Title of Invention: IDENTIFYING MODIFIED BASES USING HEMI-NATURAL NUCLEIC ACIDS Abstract: Methods, compositions, and systems are provided for characterization of modified nucleic acids. Methods are provided for sequencing hemi-natural nucleic acids such as hemi-genomic DNA, having two complementary strands, one a natural sequence and the other a synthetic sequence. The identification of modified bases can be enhanced by comparing the sequencing information from the natural sequence, which has, for example, natural base modifications, with the synthetic sequence, which typically has no base modifications. The presence and identity of a modified base can be determined by monitoring kinetics, for example the kinetics of polymer meditated nucleic acid synthesis. Detailed Description: CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser. No. 14/618,311, filed Feb. 10, 2015, which is a continuation application of U.S. patent application Ser. No. 13/914,361, filed Jun. 10, 2013, which claims the benefit of Provisional U.S. Patent Application No. 61/657,583, filed Jun. 8, 2012, the full disclosures of which are incorporated herein by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION Assays for analysis of biological processes are exploited for a variety of desired applications. For example, monitoring the activity of key biological pathways can lead to a better understanding of the functioning of those systems as well as those factors that might disrupt the proper functioning of those systems. In fact, various different disease states caused by operation or disruption of specific biological pathways are the focus of much medical research. By understanding these pathways, one can model approaches for affecting them to prevent the onset of the disease or mitigate its effects once manifested. A stereotypical example of the exploitation of biological process monitoring is in the area of pharmaceutical research and development. In particular, therapeutically relevant biological pathways, or individual steps or subsets of individual steps in those pathways, are often reproduced or modeled in in vitro systems to facilitate analysis. By observing the progress of these steps or whole pathways in the presence and absence of potential therapeutic compositions, e.g., pharmaceutical compounds or other materials, one can identify the ability of those compositions to affect the in vitro system, and potentially beneficially affect an organism in which the pathway is functioning in a detrimental way. By way of specific example, reversible methylation of the 5′ position of cytosine by methyltransferases is one of the most widely studied epigenetic modifications. In mammals, 5-methylcytosine (5-MeC) frequently occurs at CpG dinucleotides, which often cluster in regions called CpG islands that are at or near transcription start sites. Methylation of cytosine in CpG islands can interfere with transcription factor binding and is associated with transcription repression and gene regulation. In addition, DNA methylation is known to be essential for mammalian development and has been associated with cancer and other disease processes. Recently, a new 5-hydroxymethylcytosine epigenetic marker has been identified in certain cell types in the brain, suggesting that it plays a role in epigenetic control of neuronal function (S. Kriaucionis, et al., Science 2009, 324(5929): 929-30, incorporated herein by reference in its entirety for all purposes). In contrast to determining a human genome, mapping of the human methylome is a more complex task because the methylation status differs between tissue types, changes with age, and is altered by environmental factors (P. A. Jones, et al., Cancer Res 2005, 65, 11241, incorporated herein by reference in its entirety for all purposes). Comprehensive, high-resolution determination of genome-wide methylation patterns from a given sample has been challenging due to the sample preparation demands and short read lengths characteristic of current DNA sequencing technologies (K. R. Pomraning, et al., Methods 2009, 47, 142, incorporated herein by reference in its entirety for all purposes). Bisulfite sequencing is a currently used method for single-nucleotide resolution methylation profiling (S. Beck, et al., Trends Genet 2008, 24, 231; and S. J. Cokus, et al., Nature 2008, 452, 215, the disclosures of which are incorporated herein by reference in their entireties for all purposes). In another widely used technique, methylated DNA immunoprecipitation (MeDIP), an antibody against 5-MeC is used to enrich for methylated DNA sequences (M. Weber, et al., Nat Genet 2005, 37, 853, incorporated herein by reference in its entirety for all purposes). MeDIP has many advantageous attributes for genome-wide assessment of methylation status, but it does not offer as high base resolution as bisulfate treatment-based methods. In addition, it is also hampered by the same limitations of current microarray and second-generation sequencing technologies. Research efforts aimed at increasing our understanding of the human methylome would benefit greatly from the development of a new methylation profiling technology that does not suffer from the limitations described above. Accordingly, there exists a need for improved techniques for detection of modifications in nucleic acid sequences, and particularly nucleic acid methylation. Typically, modeled biological systems rely on bulk reactions that ascertain general trends of biological reactions and provide indications of how such bulk systems react to different effectors. While such systems are useful as models of bulk reactions in vivo, a substantial amount of information is lost in the averaging of these bulk reaction results. In particular, the activity of and effects on individual molecular complexes cannot generally be teased out of such bulk data collection strategies. Nanopore sequencing has been demonstrated to be capable of identifying bases in a single nucleic acid strand passed through the nanopore at single base resolution. The bases can be differentiated by their differential blocking of the nanopore as they pass through the pore. While in some cases, modified bases may be identified by their current blocking characteristics, it can