The ANK2 gene mutations are marked risk factors for autism spectrum disorder, one of the neurodevelopmental disorders (NDDs) that often extends into adulthood and has a complex etiology involving genetic and environmental factors. ANK2 encodes 2 major isoforms, AnkB-220 (220-kDa isoform of ankyrin-B) and giant AnkB-440. We previously generated a targeted knockout (KO) of giant AnkB-440 in 2 cynomolgus and 2 rhesus monkeys. While no autism-spectrum-disorder-like phenotypes were observed during infancy, we found marked brain volume loss. In this study, we conducted a longitudinal multimodal study in these giant ANK2 KO monkeys during adolescent and young adulthood. Behavioral results from these giant ANK2 KO monkeys revealed increased locomotor activity, deficient cognition (including working memory, cognitive flexibility, and operant lever-press learning), and impaired emotional regulation and social interaction. Furthermore, the giant ANK2 KO monkeys exhibited persistent structural and functional brain abnormalities, up-regulation of brain triglyceride and glycerophospholipids, and peripheral blood transcriptome signatures of immune dysregulation, which may be related to their behavioral alternations. These observations suggest that giant ANK2 depletion in non-human primates phenocopies aspects of behavioral, neural, and molecular features characteristic of NDDs. This study provides an in-depth exploratory longitudinal characterization of giant ANK2 functions in primate brains, which may contribute to translational research on NDDs.
Jian-Hong Wang, Hong-Di Huang, Yun-Chao Ji et al.· Research· 1 citation
East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.
