Skewing of the genetic architecture at the ZMYM3 human-specific 5' UTR short tandem repeat in schizophrenia

Differential expansion of a number of human short tandem repeats (STRs) at the critical core promoter and 5' untranslated region (UTR) support the hypothesis that at least some of these STRs may provide a selective advantage in human evolution. Following a genome-wide screen of all human protein-coding gene 5' UTRs based on the Ensembl database ( http://www.ensembl.org ), we previously reported that the longest STR in this interval is a (GA)₃₂, which belongs to the X-linked zinc finger MYM-type containing 3 (ZMYM3) gene. In the present study, we analyzed the evolutionary implication of this region across evolution and examined the allele and genotype distribution of the "exceptionally long" STR by direct sequencing of 486 Iranian unrelated male subjects consisting of 196 cases of schizophrenia (SCZ) and 290 controls. We found that the ZMYM3 transcript containing the STR is human-specific (ENST00000373998.5). A significant allele variance difference was observed between the cases and controls (Levene's test for equality of variances F = 4.00, p < 0.03). In addition, six alleles were observed in the SCZ patients that were not detected in the control group ("disease-only" alleles) (mid p exact < 0.0003). Those alleles were at the extreme short and long ends of the allele distribution curve and composed 4% of the genotypes in the SCZ group. In conclusion, we found skewing of the genetic architecture at the ZMYM3 STR in SCZ. Further, we found a bell-shaped distribution of alleles and selection against alleles at the extreme ends of this STR. The ZMYM3 STR sets a prototype, the evolutionary course of which determines the range of alleles in a particular species. Extreme "disease-only" alleles and genotypes may change our perspective of adaptive evolution and complex disorders. The ZMYM3 gene "exceptionally long" STR should be sequenced in SCZ and other human-specific phenotypes/characteristics.