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In particular, the present invention provides methods and compositions for uniform enrichment of target nucleic acid molecules in a microarray format. The present invention also provides for intentionally non-uniform enrichment among target nucleic acid molecules.","lang":"en","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}],"fr":[{"text":"La présente invention concerne des procédés et des compositions pour l’enrichissement d’acides nucléiques cible dans un système de microréseau. En particulier, la présente invention concerne des procédés et des compositions pour un enrichissement uniforme de molécules d’acide nucléique cible dans un format de microréseau. La présente invention concerne également un enrichissement intentionnellement non-uniforme parmi des molécules d’acide nucléique cible.","lang":"fr","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}]},"abstract_lang":["en","fr"],"has_abstract":true,"claim":{"en":[{"text":"Patent Claims 1. A method for uniform enrichment of a population of nucleic acid molecules in a sample, comprising: a) providing a sample of nucleic acid molecules comprising a plurality of target nucleic acid sequences, b) hybridizing the sample to a support comprising immobilized nucleic acid probes under conditions to support hybridization between the immobilized nucleic acid probes and the plurality of target nucleic acid sequences, wherein said immobilized nucleic acid probes are complementary to said plurality of target nucleic acid sequences, and wherein the immobilized nucleic acid probes provide uniform hybridization among said plurality of target nucleic acid sequences, and c) separating non-hybridized nucleic acid sequences from hybridized target nucleic acid sequences, thereby uniformly enriching a population of nucleic acid molecules in a sample. 2. The method according to claim 1, wherein said separating comprises washing said support. 3. The method according to claims 1-2, further comprising fragmenting said sample of nucleic acid molecules prior to said hybridizing. 4. The method according to claim 3, further comprising ligating an adaptor molecule to one or both ends of a plurality of fragmented nucleic acid molecules prior to said hybridizing. 5. The method according to claims 1-4, further comprising denaturing said sample of nucleic acid molecules prior to said hybridizing. 6. The method according to claims 1-5, further comprising eluting a plurality of hybridized target nucleic acid sequences from the support. 7. The method according to claim 6, further comprising sequencing the eluted target nucleic acid sequences. 8. The method according to claims 1-7, wherein said support is a microarray slide. 9. The method according to claims 1-7, wherein said support is a bead. 10. The method according to claims 1-9, wherein said population of nucleic acid molecules is a population of genomic DNA molecules. 11. The method according to claims 1-9, wherein said population of nucleic acid molecules is a population of amplified genomic DNA molecules. 12. The method according to claims 1-11, wherein the probes are characterized in that the frequency of the individual sequences of said immobilized nucleic acid probes corresponds to the frequency of the corresponding plurality of target nucleic acid sequences within a population of nucleic acid molecules. 13. The method according to claim 12, wherein determining the frequency comprises utilizing an empirically- fit linear regression model. 14. A composition comprising a solid support and a plurality of nucleic acid probes immobilized on said solid support, wherein each of said plurality of immobilized nucleic acid probes provides for uniform hybridization among a plurality of target nucleic acid sequences. 15. A kit for performing uniform enrichment of target nucleic acid sequences comprising one or more containers, wherein said one or more containers comprises: a) a solid support comprising immobilized nucleic acid probes, wherein said probes are selected from a group consisting of a plurality of probes hybridizable to a plurality of target nucleic acid sequences and wherein said probes provide for uniform enrichment of said plurality of target nucleic acid sequences, and b) one or more reagents for performing hybridizations, washes, and elution of target nucleic acid sequences. 16. A process for uniform enrichment of a population of nucleic acid sequences in a sample comprising a plurality of immobilized hybridization probe sequences, wherein the frequency of the individual sequences of the immobilized hybridization probes corresponds to the frequency of a plurality of corresponding target nucleic acid sequences within a population of nucleic acid molecules, and wherein said process for uniform enrichment comprises hybridizing said probes to the corresponding target nucleic acid sequences and separating non-hybridized nucleic acid sequences from hybridized target nucleic acid sequences. 17. The process according to claim 16, further comprising eluting said hybridized target nucleic acid sequences. 18. The process according to claims 16-17, wherein the immobilized hybridization probes are immobilized on a microarray slide or a bead. 19. The process according to claims 16-18, wherein determining the frequency comprises utilizing an empirically-fit linear regression model. 