in the number of molecular tags detected for that molecular weight at any particular time derived from one population of mRNA with that of the other population; and

indicating that the two populations of mRNA are different when there is a difference in the presence of the peak.

16. A computer system for correlating known characteristics of nucleic acid molecules to molecular tags with unique molecular weights that have been associated with the nucleic acid molecules or portions thereof, comprising:

a molecular tag definition table indicating the molecular weight of each molecular tag;

a defined run component for generating a mapping of each nucleic acid molecule to a molecular tag;

a molecular weight collection component for receiving an indication of the molecular weights of the molecular tags that have been associated with the nucleic acid molecules or portions thereof, separated based on a determined characteristic of the associated nucleic acid molecules or portions thereof other than the sequences of the nucleic acid molecules, and subsequently dissociated from the nucleic acid molecules or portions thereof; and

a correlation component that determines, based on the received mapping, the known characteristic of the nucleic acid molecule corresponding to the detected molecular weight, and indicates that the nucleic acid molecule has the determined characteristic.

17. The computer system of claim 16 wherein the correlation component further indicates the base sequences of the nucleic acid molecules.

18. The computer system of claim 16 wherein the correlation component further indicates whether one nucleic acid molecule is different from another nucleic acid molecule.

19. The computer system of claim 16 wherein the correlation component further identifies differences between two populations of mRNA.