Evolution Of Regulation Research Articles

Genome editing in Latin America: research achievements and regulatory evolution

Genome editing in Latin America: research achievements and regulatory evolution

Plasticity and environment-specific relationships between gene expression and fitness in Saccharomyces cerevisiae.

The environment influences how an organism's genotype determines its phenotype and how this phenotype affects its fitness. Here, to better understand this dual role of environment in the production and selection of phenotypic variation, we determined genotype-phenotype-fitness relationships for mutant strains of Saccharomyces cerevisiae in four environments. Specifically, we measured how promoter mutations of the metabolic gene TDH3 modified expression level and affected growth for four different carbon sources. In each environment, we observed a clear relationship between TDH3 expression level and fitness, but this relationship differed among environments. Mutations with similar effects on expression in different environments often had different effects on fitness and vice versa. Such environment-specific relationships between phenotype and fitness can shape the evolution of phenotypic plasticity. We also found that mutations disrupting binding sites for transcription factors had more variable effects on expression among environments than those disrupting the TATA box, which is part of the core promoter. However, mutations with the most environmentally variable effects on fitness were located in the TATA box, because of both the lack of plasticity of TATA box mutations and environment-specific fitness functions. This observation suggests that mutations affecting different molecular mechanisms contribute unequally to regulatory sequence evolution in changing environments.

Demystifying the Black Box: A Technical Analysis of Transparency Requirements in Clinical AI Systems

This analysis examines the adequacy of Ghana's current regulatory framework in addressing AI explainability in clinical decision support systems. It evaluates existing healthcare laws, derives underlying principles, and assesses their application to AI governance. The study finds significant gaps in the current regulatory regime, including a lack of AI-specific provisions, insufficient explainability requirements, and inadequate frameworks for liability and accountability. While existing principles provide a foundation, they are insufficient to fully address the challenges posed by AI in healthcare. The analysis concludes that comprehensive regulatory development is needed, including AI-specific healthcare regulations, technical standards for explainability, and enhanced regulatory capacity. This study is significant as it provides a roadmap for developing effective AI explainability regulations in Ghana's healthcare sector. It highlights the urgent need for regulatory evolution to ensure safe, ethical, and transparent use of AI in clinical decision support, potentially serving as a model for other developing nations facing similar challenges.

Number of human protein interactions correlates with structural, but not regulatory conservation of the respective genes.

The differential ratio of nonsynonymous to synonymous nucleotide substitutions (dN/dS) is a common measure of the rate of structural evolution in proteincoding genes. In addition, we recently suggested that the proportion of transposable elements in gene promoters that host functional genomic sites serves as a marker of the rate of regulatory evolution of genes. Such functional genomic regions may include transcription factor binding sites and modified histone binding loci. Here, we constructed a model of the human interactome based on 600,136 documented molecular interactions and investigated the overall relationship between the number of interactions of each protein and the rate of structural and regulatory evolution of the corresponding genes. By evaluating a total of 4,505 human genes and 1,936 molecular pathways we found a general correlation between structural and regulatory evolution rate metrics (Spearman 0.08-0.16 and 0.25-0.37 for gene and pathway levels, respectively, p < 0.01). Further exploration revealed in the established human interactome model lack of correlation between the rate of gene regulatory evolution and the number of protein interactions on gene level, and weak negative correlation (∼0.15) on pathway level. We also found a statistically significant negative correlation between the rate of gene structural evolution and the number of protein interactions (Spearman -0.11 and -0.3 for gene and pathway levels, respectively, p < 0.01). Our result suggests stronger structural rather than regulatory conservation of genes whose protein products have multiple interaction partners.

Novel Fosfomycin Resistance Mechanism in Pseudomonas entomophila Due to Atypical Pho Regulon Control of GlpT