20. The process according to claims 16-19, wherein said target nucleic acid sequences are genomic DNA sequences.","lang":"en","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}]},"claim_lang":["en"],"has_claim":true,"description":{"en":{"text":"Methods and systems for uniform enrichment of genomic regions Field of the invention The present invention provides methods and compositions for the enrichment of target nucleic acids in a microarray system. In particular, the present invention provides methods and compositions for uniform enrichment of target nucleic acid molecules in a microarray format. The present invention also provides for intentionally non-uniform enrichment among target nucleic acid molecules. Background of the invention The advent of nucleic acid microarray technology makes it possible to build an array of millions of nucleic acid sequences in a very small area, for example on a microscope slide (e.g., US 6,375,903 and US 5,143,854). Initially, such arrays were created by spotting pre-synthesized DNA sequences onto slides. However, the construction of maskless array synthesizers (MAS) as described in US 6,375,903 now allows for the in situ synthesis of oligonucleotide sequences directly on the slide itself. Using a MAS instrument, the selection of oligonucleotide sequences to be constructed on the microarray is under software control such that it is now possible to create individually customized arrays based on the particular needs of an investigator. In general, MAS-based oligonucleotide microarray synthesis technology allows for the parallel synthesis of over 4 million unique oligonucleotide features in a very small area of a standard microscope slide. With the availability of the entire genomes of hundreds of organisms, for which a reference sequence has generally been deposited into a public database, microarrays have been used to perform sequence analysis on nucleic acids isolated from a myriad of organisms. Nucleic acid microarray technology has been applied to many areas of research and diagnostics, such as gene expression and discovery, mutation detection, allelic and evolutionary sequence comparison, genome mapping, drug discovery, and more. Many applications require searching for genetic variants and mutations across the entire human genome; variants and mutations that, for example, may underlie human diseases. In the case of complex diseases, these searches generally result in a single nucleotide polymorphism (SNP) or set of SNPs associated with one or more diseases. Identifying such SNPs has proven to be an arduous, time consuming, and costly task wherein resequencing large regions of genomic DNA, usually greater than 100 kilobases (Kb) from affected individuals and/or tissue samples is frequently required to find a single base change or identify all sequence variants. The genome is typically too complex to be studied as a whole, and techniques must be used to reduce the complexity of the genome. To address this problem, one solution is to reduce certain types of abundant sequences from a DNA sample, as found in US 6,013,440. Alternatives employ methods and compositions for enriching genomic sequences as described, for example, in Albert, T. J., et al., Nat. Meth., 4 (2007) 903-5, and Okou, D.T., et al., Nat. Meth. 4(11) (2007) 907-9. Albert et al. disclose an alternative that is both cost-effective and rapid in effectively reducing the complexity of a genomic sample in a user defined way to allow for further processing and analysis. However, it is equally important to be able to enrich target sequences uniformly over the targeted region(s). If enrichment is not uniform, for example, some target sequences will be captured disproportionately compared to other target sequences thereby negating downstream applications that are dependent on approximately uniform distribution of targeted sequences. Hodges, E., et al., Nature Genetics 39(12) (2007) 1522-7 noted that a critical parameter in microarray capture was the introduction of biased target capture which greatly affects sequence coverage depth. However, Hodges offered no path forward, other than to say that probe redistribution to compensate for biased capture would necessarily introduce other types of biases that would lead to problems with downstream applications, for example sequencing applications. As such, what are needed are methods and compositions to provide uniform capture, and hence representation, of captured targets during capture and enrichment of targeted sequences in a microarray format. Conversely, an investigator might also require a conscience non-uniformity of capture, for example if an investigator envisions targeting exons over intergenic regions. Such methods would provide maximum data utility to investigators in their endeavors to understand and identify, for example, causes of disease and associated therapeutic treatments. Summary of the invention The present invention provides methods and compositions for the enrichment of target nucleic acids in a microarray system. In particular, the present invention provides methods and compositions for uniform enrichment of target nucleic acid molecules in a microarray format. The present invention also provides for intentionally non-uniform enrichment among target nucleic acid molecules. Nucleic acid enrichment reduces the complexity of a large nucleic acid