Human-specific expansion of 22q11.2 low copy repeats

Segmental duplications or low copy repeats (LCRs) constitute complex regions interspersed in the human genome. They have contributed significantly to human evolution by stimulating neo- or sub-functionalization of duplicated transcripts. The 22q11.2 region carries eight LCRs (LCR22s). One of these LCR22s was recently reported to be hypervariable in the human population. It remains unknown whether this variability exists also in non-human primates. To assess the inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. Orangutan carries three LCR22-mediated inversions of which one is the ancient haplotype since it is also present in macaque. Using fiber-FISH, lineage-specific differences in LCR22 composition were mapped. The smallest and likely ancient haplotype is present in the chimpanzee, bonobo and rhesus macaque. The absence of intra-species variation in chimpanzee indicates the LCR22-A expansion to be unique to the human population. Further, we demonstrate that LCR22-specific genes are expressed in both human and non-human primate neuronal cell lines and show expression of several primate LCR22 transcripts for the first time. The human-specificity of the expansions suggest an important role for the region in human evolution and adaptation. Author summary Low copy repeats or segmental duplications are DNA segments composed of various subunits which are duplicated across the genome. Due to the high level of sequence identity between these segments, homologous regions can misalign, resulting in reciprocal deletions and duplications, classified as genomic disorders. These regions are subject to structural variation in the human population. We recently detected extreme structural variation in one of the most complex segmental duplication regions of the human genome, the low copy repeats on chromosome 22 (LCR22s). Rearrangements between the LCR22s result in the 22q11.2 deletion/duplication syndrome, the most common human genomic disorder. However, it remains unknown whether this variability is human-specific. In this study, we investigated those LCR22s in several individuals of the different great apes and macaque. We show only the smallest haplotype is present without any intra-species variation in the Pan genus, our closest ancestors. Hence, LCR22 expansions are human-specific, suggesting a role of these LCR22s in human evolution and adaptation and hypothesize the region contributes to the 22q11.2 deletion syndrome inter-patient phenotypic variability.