Annual review of genomics and human genetics最新文献

Breast cancer is a major public health burden that disproportionately affects women of African descent. Substantial progress has been made in understanding the genetic and biological drivers of breast cancer worldwide. However, this knowledge is unevenly distributed among all women with breast cancer, particularly those of African descent. The highlights of nearly three decades of research among women of African descent point mainly to a young age at diagnosis, aggressive disease, and distinct biomarkers, as well as a clear geographical distribution of disease subtypes and genetic variants. Despite this growing wealth of information, the African population's access to genetic care and understanding of inherited risk and disease biology remain limited. This review summarizes the state of knowledge on genetic risk in African populations with breast cancer, evaluates the strengths and limitations of the methodological approaches used, and suggests innovative strategies to ensure equitable participation in cancer genetic and genomic research. We discuss genotype-phenotype correlations and the inherited risk of breast cancer, including both rare and common genetic variants. We also address the role of somatic drivers of breast cancer, disease biomarkers, treatment targets, and pharmacogenomics in this population. Finally, we provide recommendations to enable future progress in diagnosis and treatment.

Genomics has the potential to transform human health, biomedical research, and life sciences by providing deep insights into genetic variation and disease mechanisms. However, fully realizing these benefits requires a well-trained workforce equipped to handle, analyze, and interpret increasingly complex genomic and linked datasets. The rapid evolution of sequencing technologies, machine learning, and data science tools has heightened the demand for professionals proficient in bioinformatics, high-performance computing, and genomic data governance. This review presents a global perspective on workforce development in genomic data science, detailing key competencies necessary for both research and clinical applications. We discuss some of the existing training programs, competency frameworks, and regional approaches to skills development while identifying gaps in education, infrastructure, and accessibility. Additionally, we explore the integration of genomic data science into healthcare, addressing challenges such as equitable access to training and the need for cross-disciplinary expertise. Tackling these challenges is essential for cultivating a diverse, skilled workforce capable of driving advancements in genomic research, precision medicine, and public health.

Aneuploidy, characterized by the gain or loss of chromosomes, plays a critical role in both cancer and congenital aneuploidy syndromes. For any aneuploidy, we can distinguish between its general effects and its chromosome-specific effects. General effects refer to the common cellular stresses induced by aneuploidy, such as impaired proliferation, proteotoxic stress, and altered metabolism, which occur regardless of the specific chromosome involved and profoundly impact cellular and organismal functions. These generalized stresses often hinder cell fitness but can also, under certain conditions, contribute to cancer progression. In contrast, chromosome-specific effects arise from the altered dosage of particular genes on the gained or lost chromosome. These effects vary depending on the chromosome involved and can provide specific fitness effects in cancer cells or distinct developmental phenotypes in congenital aneuploidies like Down syndrome. Understanding the interplay between these two levels of effects is crucial for deciphering the outcomes of aneuploidy. This review synthesizes current knowledge and discusses future directions for unraveling the hallmarks of aneuploidy.

Integrating genomics into healthcare within the precision medicine (PM) framework poses distinct challenges in resource-limited regions like Latin America and the Caribbean (LAC). These challenges arise partly from the lack of PM models tailored for low- and middle-income countries. To address this, healthcare authorities in LAC should adopt predictive models to estimate costs and infrastructure needed for PM programs. The predominance of admixed populations in LAC adds complexity, given their underrepresentation in genomic studies. Establishing a robust regulatory framework is essential for managing ethical, legal, and privacy concerns related to genomic data. Despite these challenges, current regional efforts showcase the feasibility of integrating genomics in LAC and highlight the importance of expanded collaborations. By sharing data, resources, and expertise, LAC countries can overcome funding and infrastructural barriers while upholding ethical standards and data protection across the region.

Interpretations of the so-called genomic diversity problem in precision medicine research reflect an enduring colonial logic tied to liberal identity/difference politics, prioritizing representational equity, diversity, and inclusion over substantive engagement with Indigenous sovereignties on their own ontological terms. This review critically analyzes not the underrepresentation of diverse populations in genomics but rather how the diversity problem is framed within genomics. It argues that liberal renderings of the diversity problem perpetuate colonizing knowledge production by reconstituting indigeneity as an identity/difference category. This review calls for a rejection of this reductive philosophical foundation in defense of Indigenous sovereignties and relationalities to transform scientific knowledge production.