sample, such as a genomic DNA sample, cDNA library or mRNA library, to facilitate further processing and genetic analysis. Pre-existing nucleic acid capture methods utilize immobilized nucleic acid probes to capture target nucleic acid sequences (e.g. as found in genomic DNA, cDNA, mRNA, etc.) by hybridizing the sample to probes immobilized on a solid support. The captured target nucleic acids, as found for example in genomic DNA, are washed and eluted off of the solid support- immobilized probes. The eluted genomic sequences are more amenable to detailed genetic analysis than a genomic sample that has not been subjected to this procedure. Enrichment of target nucleic acid sequences takes nucleic acid capture one step further, by reducing the complexity of a sample wherein sequences of interest are selected for, or enriched, by selective processes. Enrichment methods and compositions are fully disclosed in US Patent Application Numbers 11/789,135 and 11/970,949 and World Intellectual Property Organization Application Number PCT/US07/010064, all of which of incorporated herein by reference in their entireties. Enrichment of target nucleic acids in a microarray format is important in reducing the complexity of a nucleic acid sample prior to, for example, sequencing or other downstream applications. However, many downstream applications strongly depend upon the resulting sequencing reads having an approximately uniform distribution over the target regions, as disproportionately high representation of some targets necessarily depletes others. Although array-based enrichment robustly enriches targeted fragments, it is contemplated that certain targets are more strongly enriched than others thereby producing biased capture or targets. As such, the present invention provides methods and compositions to address this biased target nucleic acid capture. For example, embodiments of the present invention provide for array design that is modified to redistribute probes from targets with above-average enrichment to those with below-average enrichment. In developing embodiments of the present invention, it was determined that this redistribution of probes significantly improves the uniformity of enrichment among captured targets. Conversely, the present invention also provides for array design that is modified to redistribute probes that intentionally introduce biased target capture into an array. For example, if an investigator is interested in capturing specific genomic regions over other genomic regions, the methods as described herein can be utilized to create captured bias. Certain illustrative embodiments of the invention are described below. The present invention is not limited to these embodiments. In some embodiments, the present invention comprises a solid support microarray, generally comprising support-immobilized nucleic acid probes to capture and enrich for specific nucleic acid sequences (target nucleic acids) from a sample (e.g., genomic DNA, cDNA, mRNA, tRNA, etc.). In some embodiments, the probes that are immobilized on a support represent a redistributed set of probes. For example, the redistributed probes are designed to provide uniform capture of target regions, such that capture of targets is not biased. In some embodiments, the probes that are immobilized on a support are redistributed probes, wherein said probes are designed to provide non-uniform capture of target regions, such that capture of targets is intentionally biased. In some embodiments, target nucleic acid enrichment is via hybridizing a nucleic acid sample, for example a genomic DNA sample, which may contain one or more target nucleic acid sequence(s), against a microarray comprising redistributed nucleic acid probes directed to a specific region or specific regions of the genome. After hybridization, target nucleic acid sequences present in the sample are enriched by washing the array and eluting the hybridized genomic nucleic acids from the array. Following elution, the enriched samples are assayed for the level or amount of enrichment over a control. In some embodiments, the target nucleic acid sequence(s) are further amplified using, for example, non-specific ligation- mediated PCR (LM-PCR), resulting in an amplified pool of PCR products of reduced complexity compared to the original sample for sequencing, library construction, and other applications. In some embodiments, the assay comprising redistributed probes for capture of target sequences demonstrates a uniform, unbiased capture over the target region as exemplified in Figure 1. In some embodiments, the present invention comprises a solid support, generally comprising support-immobilized nucleic acid probes to capture specific nucleic acid sequences (target nucleic acids) from a sample (e.g., genomic DNA, cDNA, mRNA, tRNA, etc.). In some embodiments, the solid support is a slide, for example a microarray slide. In some embodiments, the solid support comprises beads, whereas the beads are in solution, for example in a tube or other such container, or for example aliquoted into wells of an assay plate (e.g., 12 well, 24 well, 96 well, 384 well, and the like). In some embodiments, the probes that are immobilized on a support represent a redistributed set of probes. For example, the redistributed probes are designed to provide uniform capture of target nucleic acid molecule regions, such