Background/Objectives: Pseudomonas entomophila is a ubiquitous bacterium capable of killing insects of different orders and has become a model for host–pathogen studies and a promising tool for biological pest control. In the human pathogen Pseudomonas aeruginosa, spontaneous resistance to fosfomycin arises almost exclusively from mutations in the glycerol-3-phosphate transporter (GlpT), the drug’s sole entry route in this species. Here, we investigated whether this specificity is conserved in P. entomophila, as it could provide a valuable marker system for studying mutation rates and spectra and for selection in genetic engineering. Methods: We isolated 16 independent spontaneous fosfomycin-resistant mutants in P. entomophila, and studied the genetic basis of the resistance using a combination of sequencing, phenotyping and computational approaches. Results: We only found two mutants without alterations in glpT or any of its known regulatory elements. Whole-genome sequencing revealed unique inactivating mutations in phoU, a key regulator of the phosphate starvation (Pho) regulon. Computational analyses identified a PhoB binding site in the glpT promoter, and experiments showed that phoU inactivation reduced glpT expression nearly 20-fold. While placing a sugar-phosphate transporter under the Pho regulon may seem advantageous, bioinformatic analysis shows this configuration is atypical among pseudomonads. Conclusions: this atypical Pho regulon control of GlpT probably reflects the peculiarities of P. entomophila’s habitat and lifestyle; highlighting how readily regulatory evolution can lead to the rapid divergence of resistance mechanisms, even among closely related species.

Understanding developmental system drift.

Developmental system drift (DSD) occurs when the genetic basis for homologous traits diverges over time despite conservation of the phenotype. In this Review, we examine the key ideas, evidence and open problems arising from studies of DSD. Recent work suggests that DSD may be pervasive, having been detected across a range of different organisms and developmental processes. Although developmental research remains heavily reliant on model organisms, extrapolation of findings to non-model organisms can be error-prone if the lineages have undergone DSD. We suggest how existing data and modelling approaches may be used to detect DSD and estimate its frequency. More direct study of DSD, we propose, can inform null hypotheses for how much genetic divergence to expect on the basis of phylogenetic distance, while also contributing to principles of gene regulatory evolution.

Decrypting Corals: Does Regulatory Evolution Underlie Environmental Specialisation of Coral Cryptic Lineages?

A recent sequencing study has shown that two common Caribbean corals, Montastraea cavernosa and Siderastrea siderea, each consist of four genetically distinct lineages in the Florida Keys. These lineages are specialised to a certain depth and, to a lesser extent, to nearshore or offshore habitats. We hypothesised that the lineages' environmental specialisation is at least in part due to regulatory evolution, which would manifest as the emergence of groups of coregulated genes ('modules') demonstrating lineage-specific responses to different reef environments. Our hypothesis also predicted that genes belonging to such modules would show greater genetic divergence between lineages than other genes. Contrary to these expectations, responses of cryptic lineages to natural environmental variation were essentially the same at the genome-wide gene coexpression network level, with much fewer differences in gene expression between lineages compared to between habitats. Moreover, none of the identified coregulated gene expression modules exhibit elevated genetic divergence between lineages. Possible explanations of these unexpected results range from the leading role of algal symbionts and/or microbiome in adaptation to strong action of spatially varying selection equalising gene expression patterns despite different genetic background. We discuss how future studies could assist in discriminating between these possibilities.

Evolution of plant cell-type-specific cis-regulatory elements.

Cis-regulatory elements (CREs) are critical in regulating gene expression, and yet understanding of CRE evolution remains challenging. Here, we constructed a comprehensive single-cell atlas of chromatin accessibility in Oryza sativa, integrating data from 103,911 nuclei representing 126 discrete cell states across nine distinct organs. We used comparative genomics to compare cell-type resolved chromatin accessibility between O. sativa and 57,552 nuclei from four additional grass species (Zea mays, Sorghum bicolor, Panicum miliaceum, and Urochloa fusca). Accessible chromatin regions (ACRs) had different levels of conservation depending on the degree of cell-type specificity. We found a complex relationship between ACRs with conserved noncoding sequences, cell-type specificity, conservation, and tissue-specific switching. Additionally, we found that epidermal ACRs were less conserved compared to other cell types, potentially indicating that more rapid regulatory evolution has occurred in the L1-derived epidermal layer of these species. Finally, we identified and characterized a conserved subset of ACRs that overlapped the repressive histone modification H3K27me3, implicating them as potentially silencer-like CREs maintained by evolution. Collectively, this comparative genomics approach highlights the dynamics of plant cell-type-specific CRE evolution.

Comparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development.

