Unfolding Mental disorders through recent evolution of brain cortical FOLDing; “finanziato dall’Unione europea – Next Generation EU”

The UMFOLD project aims to identify the most recent evolutionary innovations that define the anatomy of the modern human brain and to connect them with their consequences on mental health. Indeed, recent research has shown that genetic contributions from archaic humans such as Neanderthals, might have had a disproportionate impact on present-day neuropsychiatric disorders and behavioral traits in non-African human subjects. Independent research also found dramatic differences in morphological features derived from Brain Magnetic Resonance Imaging (MRI), chiefly brain globularity and cortical sulci. This suggests that recent evolutionary changes affecting brain morphology, and cortical folding in particular, are connected with the development of neuropsychiatric illnesses characteristic of the modern human mental condition. We will exploit large biobanks that combine genetic and brain MRI data: UK Biobank and Adolescent Brain Cognitive Development Study, hosting 40k adult donors and developmental data for 12k adolescent donors respectively. Leveraging the genetic variants derived from Neanderthal introgression recorded in these biobanks we will explore the archaic hominin contribution to the genetic basis of brain MRI features, with a focus on cortical sulci. We will associate the archaic dosage at introgressed loci to sulcal shape descriptors, effectively performing an Archaic Loci Association Study (ALAS), adopting specific algorithms aimed at finding impact of rare variants. Then we will try to predict mental conditions using the genome-wide burden of introgressed sequence and weighting it by the discovered associations between archaic loci and cortical sulci. Moreover this analysis will be replicated focusing only on “modern human defining” genomic regions, that is DNA that diverged since the separation between archaic and modern humans. The project is run by two Research Units: one from the university of Torino, led by Dr. Davide Marnetto (the project PI) and including Dr. Fabrizio Pizzagalli, with an expertise of computational genomics and brain imaging genetics, respectively; the other from the University of Padova, led by Prof. Luca Pagani which will provide the molecular anthropology know-how to dissect archaic haplotypes from extant genomes. The researchers will build upon a mature state of the art, synergistically engage their know-how, and capitalize on a strong international network covering the aspects of Brain imaging and Neanderthal introgression. In line with objective 3 of the Health cluster within the “Human Wellbeing” strategic topic, the goal of the UMFOLD project is to better understand the etiology of mental disorders and to provide diagnostic tools based on predictive genomics that will help in effectively reducing the disease burden.