that capture of targets is not biased, and such that the frequency of each individual sequence of the immobilized probes corresponds to the frequency of the corresponding target nucleic acid sequence within the population of the target nucleic acid molecules. In some embodiments, the probes that are immobilized on a support are redistributed probes, wherein said probes are designed to provide non-uniform capture of target regions, such that capture of targets is intentionally biased. In some embodiments, the sample is fragmented, for example by sonication, or other methods capable of fragmenting nucleic acids. In some embodiments, the fragmented sample (e.g., fragmented genomic DNA, cDNA, etc.) is modified by ligation to linkers on one or both of the 5' and 3' ends. In some embodiments, the 5' and 3' ends of a fragmented sample are first prepared for ligation with a linker, for example by performing a \"fill in\" reaction with Klenow enzyme. The preparation of nucleic acid ends for subsequent ligation to linkers is well known in the art, and can be found in any molecular cloning manual such as \"Molecular Cloning: A Laboratory Manual, Sambrook, et al. Eds, Cold Spring Harbor Laboratory Press\", which is herein incorporated be reference in its entirety. Indeed, exemplary methods for performing all molecular cloning, hybridization, washing, and elution techniques as used herein can be found in \"Molecular Cloning: A Laboratory Manual\", Sambrook, et al., Eds, Cold Spring Harbor Press as well as \"A Molecular Cloning Manual: DNA Microarrays\", Bowtell, et al., Eds, Cold Spring Harbor Press (incorporated herein by reference in their entireties) as well as other technical manuals and reference guides known to skilled artisans. In some embodiments, the fragmented and linker-adapted nucleic acid sample is hybridized to an array comprising redistributed probes designed to capture target sequences in an unbiased manner, and the targeted sequences are captured. In other embodiments, the fragmented and linker-adapted nucleic acid sample is hybridized to an array comprising redistributed probes designed to intentionally capture target sequences in a biased manner, and the target sequences are captured. The use of linkers for enrichment methods and enrichment methods in general are well known and fully described in US Patent Application Numbers 11/789,135 and 1 1/970,949 and World Intellectual Property Organization Application Number PCT/US07/010064, and further in Albert, TJ., et al., Nat. Meth. 4 (2007) 903-5, Okou, D.T., Nat. Meth. 4(11) (2007) 907-9 and Hodges, E., et al., Nature Genetics 39(12) (2007) 1522-7; all of which of incorporated herein by reference in their entireties. Following hybridization, non-targeted nucleic acids are washed from the microarray and the bound, targeted nucleic acids are eluted from the array following protocols known in the art. The quality of the enriched sample is calculated and fold enrichment is determined and communicated to the user. In some embodiments, the calculation of enrichment comprises fold enrichment as compared to a control enrichment sample. Samples of sufficient quality are used for downstream applications, such as sequencing, cloning, library construction, etc. The present invention is not limited by any downstream use of enriched nucleic acids, and a skilled artisan will understand the myriad uses such a sample would provide including, but not limited to, sequencing, SNP detection for discovery and correlation with disease states and risk factors, use of targeted sequences in drug discovery applications, etc. Enriched target sequences can be assessed for, for example, the quality of microarray based enriched target nucleic acids (e.g., level of effectiveness of the unbiased (or intentionally biased) enrichment methods as described herein). Such assessment not only provides insight into the general effectiveness of the enrichment technology, but it also provides an investigator a method of accessing the quality of the enriched nucleic acids prior to spending precious time and resources on downstream applications with a sample that is not appropriately enriched. In some embodiments, the assessing of the quality of the target nucleic acids is performed by testing the enrichment of a subset of reference sequences, for example conserved regions in a genome, as found in US Patent Provisional Application 61/026,596, incorporated herein by reference in its entirety. In one embodiment, the present invention comprises a method for uniform enrichment of a population of nucleic acid molecules in a sample, comprising providing a sample of nucleic acid molecules comprising a plurality of target nucleic acid sequences, hybridizing the sample to a support comprising immobilized nucleic acid probes under conditions to support hybridization between the immobilized nucleic acid probes and the plurality of target nucleic acid sequences, wherein said immobilized nucleic acid probes are complementary to said plurality of target nucleic acid sequences, and wherein said immobilized nucleic acid probes provide uniform hybridization among said plurality of target nucleic acid sequences, and separating non-hybridized nucleic acid sequences from hybridized target nucleic acid sequences thereby enriching a population of nucleic acid molecules in a sample. In some embodiments, separating the