Publications

Abstract

Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order1. Infections in bats are largely asymptomatic2,3, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. 4,5), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.

Abstract

Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP–chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections

Abstract

Mutations of the human FOXP2 gene have been shown to cause severe difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech (developmental verbal dyspraxia or DVD). Affected individuals are impaired in multiple aspects of expressive and receptive linguistic processing and ­display abnormal grey matter volume and functional activation patterns in cortical and subcortical brain regions. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. This chapter describes the successful use of FOXP2 as a unique molecular window into neurogenetic pathways that are important for speech and language development, adopting several complementary strategies. These include direct functional investigations of FOXP2 splice variants and the effects of etiological mutations. FOXP2’s role as a transcription factor also enabled the development of functional genomic routes for dissecting neurogenetic mechanisms that may be relevant for speech and language. By identifying downstream target genes regulated by FOXP2, it was possible to identify common regulatory themes in modulating synaptic plasticity, neurodevelopment, and axon guidance. These targets represent novel entrypoints into in vivo pathways that may be disturbed in speech and language disorders. The identification of FOXP2 target genes has also led to the discovery of a shared neurogenetic pathway between clinically distinct language disorders; the rare Mendelian form of DVD and a complex and more common form of language ­disorder known as Specific Language Impairment.