Genome architecture and diseases: the 16p11.2 paradigm

Description

Abstract

Copy number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 (breakpoint) CNV found in 1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220kb BP2-BP3 CNV is a likewise potent driver of neuropsychiatric, anatomical and metabolic pathologies. These two CNVs-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping and concomitant expression changes, as well as genetic interaction between genes mapping within both intervals, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. These recurrent pathogenic deletions and duplications are mediated by a complex set of highly identical and directly oriented segmental duplications. This disease-predisposing architecture results from recent, Homo sapiens-specific duplications (i.e. absent in Neandertal and Denisova) of a segment including the BOLA2 gene, the latest among a series of genomic changes that dramatically restructured the region during hominid evolution. Our results show that BOLA2 participates in iron homeostasis and a lower dosage is associated with anemia. These data highlight a potential adaptive role of the human-specific expansion of BOLA2 in improving iron metabolism. Finally, we combined phenotyping of carriers of rare copy variant at 16p11.2, Mendelian randomization and animal modeling to identify the causative gene in a Genome-wide association studies (GWAS) locus for age at menarche. Our interdisciplinary approach allowed overcoming the GWAS recurrent inability to link a susceptibility locus with causal gene(s).