hybridized and non-hybridized sequences comprises washing the support such that non-hybridized nucleic acid sequences are removed from the support. In some embodiments, the nucleic acid molecules are fragmented prior to hybridization and in further embodiments the fragments are ligated to adaptor molecules at one or both ends, hi some embodiments, the linker adapted fragmented nucleic acid molecules are denatured prior to hybridization. In some embodiments, the hybridized target nucleic acid sequences are eluted from the support and oftentimes sequenced after elution. In some embodiments, the support is a solid support, wherein said solid support is a microarray slide or a bead, hi preferred embodiments, the nucleic acid molecules are genomic DNA molecules or amplified genomic DNA molecules. In preferred embodiments, the nucleic acid probes are characterized in that the frequency of the individual sequences of the immobilized nucleic acid probes corresponds to the frequency of the corresponding plurality of target nucleic acid sequences within a population of nucleic acid molecules, wherein determining the frequency comprises utilizing an empirically- fit linear regression model. In one embodiment, the present invention comprises a solid support and a plurality of nucleic acid probes immobilized on said solid support, wherein each of said plurality of immobilized nucleic acid probes provides for uniform hybridization among a plurality of target nucleic acid sequences. hi one embodiment, the present invention provides a kit for performing uniform enrichment of target nucleic acid sequences comprising one or more containers, wherein said one or more containers comprises a solid support comprising immobilized nucleic acid probes, wherein said probes are selected from a group consisting of a plurality of probes hybridizable to a plurality of target nucleic acid sequences and wherein said probes provide for uniform enrichment of said plurality of target nucleic acid sequences, and one or more reagents for performing hybridizations, washes, and elution of target nucleic acid sequences. In one embodiment, the present invention provides a process for uniform enrichment of a population of nucleic acid sequences in a sample comprising a plurality of immobilized hybridization probe sequences wherein the frequency of the individual sequences of the immobilized hybridization probes corresponds to the frequency of a plurality of corresponding target nucleic acid sequences within a population of nucleic acid molecules, and wherein said process for uniform enrichment comprises hybridizing said probes to corresponding target nucleic acid sequences and separating non-hybridized nucleic acid sequences from hybridized target nucleic acid sequences. In some embodiments, the process further comprises eluting the hybridized target nucleic acid sequences. In preferred embodiments, the hybridization of probe and target sequences within the process is performed on a solid support such as a microarray slide or bead. In preferred embodiments, determining the frequency of probe sequences comprises utilizing an empirically- fit linear regression model. In some embodiments, the sample used in the process is a genomic DNA sample. Definitions As used herein, the term \"sample\" is used in its broadest sense. In one sense, it is meant to include a nucleic acid specimen obtained from any source. Biological nucleic acid samples may be obtained from animals (including humans) and encompass nucleic acids isolated from fluids, solids, tissues, etc. Biological nucleic acid sample may also come from non-human animals, including, but are not limited to, vertebrates such as rodents, non-human primates, ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, canines, felines, aves, etc. Biological nucleic acids may also be obtained from prokaryotes, like bacteria and other non- animal eukaryotes such as plants. It is contemplated that the present invention is not limited by the source of nucleic acids sample, and any nucleic acid from any biological Kingdom finds utility in methods as described herein. As used herein, the term \"nucleic acid molecule\" refers to any nucleic acid containing molecule, including but not limited to, DNA or RNA. The term encompasses sequences that include any of the known base analogs of DNA and RNA including, but not limited to, 4-acetylcytosine, 8-hydroxy-N6- methyladenosine, aziridinylcytosine, pseudoisocytosine, 5-(carboxyhydroxyl- methyl) uracil, 5-fluorouracil, 5-bromouracil, 5- carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, dihydrouracil, inosine, N6-isopentenyladenine, 1-methyladenine, 1 -methylpseudo- uracil, 1-methylguanine, 1 -methylinosine, 2,2-dimethyl guanine, 2-methyladenine, 2-methylguanine, 3 -methyl cytosine, 5-methylcytosine, N6-methyladenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyamino- methyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarbonylmethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, oxybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N- uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, pseudouracil, queosine, 2-thiocytosine, and 2,6-diaminopurine. The used herein, the term \"oligonucleotide\" refers to a molecule comprised of two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and usually more than ten. The exact size will depend on many factors, which in turn depends on the ultimate function or use of the oligonucleotide. The oligonucleotide may be generated in any manner, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof. The term oligonucleotide may also be used interchangeably with the term \"polynucleotide.