be difficult to differentiate these bases from the four canonical bases and from other modified bases. There exists a need for improved nanopore sequencing that provides more reliable information about the modified bases that occur in natural nucleic acids. BRIEF SUMMARY OF THE INVENTION In some aspects, the invention provides a method for sequencing a nucleic acid template and identifying modified bases therein comprising: providing a substrate having an upper solution above the substrate and a lower solution below the substrate, the substrate comprising a nanopore connecting the upper solution and lower solution, the nanopore sized to pass a single stranded nucleic acid; providing a voltage across the nanopore to produce a measurable current flow through the nanopore; controlling the rate of translation of a single stranded portion of the template nucleic acid through the pore with a processive enzyme associated with a template nucleic acid; measuring the current through the nanopore over time as it is translated through the nanopore; determining the sequence of a portion of the template nucleic acid as it translates through the pore using the measured current over time; and determining the presence of modified nucleic acids in the template nucleic acid by correlating changes in the rate of transport of the nucleic acid to changes through the nanopore to the kinetics of the processive enzyme from the interaction of the modified base with the processive enzyme. The template nucleic acid can be sequenced multiple times. The processive enzyme can comprise a polymerase, exonuclease, or helicase activity. The processive enzyme can comprise a DNA polymerase. The DNA polymerase can have a 3′ to 5′ exonuclease activity. The processive enzyme can comprise a helicase. In some aspects, the invention provides a method for sequencing a nucleic acid comprising: providing a substrate having an upper solution above the substrate and a lower solution below the substrate, the substrate comprising a nanopore connecting the upper solution and lower solution, the nanopore sized to pass a single stranded nucleic acid; providing a voltage across the nanopore to produce a measurable current flow through the nanopore; controlling the rate of translation of a single stranded portion of the template nucleic acid through the pore with a processive enzyme associated with the template nucleic acid; measuring the current through the nanopore over time as it is translated through the nanopore; and determining the sequence of a portion of the template nucleic acid as it translates through the pore using the measured current over time; wherein the template nucleic acid comprises hemi-genomic DNA comprising a genomic strand and a nascent strand. The nascent strand can be translated through the pore. The genomic strand can be translated through the pore. The genomic strand and nascent strand can be attached through a hairpin loop and both strands are translated through the pore. The processive enzyme can comprise polymerase, exonuclease, or helicase activity. The processive enzyme can comprise a DNA polymerase. The DNA polymerase can have a 3′ to 5′ exonuclease activity. The processive enzyme can comprise a helicase. The template nucleic acid can be sequenced multiple times. In some aspects, the invention provides a nucleic acid template for nanopore sequencing comprising a strand comprising natural nucleic acid sequence and a synthetic nucleic acid sequence that is complementary to the natural nucleic acid sequence. The nucleic acid template can comprise the natural sequence hybridized to the synthetic sequence, and the sequences connected through a hairpin loop. The natural sequence and the synthetic sequence can be part of a nucleic acid strand that is hybridized to a synthetic strand. The nucleic acid template can comprise a second synthetic sequence that is substantially identical with the natural sequence. The natural sequence can be 5′ of the synthetic sequence. The natural sequence can be 3′ of the synthetic sequence. The nucleic acid can comprise DNA and the natural sequence can comprise a genomic sequence. In some aspects, the invention provides a method for sequencing a nucleic acid comprising: providing a substrate having an upper solution above the substrate and a lower solution below the substrate, the substrate comprising a nanopore connecting the upper solution and lower solution, the nanopore sized to pass a single stranded nucleic acid; providing a voltage across the nanopore to produce a measurable current flow through the nanopore; controlling the rate of translation of a single stranded portion of the template nucleic acid through the pore with a processive enzyme associated with a template nucleic acid; measuring the current through the nanopore over time as it is translated through the nanopore; and determining the sequence of a portion of the template nucleic acid as it translates through the pore using the measured current over time; wherein the template nucleic acid comprises a strand comprising natural nucleic acid sequence and a synthetic nucleic acid sequence that is complementary to the natural nucleic acid sequence, whereby both the natural nucleic acid sequence and the synthetic nucleic acid sequences are translated through the pore. The method can further comprise using sequence information from the synthetic sequence to identify a modified base present in the natural nucleic acid sequence. The template nucleic acid can further comprise a second synthetic sequence that is substantially identical with the natural sequence. The processive enzyme can comprise polymerase, exonuclease, or helicase activity. The processive enzyme can comprise a DNA polymerase. The processive enzyme can comprise a helicase. The template nucleic acid can be sequenced multiple times. In some aspects, the invention provides a method for nanopore sequencing with reduced error comprising; providing a substrate having an upper solution above the substrate and a lower solution below the substrate, the substrate comprising a plurality of nanopores connecting the upper solution and lower solution, the nanopores sized to pass single stranded nucleic acids; providing a voltage across the nanopores to produce a