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The packaging of the male haploid genome within the differentiating spermatid nucleus is facilitated by small basic nuclear proteins called protamines. Although the majority of the DNA in human sperm chromatin is bound by these proteins, a small percentage retains a nucleosomal-like component. These histone-enriched regions may possess enhanced nuclease sensitivity and have been postulated to designate certain genes involved in early embryogenesis. We have shown previously that the chromatin domain containing the two human protamines PRM1 and PRM2 and the transition protein TNP2 forms a DNase I-sensitive conformation in pachytene spermatocytes, a requisite event prior to the haploid expression of its members in round spermatids (Kramer, J. A, McCarrey, J., Djakiew, D., and Krawetz, S. A. (1998) Development 125, 4749–4755). Interestingly, this configuration persists in mature spermatozoa …