DNF Seminar: Prof. Alexandre Reymond will give a talk on Feb. 18,2021

This event will take place on a virtual space on 
Thursday, February 18th at 12:15 through the following Zoom link:

Alexandre Reymond, CIG – UNIL
 “Genome architecture and disease: the 16p11.2 paradigm” 


The recurrent 600 kbp deletions and duplications at human chromosome 16p11.2 are among the most frequent genetic causes of neurodevelopmental and psychiatric disorders, as they are found in 1% of individuals with autism spectrum disorders and schizophrenia. These rearrangements cause reciprocal defects in head size, body weight and as described below age of menarche (AaM).

These rearrangements are mediated by human-specific duplications that appeared at the beginning of the modern human lineage, suggesting that their expansion has a possible evolutionary advantage that outweighs the accompanying chromosomal instability. These duplications include BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by its rapid expansion, we assessed hematological traits in individuals who have lost or gained copies of BOLA2. The 16p11.2 deletion is strongly associated with anemia (P=4e-7, OR=5) and upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and anemia (P=2e-3). Consistent with human data, the 16p11.2 deletion mouse model and Bola2-deficient mice showed early evidence of iron deficiency. The rapid expansion of BOLA2 might have evolved to protect humans against iron deficiency as our species successfully expanded its ecological range at the cost of increased predisposition to rearrangements associated with autism.

We leveraged biobank-scale phenotype data, Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for AaM. The dosage of the 16p11.2 interval is correlated with AaM and an increase in reproductive tract disorders. Likewise, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent assays identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.