Annual review of genomics and human genetics最新文献

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.

Social and behavioral scientists increasingly work with geneticists or adapt the methods of genetic research to investigate genomic variation in a wide variety of behavioral and social phenotypes. Using genome-wide association studies, these social and behavioral genomics (SBG) researchers generate polygenic indexes (PGIs)-weighted sums of the estimated effects of each genetic variant on an individual's phenotype. This review examines the ethical, conceptual, and social issues in SBG research and its downstream applications. In particular, it focuses on PGIs for ethically sensitive SBG phenotypes-those that (a) can be viewed as consequential to social status (e.g., obesity and substance-use disorders), (b) are contributing or have historically contributed to harmful stereotypes about minoritized groups and threaten to reify the biologization of social identities (e.g., financial prowess and athleticism), and/or (c) are central to a minoritized group's identity (e.g., sexual orientation and sexual behavior).

Genetic counselors have a complex relationship with disability communities due to both the legacy of eugenics and their ongoing role counseling families about prenatal testing. Drawing on a social model of disability and highlighting mistaken assumptions about quality of life for people with disabilities, scholars and activists have raised concerns about genetic technologies that strive to eliminate disability. We review the disability rights critique of prenatal screening and emphasize its ongoing relevance to genetic counseling. We then consider disability perspectives on prognostication in genetics and highlight disability-informed critiques of gene therapies. We close by reviewing efforts by, and opportunities within, the genetic counseling profession to center the perspectives of people with disabilities in genetic counseling practice and education.

Genetic variation is a major determinant of drug response across populations. Owing to advances in sequencing technologies over the last two decades, several clinically actionable variants or haplotypes have been characterized in genes that encode proteins mediating drug pharmacokinetics or pharmacodynamics. Therefore, clinical application of pharmacogenomics has gained significant traction as a promising tool for enabling drug therapy optimization to mitigate adverse drug reactions while promoting drug efficacy. However, the implementation of pharmacogenetics testing has been slow in African settings and other resource-limited global regions. Moreover, there is a need to address gaps in various pharmacogenomics knowledgebases, especially regarding the genetic diversity in underrepresented populations. It is also important to ensure that emerging assays and technologies do not heighten existing healthcare disparities affecting African populations. We present the status of pharmacogenomics in Africa, highlighting its potential to impact health outcomes in the safe and efficacious use of medicines.

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.

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.

In this short memoir, I recount the series of improbable interactions and events that led me from medical school to a leadership role in the Human Genome Project.

RNA sequencing (RNA-seq) enables the accurate measurement of multiple transcriptomic phenotypes for modeling the impacts of disease variants. Advances in technologies, experimental protocols, and analysis strategies are rapidly expanding the application of RNA-seq to identify disease biomarkers, tissue- and cell-type-specific impacts, and the spatial localization of disease-associated mechanisms. Ongoing international efforts to construct biobank-scale transcriptomic repositories with matched genomic data across diverse population groups are further increasing the utility of RNA-seq approaches by providing large-scale normative reference resources. The availability of these resources, combined with improved computational analysis pipelines, has enabled the detection of aberrant transcriptomic phenotypes underlying rare diseases. Further expansion of these resources, across both somatic and developmental tissues, is expected to soon provide unprecedented insights to resolve disease origin, mechanism of action, and causal gene contributions, suggesting the continued high utility of RNA-seq in disease diagnosis.

A decade ago, the US Supreme Court decided Association for Molecular Pathology v. Myriad Genetics, Inc., concluding that isolated genes were not patentable subject matter. Beyond being a mere patent dispute, the case was a political and cultural phenomenon, viewed as a harbinger for the health of the biotechnology industry. With a decade of perspective, though, Myriad's impact seems much narrower. The law surrounding patentable subject matter-while greatly transformed-only centered on Myriad in small part. The case had only a modest impact on patenting practices both in and outside the United States. And persistent efforts to legislatively overturn the decision have not borne fruit. The significance of Myriad thus remains, even a decade later, hidden by larger developments in science and law that have occurred since the case was decided.

Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage and clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, and splicing factors, which are essential to maintain functional HSPCs and are frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, and smoking, increase the risk of acquiring CH and/or may increase CH fitness. CH has emerged as a novel risk factor in many age-related diseases, such as hematologic malignancies, cardiovascular disease, diabetes, and autoimmune disorders, among others. Future characterization of the mechanisms driving CH evolution will be critical to develop preventative and therapeutic approaches.