measurable current flow through the nanopores; measuring the current through the nanopores over time as the nucleic acid templates are translated through the nanopore; measuring the sequence of a portion of a plurality template nucleic acids as they translate through the pore using the measured current over time; wherein some of the plurality of template nucleic acids comprise the same sequence, and wherein the sequence of some of the plurality of nucleic acids is measured under one set of reaction conditions, and the sequence of some of the plurality of nucleic acids is measured under a second set of reaction conditions, where the first and second reaction conditions each provide different error profiles, and determining a sequence by combining the measured sequences under the first and second reaction conditions to obtain a reduced error rate than for a sequence determined under one reaction condition. The method can further comprise controlling the rate of translation of a single stranded portion of the template nucleic acid through the pore with a processive enzyme associated with a template nucleic acid. The two reaction conditions can comprise two different types of nanopores. The two reaction conditions can comprise two different types of processive enzymes. The combined sequences can represent sequences on a single molecule. The combined sequences can represent sequences on different molecules. The change in reaction condition can comprise a change in the temperature, pH, or in the level of divalent cation or a combination of these. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a method of the invention in which modified base detection and sequencing is carried out in a nanopore with a polymerase translating enzyme. FIG. 2 illustrates a method of the invention in which modified base detection and sequencing is carried out in a nanopore with an exonuclease translating enzyme. FIG. 3 illustrates a method of the invention in which modified base detection and sequencing is carried out in a nanopore with a polymerase translating enzyme. FIG. 4 illustrates a method of the invention in which modified base detection and sequencing is carried out in a nanopore with a helicase translating enzyme. In FIG. 4A, nucleotides 430, 432, and 434 are within the nanopore and nucleotide 414 is associated with the enzyme, in FIG. 4B, nucleotides 430, 432, and 434 have passed through the nanopore and nucleotide 414 is within the nanopore. FIG. 5 illustrates a method of the invention in which repeated modified base detection and sequencing is carried out on the same molecule in a nanopore with a helicase translating enzyme. FIG. 5A shows a DNA strand being sequenced with nanopore extending through a substrate. In FIG. 5B the applied voltage across the nanopore is reversed in order to pull the DNA strand up into the pore. FIG. 5C shows how a DNA strand can re-anneal with its complementary strand. FIG. 5D illustrates how the process can be repeated. FIG. 6 illustrates how nanopore loading and sequencing/modified base detection are carried out with a polymerase translating enzyme and a circular template. In FIG. 6A, a complex is formed between the circular nucleic acid and the polymerase enzyme. In FIG. 6B, polymerase mediated nucleic acid synthesis is carried out around the circle until it begins to displace the nascent strand. In FIG. 6C, the complex having the extended nascent strand is loaded into a nanopore. In FIG. 6D, sequencing and detection of base modification is carried out by adding the reagents for polymerase mediated nucleic acid added, and applying a voltage to hold the polymerase on the nanopore and to provide a force on the strand. FIG. 7 illustrates how nanopore loading and sequencing/modified base detection are carried out with a helicase translating enzyme. In FIG. 7A, a helicase is mixed with a nucleic acid. In FIG. 7B, the helicase forms a complex with the nucleic acid. In FIG. 7C, a voltage is applied across the nanopore to draw the strand into the pore. In FIG. 7D, the helicase activity pulls apart the strands, paying out one strand through the pore as the voltage applied pulls the strand through the pore at a rate controlled by the helicase. FIG. 8 illustrates using a splint oligo to deliver a hairpin blocker into a nanopore. FIG. 8A shows an example of the structure of a template nucleic acid having a splint strand hybridized so as to prevent formation of the hairpin structure until its removal. FIG. 8B shows how the hairpin forms on one side of the nanopore after the splint strand has been displaced, forming a blockage. FIG. 9 shows some representative modified bases. FIG. 10 shows a method for making hemi-natural nucleic acid with a 3′ overhang. FIG. 11 shows a method for making hemi-natural nucleic acid with a 5′ overhang. FIG. 12 shows alternative adaptors for making hemi-natural nucleic acid templates. FIG. 12A shows an adaptor with a hairpin that can be used, for example to put a hairpin at one end of the double stranded natural nucleic acid fragment. FIG. 12B shows an adaptor that can be used to produce a different overhang region on each strand. FIG. 12C illustrates an adaptor having a primer with a 5′ non-hybridized portion that can be used to produce a 5′ single stranded overhang for loading into the nanopore. FIG. 13 illustrates the end of a template for loading having an overhang region for loading into the nanopore, and a non-complementary region in the other strand. FIG. 14 shows representative structures for the hemi-natural nucleic acid (e.g. hemi-genomic DNA) templates of the invention. FIGS. 14A, 14B, 14C, and 14D show different types of templates with a natural sequence, a complementary sequence, and a hairpin nucleic acid connecting the sequences. FIG. 14E shows a template nucleic acid with a natural sequence and a synthetic sequence connected by a connecting nucleic acid in one strand, with a complementary synthetic strand hybridized to it. FIG. 14F shows a template nucleic acid having a natural sequence and a synthetic sequence on the same strand connected by a connecting nucleic acid. FIG. 14G shows a template nucleic acid with a natural sequence connected through a connector nucleic acid to synthetic sequence. FIG. 15A shows a method for