Current Opinion in Genetics & Development最新文献

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.

Evolution of the cerebral cortex is thought to have been critical for the emergence of our cognitive abilities. Major features of cortical evolution include increased neuron number and connectivity and altered morpho-electric properties of cortical neurons. Significant progress has been made in identifying human-specific genetic modifiers (HSGMs), some of which are involved in shaping these features of cortical architecture. But how did these evolutionary changes support the emergence of our cognitive abilities? Here, we highlight recent studies aimed at examining the impact of HSGMs on cortical circuit function and behavior. We also discuss the need for greater insight into the link between evolution of cortical architecture and the functional and computational properties of neuronal circuits, as we seek to provide a neurobiological foundation for human cognition.

N⁶-methyladenosine (m⁶A) is the most abundant internal modification of eukaryotic mRNAs. m⁶A affects the fate of its targets in all aspects of the mRNA life cycle and has important roles in various physiological and pathophysiological processes. Aberrant m⁶A patterns have been observed in numerous cancers and appear closely linked to oncogenic phenotypes. However, most studies relied on antibody-dependent modification detection, which is known to suffer from important limitations. Novel, antibody-independent, quantitative approaches will be critical to investigate changes in the m⁶A landscape of cancers. Furthermore, pharmaceutical targeting of the m⁶A writer Methyltransferase-like 3 (METTL3) has demonstrated the potential to modulate cancer cell phenotypes. However, the enzyme also appears to be essential for the viability of healthy cells. Further refinement of therapeutic strategies is therefore needed to fully realize the potential of m⁶A-related cancer therapies.

The aim of regenerative medicine is to restore specific functions to damaged cells or tissues. A crucial aspect of success lies in effectively reintegrating these cells or tissues within the recipient organism. This is particularly pertinent for diabetes, where islet function relies on the close connection of beta cells to the bloodstream for glucose sensing and insulin release. Central to this approach is the need to establish a fast connection with the host’s vascular system. In this review, we explore the intricate relationships between endocrine, vascular, and immune cell interactions in transplantation outcomes. We also delve into recent strategies aimed at enhancing engraftment, along with the utilization of in vitro platforms to model cellular interactions.

Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.

The human brain is composed of increasingly recognized heterogeneous cell types. Applying single-cell genomics to brain tissue can elucidate relative cell type proportions as well as differential gene expression and regulation among humans and other species. Here, we review recent studies that utilized high-throughput genomics approaches to compare brains among species at single-cell resolution. These studies identified genomic elements that are similar among species as well as evolutionary novelties on the human lineage. We focus on those human-relevant innovations and discuss the biological implications of these modifications. Finally, we discuss areas of comparative single-cell genomics that remain unexplored either due to needed technological advances or due to biological availability at the brain region or species level.