Understanding the cellular and genetic mechanisms driving human-specific features of cortical development remains a challenge. We generated a cell-type resolved atlas of transcriptome and chromatin accessibility in the developing macaque and mouse prefrontal cortex (PFC). Comparing with published human data, our findings demonstrate that although the cortex cellular composition is overall conserved across species, progenitor cells show significant evolutionary divergence in cellular properties. Specifically, human neural progenitors exhibit extensive transcriptional rewiring in growth factor and extracellular matrix (ECM) pathways. Expression of the human-specific progenitor marker ITGA2 in the fetal mouse cortex increases the progenitor proliferation and the proportion of upper-layer neurons. These transcriptional divergences are primarily driven by altered activity in the distal regulatory elements. The chromatin regions with human-gained accessibility are enriched with human-specific sequence changes and polymorphisms linked to intelligence and neuropsychiatric disorders. Our results identify evolutionary changes in neural progenitors and putative gene regulatory mechanisms shaping primate brain evolution.

Evolutionary Innovations in Conserved Regulatory Elements Associate With Developmental Genes in Mammals.

Transcriptional enhancers orchestrate cell type- and time point-specific gene expression programs. Genetic variation within enhancer sequences is an important contributor to phenotypic variation including evolutionary adaptations and human disease. Certain genes and pathways may be more prone to regulatory evolution than others, with different patterns across diverse organisms, but whether such patterns exist has not been investigated at a sufficient scale. To address this question, we identified signatures of accelerated sequence evolution in conserved enhancer elements throughout the mammalian phylogeny at an unprecedented scale. While different genes and pathways were enriched for regulatory evolution in different parts of the tree, we found a striking overall pattern of pleiotropic genes involved in gene regulatory and developmental processes being enriched for accelerated enhancer evolution. These genes were connected to more enhancers than other genes, which was the basis for having an increased amount of sequence acceleration over all their enhancers combined. We provide evidence that sequence acceleration is associated with turnover of regulatory function. Detailed study of one acceleration event in an enhancer of HES1 revealed that sequence evolution led to a new activity domain in the developing limb that emerged concurrently with the evolution of digit reduction in hoofed mammals. Our results provide evidence that enhancer evolution has been a frequent contributor to regulatory innovation at conserved developmental signaling genes in mammals.

Pervasive tissue-, genetic background-, and allele-specific gene expression effects in Drosophila melanogaster.

The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression, trans effects were more tissue-specific than cis effects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cis and trans regulatory evolution.

Regulatory Challenges and Frameworks for Fog Computing in Healthcare.

The integration of fog computing into healthcare promises significant advancements in real-time data analytics and patient care by decentralizing data processing closer to the source. This shift, however, introduces complex regulatory, privacy, and security challenges that are not adequately addressed by existing frameworks designed for centralized systems. The distributed nature of fog computing complicates the uniform application of security measures and compliance with diverse international regulations, raising concerns about data privacy, security vulnerabilities, and legal accountability. This review explores these challenges in depth, discussing the implications of fog computing's decentralized architecture for data privacy, the difficulties in achieving consistent security across dispersed nodes, and the complexities of ensuring compliance in multi-jurisdictional environments. It also examines specific regulatory frameworks, including Health Insurance Portability and Accountability (HIPAA) in the United States, General Data Protection Regulation (GDPR) in the European Union, and emerging laws in Asia and Brazil, highlighting the gaps and the need for regulatory evolution to better accommodate the nuances of fog computing. The review advocates for a proactive regulatory approach, emphasizing the development of specific guidelines, international collaboration, and public-private partnerships to enhance compliance and support innovation. By embedding privacy and security by design and leveraging advanced technologies, healthcare providers can navigate the regulatory landscape effectively, ensuring that fog computing realizes its full potential as a transformative healthcare technology without compromising patient trust or data integrity.

The Transformative Impact of Financial Technology (FinTech) on Regulatory Compliance in the Banking Sector

Financial Technology (FinTech) has emerged as a disruptive force in the banking sector, revolutionizing the way financial services are delivered and consumed. This review explores the transformative impact of FinTech on regulatory compliance within the banking industry. The integration of advanced technologies such as artificial intelligence, blockchain, and big data analytics has enabled financial institutions to enhance operational efficiency, improve customer experience, and expand market reach. However, these innovations have also posed unprecedented challenges to traditional regulatory frameworks designed to safeguard financial stability and consumer protection. This review examines how FinTech innovations have necessitated regulatory adaptation and evolution. It highlights the complexities introduced by novel financial products, digital payment systems, and decentralized finance (DeFi) platforms, which often operate beyond conventional regulatory boundaries. Regulatory compliance in areas such as anti-money laundering (AML), know your customer (KYC) requirements, and data privacy has become more intricate as FinTech solutions blur geographical and jurisdictional lines. Moreover, the strategies employed by regulatory bodies and financial institutions to address these challenges effectively. These include leveraging regulatory technology (RegTech) solutions for enhanced monitoring and compliance automation, fostering collaboration between regulators and industry stakeholders, and advocating for agile regulatory frameworks capable of accommodating rapid technological advancements. Looking ahead, the review anticipates ongoing shifts in regulatory paradigms to accommodate the transformative impact of FinTech. It emphasizes the importance of proactive regulatory approaches that balance innovation with risk management, ensuring the integrity and resilience of the banking sector amidst a rapidly evolving digital landscape. This provides a comprehensive overview of how FinTech is reshaping regulatory compliance in banking. It underscores the need for adaptive regulatory strategies and collaborative efforts to harness the full potential of FinTech while safeguarding financial stability and consumer trust.