obtaining a template for nanopore sequencing having a natural sequence and a synthetic sequence that are substantially identical with a complementary synthetic sequence between. FIG. 15B shows a method for obtaining a template for nanopore sequencing having a natural sequence and a synthetic sequence that are substantially identical with a complementary natural sequence between. DETAILED DESCRIPTION OF THE INVENTION The invention provides devices, methods, and compositions for sequencing nucleic acids and for identifying modified bases using nanopores. Single-stranded nucleic acids are transported through a nanopore using at translating enzyme to control the rate of transport the nucleic acid. An applied voltage passes ions through the nanopore while the nucleic acid is being translated. Each of the bases in the nucleic acid blocks the pore in a measurably different way, allowing for identification of the bases in the strand, and thereby sequencing the nucleic acid. The bases are identified, for example, by current or capacitance changes. The invention allows for the improved identification of non-natural, or modified bases by correlating the kinetics of passage of the bases through the pore with the kinetics of the translating enzyme. We have determined that under certain conditions, the kinetics of the translating enzyme can be directly determined by measuring the transport of the bases through the nanopore. In particular, the applied voltage is adjusted to apply a force to the translated nucleic acid strand such that the rate of translation of the nucleic acid through the pore is substantially equivalent to the rate of processing the nucleic acid by the translating enzyme. We have found that sequencing of nucleic acids, and the identification of modified nucleic acids can be significantly enhanced by using a hemi-natural nucleic acid, and in particular a hemi-genomic DNA strand. In a hemi-natural nucleic acid, one strand is the natural strand, e.g. the strand from the organism, and the other strand is a synthesized (or nascent) strand. The nascent strand is typically produced with only the four canonical bases (A, G, C and T, or A, G, C and U). An advantage of using hemi-natural nucleic acids in nanopore sequencing of nucleic acids with modified bases is that only one of the strands that is interacting with the translating enzyme will contain the modified bases. This can significantly reduce the complexity of the calling of the modified base in some cases as compared to analyzing a fully natural nucleic acid. There are two modes for using hemi-natural nucleic acids in nanopore sequencing, one in which the nascent strand is transported through the pore, and the other, in which the genomic strand is translated through the pore. When passing only the nascent strand of the hemi-natural nucleic acid through the pore, no modified bases are translated through the pore, and yet their presence can be determined by the changes in rate that they cause at the transporting enzyme. Use of the nascent strand has the advantage that, since the modified bases do not translate through the pores, one only has to call out the identity of four bases using current or capacitance, and there is no need uncertainty caused by passage of a different base through the pore. This method can also be useful with modified bases that have structures that make it difficult for the base to pass through the pore. This can be the case, for example, for a glucosylated base, where the sugar moiety is large enough that it may not make it through the nanopore. In some cases, the genomic strand of the hemi-natural nucleic acid can be translated through the nanopore. For this mode, the modified base will pass through the nanopore either prior to, or after the modified base interacts with the translating protein. While this method requires calling of the modified base in addition to the four canonical bases by their relative blockage of the nanopore, it provides an additional indication of the presence of the modified base, allowing in some cases for enhanced accuracy. This mode allows for the combination of the kinetics at the translating enzyme and the relative blockage of current at the nanopore to be used to identify a modified base. Under the appropriate conditions, the modified base will pass through the nanopore a specific number of bases away from the identifiable kinetic event at the translating enzyme. We have found that hemi-natural nucleic acids, and in particular, hemi-genomic DNA can be used in nanopore sequencing even where one is not attempting to call out the modified bases in a nucleic acid sample. For example, if genomic DNA is directly used in nanopore sequencing, the modified bases in the DNA can give rise to errors in calling the identity of the four canonical bases. While this issue can be ameliorated by amplifying the genomic DNA and sequencing completely synthetic DNA, each round of amplification can give rise to defects, which will produce errors in the measured sequence. By sequencing the nascent strand of the hemi-genomic DNA, one gets the benefit that only the four canonical bases are passed through the nanopore, and since there is only one replication step to form the nascent strand, replication errors are minimized. Some aspects of the invention provide for repeated sequencing of the same molecule multiple times. In any sequencing method, including nanopore sequencing, there will be some level of errors in base calling. In addition, even for a reaction with a specific rate constant, kinetic rates measured on the single molecule level will typically result in a range of rate values for that given process, making base calling by rate difficult from only a single value. The methods of the invention are generally performed repeatedly on the same molecule providing significantly improved accuracy. Repeated sequencing approaches are described in more detail below. In order to perform repeated sequencing on the same molecule, it is generally desirable that the molecule not be released from the pore between sequence determinations. The templates of the instant invention generally have blocking groups attached to them (typically at the end). The blocking groups prevent the release of the template from