Radiant energy – Luminophor irradiation
Reexamination Certificate
2002-02-28
2004-08-03
Hannaher, Constantine (Department: 2878)
Radiant energy
Luminophor irradiation
Reexamination Certificate
active
06770892
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the molecular array scanners and, in particular, to automated adjustment of the focal distance at which a sample molecular array is positioned with respect to laser light sources and photodetectors to produce optimal data acquisition.
BACKGROUND OF THE INVENTION
The present invention is related to acquisition of molecular-array data and other types of genetic, biochemical, and chemical data from molecular arrays by molecular array scanners. A general background of molecular-array technology is first provided, in this section, to facilitate discussion of the scanning techniques described in following sections.
Array technologies have gained prominence in biological research and are likely to become important and widely used diagnostic tools in the healthcare industry. Currently, molecular-array techniques are most often used to determine the concentrations of particular nucleic-acid polymers in complex sample solutions. Molecular-array-based analytical techniques are not, however, restricted to analysis of nucleic acid solutions, but may be employed to analyze complex solutions of any type of molecule that can be optically or radiometrically scanned and that can bind with high specificity to complementary molecules synthesized within, or bound to, discrete features on the surface of an array. Because arrays are widely used for analysis of nucleic acid samples, the following background information on arrays is introduced in the context of analysis of nucleic acid solutions following a brief background of nucleic acid chemistry.
Deoxyribonucleic acid (“DNA”) and ribonucleic acid (“RNA”) are linear polymers, each synthesized from four different types of subunit molecules. The subunit molecules for DNA include: (1) deoxy-adenosine, abbreviated “A,” a purine nucleoside; (2) deoxy-thymidine, abbreviated “T,” a pyrimidine nucleoside; (3) deoxy-cytosine, abbreviated “C,” a pyrimidine nucleoside; and (4) deoxy-guanosine, abbreviated “G,” a purine nucleoside. The subunit molecules for RNA include: (1) adenosine, abbreviated “A,” a purine nucleoside; (2) uracil, abbreviated “U,” a pyrimidine nucleoside; (3) cytosine, abbreviated “C,” a pyrimidine nucleoside; and (4) guanosine, abbreviated “G,” a purine nucleoside.
FIG. 1
illustrates a short DNA polymer
100
, called an oligomer, composed of the following subunits: (1) deoxy-adenosine
102
; (2) deoxy-thymidine
104
; (3) deoxy-cytosine
106
; and (4) deoxy-guanosine
108
. When phosphorylated, subunits of DNA and RNA molecules are called “nucleotides” and are linked together through phosphodiester bonds
110
-
115
to form DNA and RNA polymers. A linear DNA molecule, such as the oligomer shown in
FIG. 1
, has a 5′ end
118
and a 3′ end
120
. A DNA polymer can be chemically characterized by writing, in sequence from the 5′ end to the 3′ end, the single letter abbreviations for the nucleotide subunits that together compose the DNA polymer. For example, the oligomer
100
shown in
FIG. 1
can be chemically represented as “ATCG.” A DNA nucleotide comprises a purine or pyrimidine base (e.g. adenine
122
of the deoxy-adenylate nucleotide
102
), a deoxy-ribose sugar (e.g. deoxy-ribose
124
of the deoxy-adenylate nucleotide
102
), and a phosphate group (e.g. phosphate
126
) that links one nucleotide to another nucleotide in the DNA polymer. In RNA polymers, the nucleotides contain ribose sugars rather than deoxy-ribose sugars. In ribose, a hydroxyl group takes the place of the 2′ hydrogen
128
in a DNA nucleotide. RNA polymers contain uridine nucleosides rather than the deoxy-thymidine nucleosides contained in DNA. The pyrimidine base uracil lacks a methyl group (
130
in
FIG. 1
) contained in the pyrimidine base thymine of deoxy-thymidine.
