Increased signal to noise in nucleic acid sequencing

1. A method for identifying a nucleotide in a template nucleic acid, comprising

(a) providing a plurality of primer-template nucleic acid hybrids, wherein the primers comprise an extendable 3′ end;

(b) after step (a) contacting the plurality with:

(i) blocked nucleotides to produce a first subset of the primer-template nucleic acid hybrids that each comprise a blocked nucleotide at the 3′ end, and

(ii) a ternary complex inhibitor to produce a second subset of the primer-template nucleic acid hybrids that each comprise a ternary complex inhibitor;

(c) after steps (a) and (b) forming ternary complexes that each comprise a polymerase, a primer-template nucleic acid hybrid of the first subset, and a cognate nucleotide, wherein the cognate nucleotide is a cognate of a next base of the template nucleic acid; and

(d) after steps (a), (b) and (c) detecting the ternary complexes, thereby identifying a nucleotide in the template nucleic acid.

2. The method of claim 1 , wherein the blocked nucleotides comprise reversibly terminated nucleotides and wherein the primer-template nucleic acid hybrids in the first subset of the primer-template nucleic acid hybrids each comprise a reversibly terminated nucleotide at the 3′ end.

3. The method of claim 2 , further comprising

(e) deblocking the reversibly terminated nucleotide at the 3′ end of the primer-template nucleic acid hybrids in the first subset.

4. The method of claim 3 , further comprising

(f) repeating steps (b) through (e) to sequence template nucleic acids in the first subset.

5. The method of claim 4 , further comprising removing the polymerase and cognate nucleotide from the primer-template nucleic acid hybrids of the first subset prior to step (f).

6. The method of claim 4 , wherein steps (b) through (f) are repeated so long as the number of the primer-template nucleic acid hybrids in the first subset is more than 50% of the plurality of primer-template nucleic acid hybrids.

7. The method of claim 4 , wherein steps (b) through (f) are repeated at least 100 times.

8. The method of claim 1 , wherein the second subset of primer-template nucleic acid hybrids comprises less than 1% of the plurality of primer-template nucleic acid hybrids.

9. The method of claim 1 , wherein the plurality of primer-template nucleic acid hybrids is attached to a solid support.

10. The method of claim 9 , wherein the plurality of primer-template nucleic acid hybrids is attached to a feature of an array.

11. The method of claim 10 , wherein the plurality of primer-template nucleic acid hybrids that is attached to the feature comprises at least 100 copies having a common sequence.

12. The method of claim 10 , wherein the primer-template nucleic acid hybrids that are attached to the feature are detected as an ensemble.

13. The method of claim 9 , wherein the plurality of primer-template nucleic acid hybrids comprises different templates that are attached to different features of an array.

14. The method of claim 1 , wherein the ternary complex inhibitor comprises an oligonucleotide moiety.

15. The method of claim 14 , wherein the oligonucleotide moiety is produced by ligating an oligonucleotide to the primer-template nucleic acid hybrids in step (b).

16. The method of claim 14 , wherein the oligonucleotide moiety is produced by polymerase-catalyzed extension of the primer-template nucleic acid hybrids in step (b).

17. The method of claim 1 , wherein unreacted blocked nucleotides are separated from the plurality of primer-template nucleic acid hybrids after step (b)(i).

18. The method of claim 17 , wherein unreacted blocked nucleotides are separated from the plurality of primer-template nucleic acid hybrids before step (b)(ii).