the pore under sequencing conditions. In some cases, the blocking groups are located on both ends of a strand that is sequenced, preventing it from being released on either side of the pore. In some cases, reversible blocking groups are employed, allowing for the release of the nucleic acid strand after sequencing is completed. We have found that hairpin regions in the nucleic acid strand can be used to prevent the nucleic acid strand from being released, for example using a nanopore that is sized to pass a single strand but not a double strand. By increasing the applied voltage, one can provide enough force to peel away the hairpin to allow release. In preferred aspects, a hairpin stopper is ligated to the end of the strand to be sequenced. The hairpin stopper has two complementary sequences and an intermediate hairpin region between them. A splint oligonucleotide is hybridized to the strand before loading. Upon loading, the splint oligonucleotide is peeled away at the pore, and the complementary regions of the hairpin stopper form a hairpin after passing through the pore. This hairpin acts as a blocker during sequencing the strand. The strand can be subsequently removed from the pore by applying enough drive voltage to peel apart the hairpin, or to change the stringency of the medium to open up the complementary regions of the hairpin. The invention is generally described by reference to a single nanopore, but the invention anticipates using arrays of nanopores from e.g. 10 nanopores to about 10 million nanopores. In some cases arrays of 10 nanopores to 1000 nanopores are used. In some cases, arrays of nanopores of about 100 to about 10,000 nanopores are used. In some cases, arrays of nanopore from about 1,000 to about 1 million nanopores are used. Methods of carrying out nanopore sequencing in arrays of nanopores is described, for example in U.S. Ser. No. 13/083,320 filed Apr. 8, 2011. The mode that is applied can be chosen based on the type of translating enzyme that is used, and which strand is being translated through the pore. For example, the mode that is selected can depend on whether the translating enzyme is a polymerase, an exonuclease, or a helicase. FIG. 1 shows an example of an embodiment of the invention using a polymerase enzyme as the translating enzyme in which the polymerase pulls the single stranded nucleic acid up through the pore as it adds nucleotides to a growing strand. A substrate 102 has a nanopore 104 extending through it. As shown in the figure, the substrate 102 comprises a lipid bilayer, and the nanopore 104 is formed using a biological transmembrane protein such as MspA. The embodiment shown could be carried out with other suitable substrates and with a nanopore such as a solid state or hybrid nanopore. The polymerase enzyme 110 is associated with a region of a nucleic acid strand (e.g. DNA) 106 which extends through the nanopore with its 5′ end. The nucleic acid strand experiences a force pulling it into the pore due to a voltage that is applied across the nanopore. Hybridized to a portion of nucleic acid strand 106 is complementary strand 108 that ends at a 3′ terminus hybridized to strand 106. A polymerase enzyme 110 is associated with nucleic acid strand at the position of the 3′ terminus of complementary strand 108. In the figure, the polymerase enzyme is shown attached to the substrate (e.g. to the biological nanopore). In some cases, the polymerase is not attached, but is held in place by the force of the electric field pulling on the nucleic acid strand 106. The medium surrounding the polymerase enzyme has the components required for nucleic acid synthesis including nucleotides and cofactors. As the polymerase adds nucleotides such as 112 to the growing complementary strand 108, the nucleic acid strand 106 is pulled up into the nanopore in the direction against the force on the nucleic acid strand from the voltage across the pore. By controlling the force on nucleic acid strand 106 (e.g. by controlling the applied voltage), the number of bases 120 between the active site of the enzyme and nanopore will remain relatively constant throughout the process. Where the number of bases between the enzyme and the nanopore is constant, the rate of passage of bases through the nanopore will be equivalent to the rate of nucleic acid synthesis by the polymerase enzyme. Where the number of bases 120 is controlled, we have determined that changes in the rate of nucleic acid synthesis due to the presence of modified bases can be used to identify modified bases in the nucleic acid strand 106. For example, consider a modified base 114 in nucleic acid strand 106 that slows or otherwise modifies the nucleic acid synthesis rate. At the instant the rate of polymerization is slowed by base 114, the rate of transport of bases through the nanopore is also slowed by the same amount. In the figure, the nanopore has a region in which the presence of three bases 130, 132, and 134 determines the current through the pore. By knowing the current level for all of the triads of bases, the bases can be called at single base resolution as the bases are drawn through the nanopore. The slowing of the polymerase by base 114 is measured as a slowing in the translation of bases 130, 132, and 134 through the pore. If the number of bases 120 between the nanopore and the modified base at the position the base slows the polymerase is known, then the presence of the modified base at that position can be determined. In some cases, modified bases can produce kinetic changes at positions other than when the modified base is in the active site of the enzyme. In fact, the changes in kinetics can occur before, during, or after the modified base is in the active site of the polymerase. In some cases, the modified base can cause a series of kinetic changes, resulting in a distinctive pattern of kinetic changes. The pattern of kinetic changes can involve 2, 3, 4, 6, 7, 8, or more kinetic changes, some or all of which can occur before, during, or after the modified base is in the active site of the polymerase. The kinetic change can be a change in the time for a one base transition in the current or capacitance signal. The kinetic change can also involve other measured parameters such as the