\" As used herein, the terms \"complementary\" or \"complementarity\" are used in reference to polynucleotides related by the base-pairing rules. For example, the sequence \"5'-A-G-T-3',\" is complementary to the sequence \"3'-T-C-A-5\\\" Complementarity may be \"partial,\" in which only some of the nucleic acids' bases are matched according to the base pairing rules. Or, there may be \"complete\" or \"total\" complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands has significant effects on, for example, the efficiency and strength of hybridization between nucleic acid strands, amplification specificity, etc. As used herein, the term \"hybridization\" is used in reference to the pairing of complementary nucleic acids. Hybridization and the strength of hybridization (i.e., the strength of the association between the nucleic acids) is impacted by such factors as the degree of complementary between the nucleic acids, stringency of the conditions involved, the Tm of the formed hybrid, and the G:C ratio within the nucleic acids. While the invention is not limited to a particular set of hybridization conditions, stringent hybridization conditions are preferably employed. Stringent hybridization conditions are sequence-dependent and will differ with varying environmental parameters (e.g., salt concentrations, and presence of organics). Generally, \"stringent\" conditions are selected to be about 5°C to 20°C lower than the thermal melting point (Tm) for the specific nucleic acid sequence at a defined ionic strength and pH. Preferably, stringent conditions are about 5°C to 10°C lower than the thermal melting point for a specific nucleic acid bound to a complementary nucleic acid. The Tm is the temperature (under defined ionic strength and pH) at which 50% of a nucleic acid (e.g., tag nucleic acid) hybridizes to a perfectly matched probe. As used herein the term \"stringency\" is used in reference to the conditions of temperature, ionic strength, and the presence of other compounds such as organic solvents, under which nucleic acid hybridizations are conducted. Under \"low stringency conditions\" a nucleic acid sequence of interest will hybridize to its exact complement, sequences with single base mismatches, closely related sequences (e.g., sequences with 90% or greater homology), and sequences having only partial homology (e.g., sequences with 50-90% homology). Under \"medium stringency conditions,\" a nucleic acid sequence of interest will hybridize only to its exact complement, sequences with single base mismatches, and closely relation sequences (e.g., 90% or greater homology). Under \"high stringency conditions,\" a nucleic acid sequence of interest will hybridize only to its exact complement, and (depending on conditions such a temperature) sequences with single base mismatches. In other words, under conditions of high stringency the temperature can be raised so as to exclude hybridization to sequences with single base mismatches. By way of example, \"stringent conditions\" or \"high stringency conditions,\" comprise hybridization in 50% formamide, 5x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5x Denhardt's solution, sonicated salmon sperm DNA (50 mg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C, with washes at 42°C in 0.2x SSC (sodium chloride/sodium citrate) and 50% formamide at 55°C, followed by a wash with O.lx SSC containing EDTA at 55 0 C. For moderately stringent conditions, it is contemplated that buffers containing 35% formamide, 5x SSC, and 0.1% (w/v) sodium dodecyl sulfate are suitable for hybridizing at 45°C for 16-72 hours. Furthermore, it is contemplated that formamide concentration may be suitably adjusted between a range of 20-45% depending on the probe length and the level of stringency desired. In some embodiments of the present invention, probe optimization is obtained for longer probes (for example, greater than 50 mers) by increasing the hybridization temperature or the formamide concentration to compensate for a change in the probe length. Additional examples of hybridization conditions are provided in many reference manuals, for example in \"Molecular Cloning: A Laboratory Manual\", as referenced and incorporated herein. Similarly, \"stringent\" wash conditions are ordinarily determined empirically for hybridization of target sequences to a corresponding probe array. For example, the arrays are first hybridized and then washed with wash buffers containing successively lower concentrations of salts, or higher concentrations of detergents, or at increasing temperatures until the signal-to-noise ratio for specific to nonspecific hybridization is high enough to facilitate detection of specific hybridization. By way of example, stringent temperature conditions will usually include temperatures in excess of about 30°C, more usually in excess of about 37°C, and occasionally in excess of about 45°C. Stringent salt conditions will ordinarily be less than about 1000 mM, usually less than about 500 mM, more usually less than about 150 mM. Stringent wash and hybridization conditions are known to those skilled