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In the recent years, DNA has emerged as a potentially viable storage technology. DNA synthesis, which refers to the task of writing the data into DNA, is perhaps the most costly part of existing storage systems. Accordingly, this high cost and low throughput limits the practical use in available DNA synthesis technologies. It has been found that the homopolymer run (i.e., the repetition of the same nucleotide) is a major factor affecting the synthesis and sequencing errors. Quite recently, [26] studied the role of batch optimization in reducing the cost of large scale DNA synthesis, for a given pool $\mathcal{S}$ of random quaternary strings of fixed length. Among other things, it was shown that the asymptotic cost savings of batch optimization are significantly greater when the strings in $\mathcal{S}$ contain repeats of the same character (homopolymer run of length one), as compared to the case where strings are unconstrained. Following the lead of [26], in this paper, we take a step forward towards the theoretical understanding of DNA synthesis, and study the homopolymer run of length $k\geq1$. Specifically, we are given a set of DNA strands $\mathcal{S}$, randomly drawn from a natural Markovian distribution modeling a general homopolymer run length constraint, that we wish to synthesize. For this problem, we prove that for any $k\geq 1$, the optimal reference strand, minimizing the cost of DNA synthesis is, perhaps surprisingly, the periodic sequence $\overline{\mathsf{ACGT}}$. It turns out that tackling the homopolymer constraint of length $k\geq2$ is a challenging problem; our main technical contribution is the representation of the DNA synthesis process as a certain constrained system, for which string techniques can be applied.