noise level in the signal, or the shape of the transition signal, for example, noise color as described in more detail below. Sequencing is performed as nucleotides added from solution, e.g. 112, lengthen complementary strand 108 and thereby pull the single nucleic acid strand into the pore. Consider the case in which base 134 has a modified base. As the nucleic acid strand is pulled up into the pore, base 134 will be present during three single base transitions. Since base 134 is modified, it will generally have a different signal than any of the canonical bases (See e.g. Mirsaidov, U. et al. Nanoelectromechanics of methylated DNA in a synthetic nanopore. Biophys. J. 96, L32-L34 (2009); Wanunu, M. et al. Discrimination of methylcytosine from hydroxymethylcytosine in DNA molecules. J. Am. Chem. Soc. 133, 486-492 (2010) and Botstein, D. & Risch, N. Discovering genotypes underlying human), each of which is incorporated by reference herein for all purposes. Thus, for three separate single base transitions, the presence of the modified base is detected. Then, some number of bases later, depending on the number of bases between the nanopore measurement position and the position at which the base affects the kinetics of the polymerase enzyme, a kinetic change from the presence of the base as it interacts with the translating enzyme will be measured. For this system, the kinetics of the interaction of the modified base with the polymerase enzyme, and the distinct current signature for the base as it passes through the pore can be used together to call out the identity and position of the modified base. The number of bases between when the base is in the nanopore and when it is in the position to provide a kinetic signature can be determined by sequencing and simultaneously determining kinetics of the base modification using a known sample. By correlating the measured kinetics with the known sequence of bases as they pass through the nanopore, the number of bases between the bases in the nanopore and position of the base when providing the kinetic signature can be determined Since, in accordance with the instant invention, conditions are used which keep the number of bases between the bases in the nanopore and the base in the active site constant, once the relevant number of bases is determined for known samples, it can be used to identify the positions of modified bases in unknown samples. The nucleic acid can comprise DNA, RNA, or mixtures of DNA and RNA. For example, in FIG. 1, both of the strands can be DNA, and the enzyme is a DNA polymerase. Alternatively, the strand passing through the nanopore can be RNA, and the nascent strand can be DNA, and the enzyme is a reverse transcriptase. Other combinations including where both strands are RNA or where either strand has RNA and DNA portions can be used. FIG. 2 shows an example of an embodiment of the invention using a 3′ to 5′ exonuclease enzyme as the translating enzyme in which the enzyme pays out the single stranded nucleic acid through the pore as it removes nucleotides from a complementary strand. The term exonuclease enzyme refers to an enzyme having exonuclease activity. Thus, for example, an exonuclease enzyme could refer to a polymerase enzyme having exonuclease activity. A substrate 202 has a nanopore 204 extending through it. As shown in the figure, the substrate 202 comprises a lipid bilayer, and the nanopore 204 is formed using a biological transmembrane protein such as MspA. The embodiment shown can be carried out with other suitable substrates and with a nanopore such as a solid state or hybrid nanopore. The exonuclease enzyme 210 is associated with a region of a nucleic acid strand (e.g. DNA) 206 which extends through the nanopore with its 5′ end. The nucleic acid strand experiences a force pulling it into the pore due to a voltage that is applied across the nanopore. Hybridized to a portion of nucleic acid strand 206 is complementary strand 208 that ends at a 3′ terminus, hybridized to strand 206. An exonuclease enzyme 210 is associated with nucleic acid strand at the position of the 3′ terminus of complementary strand 208. In the figure, the exonuclease enzyme is shown attached to the substrate (e.g. to the biological nanopore). In some cases, the exonuclease is not attached, but is held in place by the electric field applying a force pulling on the nucleic acid strand 106. The medium surrounding the exonuclease enzyme has the components required for nucleic acid synthesis including appropriate cofactors. As the exonuclease removes nucleotides such as 212 from the growing complementary strand 208, the nucleic acid strand 206 is paid out into the nanopore in the direction of the force on the nucleic acid strand from the voltage across the pore. By controlling the force on nucleic acid strand 206 (e.g. by controlling the applied voltage), the number of bases 220 between the active site of the enzyme and nanopore will remain relatively constant throughout the process. Where the number of bases between the exonuclease enzyme and the nanopore is constant, the rate of passage of bases through the nanopore will be equivalent to the rate of nucleic acid excision by the exonuclease enzyme. Where the number of 220 is controlled, we have determined that changes in the rate of nucleic acid synthesis due to the presence of modified bases can be used to identify modified bases in the nucleic acid strand 206. For example, consider a modified base 214 in nucleic acid strand 206 that slows or otherwise modifies the base excision rate. At the time the rate of polymerization is slowed by base 214, the rate of transport of bases through the nanopore is also slowed by the same amount. In the figure, the nanopore has a region in which the presence of three bases 230, 232, and 234 determines the current through the pore. By knowing the current level for all of the triads of bases, the bases can be called at single base resolution as the bases are drawn through the nanopore. The slowing of the exonuclease by base 214 is measured as a slowing in the translation of bases 230, 232, and 234 through the pore. If the number of bases 320 between the nanopore and the modified base at the position the base slows the polymerase is known, then the