in the art, and can be found in, for example, Wetmur, J. G., and Davidson, N., J MoI Biol 31 (1966) 349-70 and Wetmur, J.G., Crit Rev Bio MoI Biol 26(3/4) (1991) 227-59; incorporated herein by reference in their entireties. It is well known in the art that numerous equivalent conditions may be employed to adjust and regulate stringency conditions; factors such as the length and nature (DNA, RNA, base composition) of the probe and nature of the target (DNA, RNA, base composition, present in solution or immobilized, etc.) and the concentration of the salts and other components (e.g., the presence or absence of formamide, dextran sulfate, polyethylene glycol) are considered. As such, the components and concentrations of hybridization and wash solutions will vary to generate conditions of stringency. In preferred embodiments of the present invention, hybridization and wash solutions are utilized as found commercially available through Roche- NimbleGen (e.g., NimbleChip™ CGH Arrays, NimbleGen Hybridization Kits, etc.). As used herein, the term \"primer\" refers to an oligonucleotide, whether occurring naturally as in a purified restriction digest or produced synthetically, that is capable of acting as a point of initiation of synthesis when placed under conditions in which synthesis of a primer extension product that is complementary to a nucleic acid strand is induced, (i.e., in the presence of nucleotides and an inducing agent such as DNA polymerase and at a suitable temperature and pH). The primer is preferably single stranded for maximum efficiency in amplification, but may alternatively be double stranded. If double stranded, the primer is first treated to separate its strands before being used to prepare extension products. Preferably, the primer is an oligodeoxyribonucleotide. The primer must be sufficiently long to prime the synthesis of extension products in the presence of the inducing agent. The exact lengths of the primers will depend on many factors, including temperature, source of primer and the use of the method. The term \"polymerase chain reaction\" (\"PCR\") refers to a method for increasing the concentration of a segment of a target sequence in a mixture of genomic DNA without cloning or purification. This process for amplifying the target sequence consists of introducing a large excess of two oligonucleotide primers to the DNA mixture containing the desired target sequence, followed by a precise sequence of thermal cycling in the presence of a DNA polymerase. The two primers are complementary to their respective strands of the double stranded target sequence. To effect amplification, the mixture is denatured and the primers then annealed to their complementary sequences within the target molecule. Following annealing, the primers are extended with a polymerase so as to form a new pair of complementary strands. The steps of denaturation, primer annealing, and polymerase extension can be repeated many times (i.e., denaturation, annealing and extension constitute one \"cycle\"; there can be numerous \"cycles\") to obtain a high concentration of an amplified segment of the desired target sequence. The length of the amplified segment of the desired target sequence is determined by the relative positions of the primers with respect to each other, and therefore, this length is a controllable parameter. With PCR, it is possible to amplify a single copy of a specific target sequence in genomic DNA to a level detectable by several different methodologies known to those skilled in the art. In addition to genomic DNA, any oligonucleotide or polynucleotide sequence can be amplified with the appropriate set of primer molecules. In particular, the amplified segments created by the PCR process itself are, themselves, efficient templates for subsequent PCR amplifications. Ligation mediated PCR refers to PCR that is performed, wherein the primers are homologous (e.g., complementary) to linkers that are ligated to the ends of DNA (e.g., DNA fragments). As used herein, the term \"probe\" refers to an oligonucleotide (i.e., a sequence of nucleotides), whether occurring naturally as in a purified restriction digest or produced synthetically, recombinantly or by PCR amplification, that is capable of hybridizing to at least a portion of another oligonucleotide of interest. A probe may be single-stranded or double-stranded, however in the present invention the probes are intended to be single stranded. Probes are useful in the detection, identification and isolation of particular gene sequences As used herein, the term \"portion\" when in reference to a nucleotide sequence (as in \"a portion of a given nucleotide sequence\") refers to fragments of that sequence. The fragments may range in size from four nucleotides to the entire nucleotide sequence minus one nucleotide (10 nucleotides, 20, 30, 40, 50, 100, 200, etc.). As used herein, the term \"purified\" or \"to purify\" refers to the removal of components (e.g., contaminants) and/or contaminants from a sample. The term \"purified\" refers to molecules, either nucleic or amino acid sequences that are removed from their natural environment, isolated or separated. An \"isolated nucleic acid sequence or sample\" is therefore a purified nucleic acid sequence or sample. \"Substantially purified\" molecules are at least 60% free, preferably at least 75% free, and more