The DNA polymers that contain the organization information for living organisms occur in the nuclei of cells in pairs, forming double-stranded DNA helixes. One polymer of the pair is laid out in a 5′ to 3′ direction, and the other polymer of the pair is laid out in a 3′ to 5′ direction. The two DNA polymers in a double-stranded DNA helix are therefore described as being anti-parallel. The two DNA polymers, or strands, within a double-stranded DNA helix are bound to each other through attractive forces including hydrophobic interactions between stacked purine and pyrimidine bases and hydrogen bonding between purine and pyrimidine bases, the attractive forces emphasized by conformational constraints of DNA polymers. Because of a number of chemical and topographic constraints, double-stranded DNA helices are most stable when deoxy-adenylate subunits of one strand hydrogen bond to deoxy-thymidylate subunits of the other strand, and deoxy-guanylate subunits of one strand hydrogen bond to corresponding deoxy-cytidilate subunits of the other strand.
FIGS. 2A-B
illustrate the hydrogen bonding between the purine and pyrimidine bases of two anti-parallel DNA strands.
FIG. 2A
shows hydrogen bonding between adenine and thymine bases of corresponding adenosine and thymidine subunits, and
FIG. 2B
shows hydrogen bonding between guanine and cytosine bases of corresponding guanosine and cytosine subunits. Note that there are two hydrogen bonds
202
and
203
in the adenine/thymine base pair, and three hydrogen bonds
204
-
206
in the guanosine/cytosine base pair, as a result of which GC base pairs contribute greater thermodynamic stability to DNA duplexes than AT base pairs. AT and GC base pairs, illustrated in
FIGS. 2A-B
, are known as Watson-Crick (“WC”) base pairs.
Two DNA strands linked together by hydrogen bonds forms the familiar helix structure of a double-stranded DNA helix.
FIG. 3
illustrates a short section of a DNA double helix
300
comprising a first strand
302
and a second, anti-parallel strand
304
. The ribbon-like strands in
FIG. 3
represent the deoxyribose and phosphate backbones of the two anti-parallel strands, with hydrogen-bonding purine and pyrimidine base pairs, such as base pair
306
, interconnecting the two strands. Deoxy-guanylate subunits of one strand are generally paired with deoxy-cytidilate subunits from the other strand, and deoxy-thymidilate subunits in one strand are generally paired with deoxy-adenylate subunits from the other strand. However, non-WC base pairings may occur within double-stranded DNA.
Double-stranded DNA may be denatured, or converted into single stranded DNA, by changing the ionic strength of the solution containing the double-stranded DNA or by raising the temperature of the solution. Single-stranded DNA polymers may be renatured, or converted back into DNA duplexes, by reversing the denaturing conditions, for example by lowering the temperature of the solution containing complementary single-stranded DNA polymers. During renaturing or hybridization, complementary bases of anti-parallel DNA strands form WC base pairs in a cooperative fashion, leading to reannealing of the DNA duplex. Strictly A-T and G-C complementarity between anti-parallel polymers leads to the greatest thermodynamic stability, but partial complementarity including non-WC base pairing may also occur to produce relatively stable associations between partially-complementary polymers. In general, the longer the regions of consecutive WC base pairing between two nucleic acid polymers, the greater the stability of hybridization between the two polymers under renaturing conditions.
The ability to denature and renature double-stranded DNA has led to the development of many extremely powerful and discriminating assay technologies for identifying the presence of DNA and RNA polymers having particular base sequences or containing particular base subsequences within complex mixtures of different nucleic acid polymers, other biopolymers, and inorganic and organic chemical compounds. One such methodology is the array-based hybridization assay.
FIGS. 4-7
illustrate the principle of the array-based hybridization assay. An array (
402
in
FIG. 4
) comprises a substrate upon which a regul
Corson John F.
Curry Bo U.
Parker Russell A.
Woods Stanley P.
Zhou Xiangyang
Agilent Technologie,s Inc.
Hannaher Constantine
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