Current Opinion in Genetics & Development最新文献

Uniquely human physical traits, such as an expanded cerebral cortex and changes in limb morphology that allow us to use tools and walk upright, are in part due to human-specific genetic changes that altered when, where, and how genes are expressed during development. Over 20 000 putative regulatory elements with potential human-specific functions have been discovered. Understanding how these elements contributed to human evolution requires identifying candidates most likely to have shaped human traits, then studying them in genetically modified animal models. Here, we review the progress and challenges in generating and studying such models and propose a pathway for advancing the field. Finally, we highlight that large-scale collaborations across multiple research domains are essential to decipher what makes us human.

Synapses of the neocortex specialized during human evolution to develop over extended timescales, process vast amounts of information and increase connectivity, which is thought to underlie our advanced social and cognitive abilities. These features reflect species-specific regulations of neuron and synapse cell biology. However, despite growing understanding of the human genome and the brain transcriptome at the single-cell level, linking human-specific genetic changes to the specialization of human synapses has remained experimentally challenging. In this review, we describe recent progress in characterizing divergent morphofunctional and developmental properties of human synapses, and we discuss new insights into the underlying molecular mechanisms. We also highlight intersections between evolutionary innovations and disorder-related dysfunctions at the synapse.

Cholangiocytes are the main cell type lining the epithelium of the biliary tree of the liver. This cell type has been implicated not only in diseases affecting the biliary tree but also in chronic liver diseases targeting other hepatic cells such as hepatocytes. However, the isolation and culture of cholangiocytes have been particularly arduous, thereby limiting the development of new therapies. The emergence of organoids has the potential to address in part this challenge. Indeed, cholangiocyte organoids can be established from both the intra- and extrahepatic regions of the biliary tree, providing an advantageous platform for disease modeling and mechanism investigations. Accordingly, recent studies on cholangiocyte organoids, together with the advent of single-cell -omics, have opened the field to exciting discoveries concerning the plastic nature of these cells and their capability to adapt to different environments and stimuli. This review will focus on describing how these plasticity properties could be exploited in regenerative medicine and cell-based therapy, opening new frontiers for treating disorders affecting the biliary tree and beyond.

The genetic differences underlying unique phenotypes in humans compared to our closest primate relatives have long remained a mystery. Similarly, the genetic basis of adaptations between human groups during our expansion across the globe is poorly characterized. Uncovering the downstream phenotypic consequences of these genetic variants has been difficult, as a substantial portion lies in noncoding regions, such as cis-regulatory elements (CREs). Here, we review recent high-throughput approaches to measure the functions of CREs and the impact of variation within them. CRISPR screens can directly perturb CREs in the genome to understand downstream impacts on gene expression and phenotypes, while massively parallel reporter assays can decipher the regulatory impact of sequence variants. Machine learning has begun to be able to predict regulatory function from sequence alone, further scaling our ability to characterize genome function. Applying these tools across diverse phenotypes, model systems, and ancestries is beginning to revolutionize our understanding of noncoding variation underlying human evolution.

Phenotypic variation within the skeleton has biological, behavioral, and biomedical functional implications for individuals and species. Thus, it is critical to understand how genomic, environmental, and mediating regulatory factors combine and interact to drive skeletal trait development and evolution. Recent research efforts to clarify these mechanisms have been made possible by expanded collections of genomic and phenotypic data from in vivo skeletal tissues, as well as the development of relevant in vitro skeletal cell culture systems. This review outlines this current work and recommends that continued exploration of this complexity should include an increased focus on how interactions between genomic and physiologically relevant contexts contribute to skeletal trait variation at population and evolutionary scales.

The human brain has evolved unique capabilities compared to other vertebrates. The mechanistic basis of these derived traits remains a fundamental question in biology due to its relevance to the origin of our cognitive abilities and behavioral repertoire, as well as to human-specific aspects of neuropsychiatric and neurodegenerative diseases. Comparisons of the human brain to those of nonhuman primates and other mammals have revealed that differences in the neuromodulatory systems, especially in the dopaminergic system, may govern some of these behavioral and cognitive alterations, including increased vulnerability to certain brain disorders. In this review, we highlight and discuss recent findings of human- and primate-specific alterations of the dopaminergic system, focusing on differences in anatomy, circuitry, and molecular properties.

A number of factors contribute to cell type–specific CTCF chromatin binding, but how they act in concert to determine binding stability and functionality has not been fully elucidated. In this review, we tie together different layers of regulation to provide a holistic view of what is known. What emerges from these studies is a multifaceted system in which DNA sequence, DNA and chromatin accessibility, and cell type–specific transcription factors together contribute to CTCF binding profile and function. We discuss these findings in the light of disease settings in which changes in the chromatin landscape and transcriptional programming can disrupt CTCF’s binding profile and involvement in looping.

Our knowledge of human biology is mainly originated from studies using animal models. However, interspecies differences between human and model organisms may lead to imprecise extrapolation of results obtained from model organisms. Organoids are three-dimensional cell clusters derived from pluripotent or adult stem cells that self-organize into organ-like structures reminiscent of the cognate organ. The establishment of human organoids makes it possible to study organ or tissue pathophysiology that is specific to human beings. However, most organoids do not have organ-specific vasculature, neurons, and immune cells, hence limiting their utility in emulating complex pathophysiological phenotypes. Among the various approaches to address these limitations, xenotransplantation represents a promising ‘shortcut’. We will discuss recent advance in constructing tissue complexity in organoids, with a special focus on xenotransplantation.

Advances in sequencing technologies have enabled the comparison of high-quality genomes of diverse primate species, revealing vast amounts of divergence due to structural variation. Given their large size, structural variants (SVs) can simultaneously alter the function and regulation of multiple genes. Studies estimate that collectively more than 3.5% of the genome is divergent in humans versus other great apes, impacting thousands of genes. Functional genomics and gene-editing tools in various model systems recently emerged as an exciting frontier — investigating the wide-ranging impacts of SVs on molecular, cellular, and systems-level phenotypes. This review examines existing research and identifies future directions to broaden our understanding of the functional roles of SVs on phenotypic innovations and diversity impacting uniquely human features, ranging from cognition to metabolic adaptations.