Stem cell transcriptional profiles from mouse subspecies reveal cis -regulatory evolution at translation genes.

A key goal of evolutionary genomics is to harness molecular data to draw inferences about selective forces that have acted on genomes. The field progresses in large part through the development of advanced molecular-evolution analysis methods. Here we explored the intersection between classical sequence-based tests for selection and an empirical expression-based approach, using stem cells from Mus musculus subspecies as a model. Using a test of directional, cis -regulatory evolution across genes in pathways, we discovered a unique program of induction of translation genes in stem cells of the Southeast Asian mouse M. m. castaneus relative to its sister taxa. We then mined population-genomic sequences to pursue underlying regulatory mechanisms for this expression divergence, finding robust evidence for alleles unique to M. m. castaneus at the upstream regions of the translation genes. We interpret our data under a model of changes in lineage-specific pressures across Mus musculus in stem cells with high translational capacity. Our findings underscore the rigor of integrating expression and sequence-based methods to generate hypotheses about evolutionary events from long ago.

Transforming Continuing Professional Development for Healthcare Professionals to Meet National Goals in Saudi Arabia

ABSTRACT The Saudi Commission for Health Specialties (SCFHS), the regulatory agency for health professions in the Kingdom of Saudi Arabia (KSA), sought to evolve the continuing professional development (CPD) ecosystem for the country and to promote the concept of life-long learning for healthcare professionals. SCFHS audited its own CPD accreditation system, reviewed internationally recognised CPD accreditation criteria, adopted a new set of standards, and trained its staff and provider community in their adoption. SCFHS also deployed a range of programmes and grants to support healthcare educators and researchers engaged in CPD. SCFHS recruited and trained new staff and deployed an updated IT system to support system change. The adopted criteria and standards now align with best practices, as outlined by the Accreditation Council for Continuing Medical Education (ACCME) and the International Academy for CPD Accreditation. More than 170 educators have participated in programmes to learn effective CPD pedagogy. The adoption of new standards resulted in 396 providers seeking provider accreditation. The number of CPD accredited activities produced in the KSA and approved by the SCFHS has grown from 1,000 activities in 2002 to 10,500 in 2022. With leadership support, regulatory evolution to align with best practices supports healthcare educators and effectively expands of the diversity and quality of CPD.

EXPLORING BLOCKCHAIN TECHNOLOGY AND ITS IMPACT IN E-COMMERCE

Blockchain technology has fundamentally transformed the landscape of digital transactions and data management, deeply influencing the domain of e-commerce. Its integration across various sectors has revolutionized the access to secure, transparent, and efficient transaction mechanisms, thereby promoting financial inclusivity and advancing contemporary business practices. Moreover, blockchain enables enhanced supply chain management, robust data protection, and the decentralization of marketplaces. The purpose of this article is to examine the multi-faceted impacts of blockchain technology on e-commerce effectiveness and to assess its potential as a cornerstone for digital transformation in commercial operations. Utilizing a case study methodology, the research explores practical applications of blockchain in e-commerce, particularly focusing on systems like the IBM Food Trust for improving supply chain transparency and consumer trust. The study employs a comparative analysis to delineate the effects of blockchain on operational efficiency and consumer satisfaction. While the findings acknowledge the profound short-term benefits of blockchain implementation, they also highlight significant challenges related to scalability and regulatory frameworks that could affect long-term integration. The article concludes that continued innovation and regulatory evolution are essential for blockchain to become a major driver of economic competitiveness and digital transformation in the global market.

Deciphering regulatory architectures from synthetic single-cell expression patterns.

