14Identifying the molecular programs underlying human organ development and how they differ from 15 those in model species will advance our understanding of human health and disease. 16 Developmental gene expression profiles provide a window into the genes underlying organ 17 development as well as a direct means to compare them across species. We use a transcriptomic 18 resource for mammalian organ development to characterize the temporal profiles of human genes 19 associated with distinct disease classes and to determine, for each human gene, the similarity of its 20 spatiotemporal expression with its orthologs in rhesus macaque, mouse, rat and rabbit. We find 21 that half of human genes differ from their mouse orthologs in their temporal trajectories. These 22 include more than 200 disease genes associated with brain, heart and liver disease, for which mouse 23 models should undergo extra scrutiny. We provide a new resource that evaluates for every human 24 gene its suitability to be modeled in different mammalian species. 25 26 27 28 42 rhesus macaques) are routinely used as models of both normal human development and human 43 disease because it is generally assumed that the genes and regulatory networks underlying 44 development are largely conserved across these species. While this is generally true, there are also 45 critical differences between species during development, which underlie the large diversity of 46 3 mammalian organ phenotypes [1-6,8]. Identifying the commonalities and differences between the 47 genetic programs underlying organ development in different mammalian species is therefore 48 paramount for assessing the translatability of knowledge obtained from mammalian models to 49 understand human health and disease. Critically, gene expression profiles can be directly compared 50 between species, especially when they are derived from matching cells/organs and developmental 51 stages. Gene expression therefore offers a direct means to evaluate similarities and differences 52 between species in organ developmental programs. While the relationship between gene 53 expression and phenotypes is not linear, identifying when and where gene expression differs 54 between humans and other species will help identify the conditions (i.e., developmental stages, 55 organs, genes) under which model species may not be well suited to model human development 56 and disease. 57 58Here, we take advantage of a developmental gene expression resource [13], which densely covers 59 the development of seven major organs in humans and other mammals, to characterize the 60 spatiotemporal profiles of human disease genes and gain new insights into the symptomatology of 61 diseases. We also determine for each human gene (including disease-associated genes) the 62 similarity of its spatiotemporal expression with that of its orthologs in mouse, rat, rabbit and rhesus 63 macaque. Our analyses and datasets therefore provide a new resource for assessing the suitability 64 of different mammalian species to model the action ...

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Organ development is orchestrated by cell- and time-specific gene regulatory networks. Here we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring snATAC-seq profiles for ~90,000 cells spanning eleven stages, we mapped all major cerebellar cell types and identified candidate cis-regulatory elements (CREs). We detected extensive spatiotemporal heterogeneity among progenitor cells and characterized the regulatory programs underlying the differentiation of cerebellar neurons. Although CRE activity is predominantly cell type- and time-specific, periods of greater regulatory change are shared across cell types. There is a universal decrease in CRE conservation and pleiotropy during development and differentiation, but the degree of evolutionary constraint differs between cerebellar cell types. Our work delineates the developmental and evolutionary dynamics of gene regulation in cerebellar cells and provides general insights into mammalian organ development.