presence of the modified base at that position can be determined. In some cases, modified bases can produce kinetic changes at positions other than when than when the modified base is in the active site of the enzyme. In fact, the changes in kinetics can occur before, during, or after the modified base is in the active site of the exonuclease. In some cases, the modified base can cause a series of kinetic changes, resulting in a distinctive pattern of kinetic changes. The pattern of kinetic changes can involve 2, 3, 4, 6, 7, 8, or more kinetic changes, some or all of which can occur before, during, or after the modified base is in the active site of the exonuclease. The kinetic change can be a change in the time for a one base transition in the current or capacitance signal. The kinetic change can also involve other measured parameters such as the noise level in the signal, or the shape of the transition signal, for example, noise color as described in more detail below. Sequencing is performed as nucleotides, e.g. 212, are removed by the exonuclease from strand 208, shortening complementary strand 208 and thereby paying out the single nucleic acid strand 206 into the pore. Consider the case in which base 214 has a modified base. As the nucleic acid strand is paid out through the pore, base 214 will be interacting with the exonuclease, modifying its rate. At the time that base 214 is modifying the rate of the exonuclease enzyme, buses 230, 232, and 234 are in the nanopore, and their sequence is being determined. Then, some number of bases later, base 214 will pass through the nanopore. As it passes through the nanopore, the presence of the modified base can be determined, for example, by its current blockage characteristics. It can be useful to use a hemi-natural nucleic acid for this method in which strand 206 comprises a natural nucleic acid, and strand 208 comprises a synthetic nucleic acid. Using hemi-natural nucleic acid ensures that the measured kinetic changes are due only to bases in the genomic strand 206. For this system, the kinetics of the interaction of the modified base with the exonuclease enzyme, and the distinct current signature for the base as it passes through the pore can be used together to call out the identity and position of the modified base. Another approach is one in which strand 208 comprises a natural nucleic acid (genomic DNA). In this case, base 212 in strand 208 (prior to release) comprises a modified base. The base 212 can cause kinetic changes in the exonuclease enzyme as it interacts with the enzyme prior to or during its excision. These characteristic kinetic changes can provide the information that base 212 is a modified base, and where the number of bases between the kinetic changes at the exonuclease enzyme and the bases in the nanopore is known (as provided herein), the position of the modified base 212 on complementary strand 208 can be established. For this approach, it is useful to use hemi-genomic DNA in which strand 208 comprises genomic DNA, and strand 206 comprises synthesized DNA. FIG. 3 shows another example of an embodiment of the invention using a polymerase enzyme having strand displacement activity. In this method, the polymerase acts as the translating enzyme wherein the polymerase pays out a single stranded nascent nucleic acid through the pore as it adds nucleotides to a growing strand. A substrate 302 has a nanopore 304 extending through it. As shown in the figure, the substrate 302 comprises a lipid bilayer, and the nanopore 304 is formed using a biological transmembrane protein such as MspA. The embodiment shown could be carried out with other suitable substrates and with a nanopore such as a solid state or hybrid nanopore. The polymerase enzyme 310 is associated with a region of a circular nucleic acid strand (e.g. DNA) 208, and it synthesizes a nascent strand 306 complementary to strand 308. Strand 306 extends through the nanopore with its 5′ end. The nucleic acid strand 306 experiences a force pulling it into the pore due to a voltage that is applied across the nanopore. In the figure, the polymerase enzyme is shown attached to the substrate (e.g. to the biological nanopore). In some cases, the polymerase is not attached, but is held in place by the force of the electric field pulling on the nucleic acid strand 306. The medium surrounding the polymerase enzyme has the components required for nucleic acid synthesis including nucleotides and cofactors. As the polymerase adds nucleotides to the growing complementary strand 306, the strand 306 is paid out through the nanopore in the direction of the force on the nucleic acid strand from the voltage across the pore. By controlling the force on nucleic acid strand 306 (e.g. by controlling the applied voltage), the number of bases 120 between the active site of the enzyme and nanopore will remain relatively constant throughout the process. Where the number of bases between the enzyme and the nanopore is constant, the rate of passage of bases through the nanopore will be equivalent to the rate of nucleic acid synthesis by the polymerase enzyme. Where the number of bases 320 is controlled, we have determined that changes in the rate of nucleic acid synthesis due to the presence of modified bases can be used to identify modified bases in the circular nucleic acid strand 306. Here, hemi-natural nucleic acid is used as strand 308 represents a natural nucleic acid, and strand 306 is a synthetic strand. For example, consider a modified base 314 in nucleic acid strand 308 that slows or otherwise modifies the nucleic acid synthesis rate. At the time the rate of polymerization is slowed by base 314, the rate of transport of bases through the nanopore is also slowed by the same amount. In the figure, the nanopore has a region in which the presence of three bases 330, 332, and 334 determines the current through the pore. By knowing the current level for all of the triads of bases, the bases can be called at single base resolution as the bases are drawn through the nanopore. The slowing of the polymerase by base 314 is measured as a slowing in the translation of bases 330, 332, and 334 through the pore. If the number of bases 320 between the nanopore and the modified base at the position