Novel genomic feature in the brain-specific BRSK2 (Controls)

Background: The human BRSK2 (Brain-specific Serine/Threonine Kinase 2) is mainly expressed in the brain and is required for neuronal polarization and differentiation. This gene contains the longest 5′ untranslated region (5′ UTR) pentanucleotide short tandem repeat (STR), (CGGCT)6, in human. We hypothesized that this exceptional length may confer selective advantage in cognitive functioning.Methods: We sequenced the region spanning (CGGCT)6 in a sample of 339 unrelated Iranian individuals, consisting of cases affected by late-onset neurocognitive disorder (NCD) (N=163) and matched controls (N=176). Following to our sequencing results, we mapped CGGCT motifs/repeats across the human genome and studied this region across several primate and rodent genomes.Results: We found that (CGGCT)6 is part of a compound island of numerous consecutive CGGCT motifs/repeats, ranging from 1 and 6-repeats, stretching the BRSK2 core promoter and 5′ UTR. This island is flanked by a CGG-STR in its downstream. Across the human genome, the CGGCT island was unique with respect to density, complexity, and repeat length of CGGCT motifs and repeats. The evolution of the CGGCT island and CGG-STR coincided with the phylogenetic distance of several primates and rodents, signifying directional (rather than random) evolution of this island in these species. While (CGGCT)6 was strictly monomorphic in the human samples studied, a 7-repeat of this motif was detected in the controls only. In another CGGCT-repeat inside the CGGCT island, there was a significant excess of homozygosity for a long allele (4-repeat) in the controls (Mid-P=0.02). At the same locus, a 3-repeat allele was detected in the NCD group only. Moreover, alleles were detected at the extreme short and long lengths of CGG-STR in the NCD group only. Finally, a 5′ UTR G to T point mutation, flanking the CGGCT island was detected in one individual with NCD.Conclusion: We report a novel genomic feature, consisting of a CGGCT motif/repeat island and CGG STR in BRSK2 that coincide with directional evolution of primates. Several polymorphic and rare alleles across this region were divergently distributed in the NCD and control groups, signifying a link between this region and cognitive functions in human.