22q11.2 Low Copy Repeats Expanded in the Human Lineage

Abstract

Segmental duplications or low copy repeats (LCRs) constitute duplicated regions interspersed in the human genome, currently neglected in standard analyses due to their extreme complexity. Recent functional studies have indicated the potential of genes within LCRs in synaptogenesis, neuronal migration, and neocortical expansion in the human lineage. One of the regions with the highest proportion of duplicated sequence is the 22q11.2 locus, carrying eight LCRs (LCR22-A until LCR22-H), and rearrangements between them cause the 22q11.2 deletion syndrome. The LCR22-A block was recently reported to be hypervariable in the human population. It remains unknown whether this variability also exists in non-human primates, since research is strongly hampered by the presence of sequence gaps in the human and non-human primate reference genomes. To chart the LCR22 haplotypes and the associated inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. A minimal and likely ancient haplotype is present in the chimpanzee, bonobo, and rhesus monkey without intra-species variation. In addition, the optical maps identified assembly errors and closed gaps in the orthologous chromosome 22 reference sequences. These findings indicate the LCR22 expansion to be unique to the human population, which might indicate involvement of the region in human evolution and adaptation. Those maps will enable LCR22-specific functional studies and investigate potential associations with the phenotypic variability in the 22q11.2 deletion syndrome.

A Chinese family with cat eye syndrome and abnormality of eye movement: First case report

“…Intra-genome duplicates greater than 1 kb in length and with at least 90% sequence similarity are termed low-copy repeats (LCRs) ( 4 ). When two homologous LCRs are less than 10 Mb apart from each other, they result in chromosomal or chromatid mislocations and unequal crossovers, resulting in the deletion or duplication of genomic segments between LCRs ( 13 ). Chromosome 22q11.2 harbors eight LCRs termed LCR22A-LCR22H, therefore, LCR22s are an ideal substrate for non-allelic homologous recombination (NAHR), resulting in rearrangements of 22q11.2 ( Supplementary Figures S1B,C ) ( 14 ).…”

Low copy repeats in the genome: from neglected to respected

“…In addition, an astonishing number of structural variants was identified in the 22q11.2 locus, with more than 25 haplotypes of the first chromosome 22q11 LCR block ranging in size from 200 kb to over 2 Mb [52,53]. The variability was considered human-specific in comparison to the shorter haplotypes of great apes [54]. The locus is associated with deletions causing the 22q11.2 deletion syndrome (MIM 192430), characterized by a variable phenotypic expression and penetrance.…”

Impact and characterization of serial structural variations across humans and great apes

“…The first case discovered this way lies in chromosomal region 22q11, which can harbor local duplications and deletions associated with the DiGeorge Syndrome. The region contains a network of segmental duplications which are highly variable across humans and thought to represent mediators of the 22q11.2 deletion syndrome 48 (Figure 4A). One sSV locus maps to a 1,200 kbp block of SDs flanking the region.…”