preferably at least 90% free from other components with which they are naturally associated. Description of the Figures Figure 1 demonstrates exemplary probe redistribution data using empirical optimization to mitigate locally-biased target capture: a) read depths along the core 200kbp region of nested target intervals in five separate capture experiments demonstrate larger target regions correlate with lower sequencing depth; b) capture response calculated within one localized window by fitting windowed read depth to capture probe density across the capture experiments; c) capture response along the targeted region demonstrates areas of bias with excessive or insufficient capture; d) a control array demonstrates probes uniformly distributed along the target; e) whereas in the optimized array probes are redistributed non-uniformly so as to achieve a uniform distribution of reads following capture and sequencing. Figure 2 demonstrates the relative coverage depth plotted along the capture target region of an exemplary control (Control, light line) and rebalanced (Rebal, dark line) probe redistribution experiment. The variance in coverage is less severe for the redistributed array when compared to the control array. Figure 3 demonstrates exemplary schematics for target enrichment: a) a schematic depicting nucleic acid molecules and probe utilization as found in an embodiment of the present invention, prior to probe redistribution, and b) a schematic of an exemplary microarray genomic target enrichment strategy of the present invention. Figure 4 demonstrates the effect of exon length on probe density. Figure 5 demonstrates lack of any aggregate-level effect of exon length on probe capture response. Figure 6 depicts a comparison of the standard deviations of the target locus sequence coverage distributions from experiments using five different rebalanced designs (RebalA through RebalE) and a baseline (HumanExon7Chip) following a standard tiling design. Detailed description of the invention Targeted genomic sequencing is one of the most important biomedical applications of next-generation sequencing technologies. A revolutionary way to target next generation sequencing utilizes oligonucleotide microarrays as sample preparation devices. These arrays capture regions of the genome defined by the array probes, which are then eluted and, for example, sequenced. Because of the relatively high per run cost of next generation sequencing, it is important to have robust quality control metrics that ensure that only samples that are highly enriched for target regions are sequenced. Two important characteristics of successfully captured samples are 1) highly enriched for targeted regions, and 2) uniformly enriched across all targeted regions. The present invention provides assays that demonstrate uniform enrichment across target areas of a genome. Sequence capture in a microarray format facilitates selective enrichment of nucleic acids prior to downstream applications, for example sequencing. When performing selective enrichment, a nucleic acid sample, for example a DNA or RNA sample, is hybridized to a microarray comprised of oligonucleotide probes complementary to desired target sequences. The targeted, captured nucleic acids are eluted from the array, with the resulting fraction being enriched by several orders of magnitude for targeted fragments when compared to a control array. Enrichment methods are more completely described in US Patent Application Numbers 11/789,135 and 11/970,949 and World Intellectual Property Organization Application Number PCT/US07/010064, and further in Albert, T.J., et al., Nat. Meth., 4 (2007) 903-5, Okou, D.T., et al., Nat. Meth. 4(11) (2007) 907-9 and Hodges, E., et al., Nature Genetics 39(12) (2007) 1522-7; all of which of incorporated herein by reference in their entireties. Many downstream applications strongly depend upon, for example, an approximately uniform distribution of capture over the target capture region, as it is contemplated that disproportionately high representation of some targets deplete other targets. In developing embodiments of the present invention, novel methods were developed to deal with this biased, disproportionate target capture, wherein probes are redistribution from targets demonstrating above average enrichment to probes demonstrating below average enrichment. As demonstrated herein, the probe redistribution methods of the present method significantly improve the uniformity of enrichment among captured targets. The present invention provides methods for determining and designing microarrays comprising redistributed oligonucleotide probes to allow for uniform, or intentionally non-uniform, capture of target nucleic acid molecules. In developing embodiments of the present invention, capture and sequencing microarray experiments were performed using a nested set of target regions centered on human chromosome 17q21.31. As an indirect measure of target sequence relative abundance following capture, the depth of sequence coverage was calculated as the number of reads containing a given target base averaged over the target area. It was observed that a significant and reproducible bias among the common target regions existed among the microarrays, such that coverage depth spanned nearly three orders of magnitude and was highly correlated between experiments (pairwise 0.85