Precise spatiotemporal regulation of gene expression is critical for the development and functioning of complex, multicellular organisms. Enhancers play a fundamental role in the regulation of gene expression, but the molecular underpinnings of enhancer-mediated gene activation remain poorly understood. Many mammalian genes are dependent on the activity of multiple enhancers, which can be separated from their target genes by large genomic distances. Accurate gene regulation therefore relies on specific interactions between enhancers and their target genes in 3D nuclear space. In this review, we discuss recent insights into the mechanisms by which enhancers cooperate to regulate precise and robust gene expression levels. We also review recent progress in our understanding of the molecular drivers of specific 3D interactions between enhancers and their target genes. We conclude by discussing current models of the molecular mechanisms by which enhancers activate gene expression in their 3D chromatin context.

Tremendous progress has been made in identifying genetic variants associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorder (ASD). However, the extensive (and growing) lists of associated genetic variants have led to a bottleneck in understanding the function of these genetic changes. To overcome this, functional genomics approaches-including high-throughput and high-content screens, in vivo Perturb-seq, and multiomics profiling-are being deployed across cellular and animal models at scale. Here, we first discuss recent findings on NDDs gleaned from human genetics studies. We then review recent technological advances and findings from functional neurogenomics in the context of ASD and other NDDs. Finally, we discuss how these methods might be applied in the future to refine efforts to identify convergent mechanisms impacted by multiple disease-associated genetic variants, as well as how they can advance the development of new therapeutic strategies.

Collectively, various tandem and interspersed repetitive sequences make up approximately half the human genome, yet we have only begun to understand the potential functions of "junk" DNA. Here, we provide a brief overview of various types of repeats, but a full treatment of the repeat genome (repeatome) is beyond the scope of any review. Hence, we focus primarily on less established functions of a few major repeat classes, including pericentromeric satellites and abundant degenerate interspersed repeats, short interspersed nuclear elements (Alu), and long interspersed nuclear elements (L1). A theme developed throughout is how sequence organization in the human karyotype provides insights into potential functions within nuclear structure. For example, millions of small tandem major satellite repeats can form bodies that sequester nuclear factors, or the segmental organization of interspersed repeats may underpin the nuclear compartmentalization of heterochromatin and euchromatin. Decoding the vast repeatome is an exciting frontier being enabled by recent technological advancements. However, identifying the extent of meaningful information in repeats will likely require concepts that go well beyond impacts for individual genes, to new ways to identify and interpret broad patterns of genome-wide organization and nucleus-wide regulation.

Rare genetic variants have illuminated mechanisms of common diseases and have even led to novel treatment approaches. Some copy number variants (CNVs) have been associated with extraordinary risk for complex neuropsychiatric phenotypes and thus offer a valuable entry point for investigating the biological mechanisms and pathways underlying autism, intellectual disability, and schizophrenia, among other neuropsychiatric disorders. For example, cellular and animal models of multiple CNVs have identified mitochondrial dysregulation as a key pathway underlying these disorders. In the clinic, there is a growing potential for improving the quality of life of individuals affected by these rare variants. Early targeted intervention leveraging data from robust clinical studies will be critical for providing patients and their families with the best possible outcomes. In this review, we highlight the current challenges and opportunities in the field of neurodevelopmental CNV research in both the lab and the clinic.

Over the last decade, a set of very short (3-51 nt) and highly conserved microexons have been found to crucially influence a set of diverse protein functions and interactions. Advancements in RNA sequencing and analysis pipelines have revealed an enrichment for the alternative splicing of microexons in a subset of tissues and cell types, especially across the central nervous system. Microexons are thought to fine-tune important developmental processes such as synaptogenesis by preserving the protein's reading frame upon inclusion. Dysregulation of microexon splicing has been linked to several neurological conditions, including autism spectrum disorder and schizophrenia, as well as metabolic disorders like diabetes and various cancer types. This review discusses the expanding body of literature on the molecular and organismal consequences of microexon inclusion, emphasizing their evolutionary conservation, tissue specificity, and functional diversity. It also explores the potential for therapeutic interventions, including pharmacological modulation, on microexon splicing and splicing regulators like SRRM3 and SRRM4, offering perspectives on targeting diseases related to microexon misregulation. More research is needed to better understand similarities and differences between microexon functions across tissues, pathologies, and species.