The human reference genome predicts a BlpI fragment of approximately 900 bp.

We also included two controls: mouse DNA (no orthologous sequence) and the 8 kb vector from which the probe was transcribed. (B) We performed Southern blot analysis on 18 human individuals by probing for the 30 bp repeat after digesting with BlpI. The repeat region also shows enrichment for p300/CBP binding and DNase I hypersensitivity in the developing human brain. There is an abnormally large number of genomic DNA sequencing reads mapping to the tandem repeat region, consistent with this repeat being further expanded in human individuals. More distantly related placental mammals, out to Afrotheria, have a region that aligns to the 30 bp segment, but with insertions or deletions. The human reference assembly predicts ten copies of the 30 bp segment while chimpanzees and other simians have a single copy of the 30 bp segment. Human-Specific Tandem Repeat Region Is Composed of 30-mer Sequence Units Repeated Head-to-Tail in Multi-kilobase Arrays (A) The tandem repeat is located in the third intron of CACNA1C. Changes in the structure and sequence of these arrays likely contribute to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations.ĬACNA1C GWAS bipolar disorder chimpanzee copy-number variation human evolution minisatellite psychiatric disease schizophrenia tandem repeat.Ĭopyright © 2018. Different human arrays vary in the magnitude of enhancer activity, and the 30-mer arrays associated with increased psychiatric disease risk status have decreased enhancer activity. The tandem repeat arrays function as enhancers that increase reporter gene expression in a human neural progenitor cell line. Particular sequence variants of the 30-mer are associated with risk status at several flanking single-nucleotide polymorphisms in the third intron of CACNA1C that have previously been linked to BD and SCZ. The large 30-mer repeat region is polymorphic in both size and sequence in human populations. This large tandem repeat is unstable using standard polymerase chain reaction and bacterial cloning techniques, which may have resulted in its incorrect size in the human reference genome. We have identified a human-specific tandem repeat in this region that is composed of 30 bp units, often repeated hundreds of times. However, the causative mutation is not yet known. Genome-wide association studies have strongly and repeatedly linked risk for both of these neuropsychiatric diseases to a 100 kb interval in the third intron of the human calcium channel gene CACNA1C. Bipolar disorder (BD) and schizophrenia (SCZ) are highly heritable diseases that affect more than 3% of individuals worldwide.

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