For the vast majority of genes in sequenced genomes, there is limited understanding of how they are regulated. Without such knowledge, it is not possible to perform a quantitative theory-experiment dialogue on how such genes give rise to physiological and evolutionary adaptation. One category of high-throughput experiments used to understand the sequence-phenotype relationship of the transcriptome is massively parallel reporter assays (MPRAs). However, to improve the versatility and scalability of MPRA pipelines, we need a "theory of the experiment" to help us better understand the impact of various biological and experimental parameters on the interpretation of experimental data. These parameters include binding site copy number, where a large number of specific binding sites may titrate away transcription factors, as well as the presence of overlapping binding sites, which may affect analysis of the degree of mutual dependence between mutations in the regulatory region and expression levels. To that end, in this paper we create tens of thousands of synthetic single-cell gene expression outputs using both equilibrium and out-of-equilibrium models. These models make it possible to imitate the summary statistics (information footprints and expression shift matrices) used to characterize the output of MPRAs and from this summary statistic to infer the underlying regulatory architecture. Specifically, we use a more refined implementation of the so-called thermodynamic models in which the binding energies of each sequence variant are derived from energy matrices. Our simulations reveal important effects of the parameters on MPRA data and we demonstrate our ability to optimize MPRA experimental designs with the goal of generating thermodynamic models of the transcriptome with base-pair specificity. Further, this approach makes it possible to carefully examine the mapping between mutations in binding sites and their corresponding expression profiles, a tool useful not only for better designing MPRAs, but also for exploring regulatory evolution.

The Principle of Proportionality: Unraveling the Practical Application of Proportionality in the EU Regulations and the Solvency II Directive for Insurance Undertakings

Proportionality, pivotal to EU regulations and Solvency II, tailors rules to insurers’ size and complexity. Inconsistent application by supervisory authorities (NSAs) necessitates clarity to prevent undue costs. This study examines the issue via a review of the literature and industry discussions, emphasizing Solvency II’s introduction of proportionality and the varied interpretations it evokes. Transparent communication is crucial, and regulatory evolution must align with market dynamics, with the European Insurance and Occupational Pensions Authority (EIOPA) fostering convergence. Assessing proportionality mandates a comprehensive evaluation of an insurer’s nature, scale, and complexity. Regulatory distinctions between first-party and third-party risks could enhance market efficiency. Ultimately, a holistic, market-oriented approach is essential for proportionate regulation in the insurance sector, requiring concerted efforts to elucidate frameworks, foster transparency, and align regulatory evolution with market dynamics.

The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model.

Gene expression is temporally and spatially regulated by the interaction of transcription factors (TFs) and cis-regulatory elements (CREs). The uneven distribution of TF binding sites across the genome poses challenges in understanding how this distribution evolves to regulate spatio-temporal gene expression and consequent heritable phenotypic variation. In this study, chromatin accessibility profiles and gene expression profiles were collected from several species including mammals (human, mouse, bovine), fish (zebrafish and medaka), and chicken. Transcription factor binding sites clustered regions (TFCRs) at different embryonic stages were characterized to investigate regulatory evolution. The study revealed dynamic changes in TFCR distribution during embryonic development and species evolution. The synchronization between TFCR complexity and gene expression was assessed across species using RegulatoryScore. Additionally, an explainable machine learning model highlighted the importance of the distance between TFCR and promoter in the coordinated regulation of TFCRs on gene expression. Our results revealed the developmental and evolutionary dynamics of TFCRs during embryonic development from fish, chicken to mammals. These data provide valuable resources for exploring the relationship between transcriptional regulation and phenotypic differences during embryonic development.

Rapid response of fly populations to gene dosage across development and generations

Although the effects of genetic and environmental perturbations on multicellular organisms are rarely restricted to single phenotypic layers, our current understanding of how developmental programs react to these challenges remains limited. Here, we have examined the phenotypic consequences of disturbing the bicoid regulatory network in early Drosophila embryos. We generated flies with two extra copies of bicoid, which causes a posterior shift of the network’s regulatory outputs and a decrease in fitness. We subjected these flies to EMS mutagenesis, followed by experimental evolution. After only 8–15 generations, experimental populations have normalized patterns of gene expression and increased survival. Using a phenomics approach, we find that populations were normalized through rapid increases in embryo size driven by maternal changes in metabolism and ovariole development. We extend our results to additional populations of flies, demonstrating predictability. Together, our results necessitate a broader view of regulatory network evolution at the systems level.