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Effects of reference databases’ refinements on the validity of molecular definitions of 15,371 candidate human-specific regulatory sequences

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the idea that unique to human phenotypes result from human-specific changes to genomic regulatory networks (GRNs). The sequence quality of reference genome databases is essential for the accurate definition of regulatory DNA segments as candidate HSRS. It is unclear how database improvements would affect the validity of the HSRS’ definition. Sequence conservation analysis of 15,371 candidate HSRS was carried out using the most recent releases of reference genomes’ databases of humans and nonhuman primates (NHP) defining the conservation threshold as the minimum ratio of bases that must remap of 1.00. This analysis identifies 3,793 regulatory DNA segments that lack evidence of human-specific mutations and represent regulatory sequences highly conserved in humans, Bonobo, and Chimpanzee. Present analysis revealed a major database refinement’s effect on the validity of HSRS’ definition and suggests that human-specific phenotypes may evolve as a results of integration into human-specific GRNs of both conserved in NHP and human-specific genomic regulatory elements.