Mostly natural DNA sequencing by synthesis

A method of determining a target DNA sequence, said method comprising:

• a) hybridizing a plurality of polynucleotides that comprise the target DNA sequence with a primer to form a plurality of hybridized templates;
• b) contacting the plurality of hybridized templates with i) a DNA polymerase and ii) a first single nucleotide solution, wherein the single nucleotide solution comprises non-terminating, labeled and non-labeled nucleotides, and wherein said percentage of labeled nucleotides incorporated by the DNA polymerase is 20% or less of the total number of nucleotides incorporated, under conditions to allow target DNA-dependent extension from the primer if the appropriate single nucleotide is present;
• c) washing to remove unincorporated nucleotides;
• and
• d) detecting the presence or absence of an incorporated, labeled nucleotide among the plurality of hybridized templates, wherein, when the presence of an incorporated, labeled nucleotide is detected, the presence and size, or absence of a stretch of more than one base of the same type in tandem is also detected,
• thereby determining the target DNA sequence.