the base slows the polymerase is known, then the presence of the modified base at that position can be determined. In some cases, modified bases can produce kinetic changes at positions other than when than when the modified base is in the active site of the enzyme. In fact, the changes in kinetics can occur before, during, or after the modified base is in the active site of the polymerase. In some cases, the modified base can cause a series of kinetic changes, resulting in a distinctive pattern of kinetic changes. The pattern of kinetic changes can involve 2, 3, 4, 6, 7, 8, or more kinetic changes, some or all of which can occur before, during, or after the modified base is in the active site of the polymerase. The kinetic change can be a change in the time for a one base transition in the current or capacitance signal. The kinetic change can also involve other measured parameters such as the noise level in the signal, or the shape of the transition signal, for example, noise color as described in more detail below. Sequencing is performed as nucleotides added from solution lengthen complementary strand 306 and thereby pay out the single nucleic acid strand through the pore. FIG. 4 shows an example of an embodiment of the invention using a helicase enzyme as the translating enzyme in which the helicase pays out the single stranded nucleic acid through the pore as it separates two DNA strands. In FIG. 4A substrate 402 has a nanopore 404 extending through it. As shown in the figure, the substrate 402 comprises a lipid bilayer, and the nanopore 404 is formed using a biological transmembrane protein such as MspA. The embodiment shown could be carried out with other suitable substrates and with a nanopore such as a solid state or hybrid nanopore. The helicase enzyme 410 is associated with a region of a DNA strand 406 which extends through the nanopore. Depending on how the sample is loaded, the helicase can either pay out through the pore a strand having a 5′ end or a strand having a 3′ end. Controlling which end is extended into the nanopore can be controlled by controlling which of the strands has an over-hanging single stranded portion at its end. The nucleic acid strand experiences a force pulling it into the pore due to a voltage that is applied across the nanopore. The helicase can either be attached to the substrate, or it can be held in place by the force of the electric field pulling on the nucleic acid strand 306. The medium surrounding the polymerase enzyme has the components required for helicase activity including, where required, ATP. As the helicase separates the double stranded DNA, DNA strand 406 is paid out through the nanopore in the direction of the force on the nucleic acid strand from the voltage across the pore. By controlling the force on nucleic acid strand 406 (e.g. by controlling the applied voltage), the number of bases 420 between the active site of the enzyme and nanopore will remain relatively constant throughout the process. Where the number of bases between the enzyme and the nanopore is constant, the rate of passage of bases through the nanopore will be equivalent to the rate of separation of DNA strands by the helicase enzyme. Where the number of bases 120 is controlled, we have determined that changes in the rate of nucleic acid synthesis due to the presence of modified bases can be used to identify modified bases in the nucleic acid strand 406. In some cases, the helicase is initiated only after it is loaded. The helicase can be initiated by adding metal cofactors, adding ATP or an ATP analog, or using a helicase that is inhibited, and adding a reagent that removes an inhibitor. For example, the template strand can have a blocking group on strand 408 preventing the helicase from separating the strands. A group that removes the blocking group, e.g. a single-stranded restriction enzyme that breaks the strand can be added. Blockers for helicase include streptavidin, an abasic site, an O—Me group, a pyrimidine dimer, 8-OxoG or a crosslinked protein. The blocking group can be built into the hemi-natural nucleic acid during sample preparation. Consider a modified base 414 in nucleic acid strand 406 that slows or otherwise modifies the helicase rate. At the instant the rate is slowed by base 414, the rate of transport of bases through the nanopore is also slowed by the same amount. In the figure, the nanopore has a region in which the presence of three bases 430, 432, and 434 determines the current through the pore. By knowing the current level for all of the triads of bases, the bases can be called at single base resolution as the bases are drawn through the nanopore. The slowing of the helicase by base 414 is measured as a slowing in the translation of bases 430, 432, and 434 through the pore. If the number of bases 420 between the nanopore and the modified base at the position the base slows the polymerase is known, then the presence of the modified base at that position can be determined. In some cases, modified bases can produce kinetic changes at positions other than when than when the modified base is in the active site of the enzyme. In fact the changes in kinetics can occur before, during, or after the modified base is in the active site of the helicase. In some cases, the modified base can cause a series of kinetic changes, resulting in a distinctive pattern of kinetic changes. The pattern of kinetic changes can involve 2, 3, 4, 6, 7, 8, or more kinetic changes, some or all of which can occur before, during, or after the modified base is in the active site of the helicase. The kinetic change can be a change in the time for a one base transition in the current or capacitance signal. The kinetic change can also involve other measured parameters such
{'application_number': '<application-reference appl-type="utility">\n<document-id>\n<country>US</country>\n<doc-number>14831599</doc-number>\n<date>20150820</date>\n</document-id>\n</application-reference>', 'publication_number': '<publication-reference>\n<document-id>\n<country>US</country>\n<doc-number>20160010148</doc-number>\n<kind>A1</kind>\n<date>20160114</date>\n</document-id>\n</publication-reference>', 'source_file': './application/2016/ipa160114.xml', 'source_data': 'USPTO-Application'}