Genetic Theory Research Articles

Insertion-deletions are depleted in protein regions with predicted secondary structure.

A fundamental goal in evolutionary biology and population genetics is to understand how selection shapes the fate of new mutations. Here we test the null hypothesis that insertion-deletion events (indels) in protein coding regions occur randomly with respect to secondary structures. We identified indels across 11,444 sequence alignments in mouse, rat, human, chimp, and dog genomes, then quantified their overlap with four different types of secondary structure - alpha helices, beta strands, protein bends, and protein turns - predicted by deep-learning methods of AlphaFold2. Indels overlapped secondary structures 54% as much as expected, and were especially under-represented over beta strands, which tend to form internal, stable regions of proteins. In contrast, indels were enriched by 155% over regions without any predicted secondary structures. These skews were stronger in the rodent lineages compared to the primate lineages, consistent with population genetic theory predicting that natural selection will be more efficient in species with larger effective population sizes. Nonsynonymous substitutions were also less common in regions of protein secondary structure, although not as strongly reduced as in indels. In a complementary analysis of thousands of human genomes, we showed that indels overlapping secondary structure segregated at significantly lower frequency than indels outside of secondary structure. Taken together, our study shows that indels are selected against if they overlap secondary structure, presumably because they disrupt the tertiary structure and function of a protein.

"Microtia, Branchial Cleft Fistula, and Tetralogy of Fallot: A Possible Association".

When searching over associations between congenital ear abnormalities, especially microtia and affiliated deformities like cleft lip or palate and congenital heart diseases, some clinical analysis and genetic theories are found. A 10-year-old boy sent to the plastic surgery hospital was puzzled by a congenital anterior auricular fistula with fluid trace for more than 9 years. The preoperative diagnoses were branchial cleft fistula and congenital left ear deformity with postoperation of TOF. By browsing over studies on genetic concerns and clinical performance, it may be attributed to a possible association between microtia, branchial cleft fistula, and tetralogy of Fallot, though whose fundamental mechanisms remain concerned.

Distribution theories for genetic line of least resistance and evolvability measures.

Quantitative genetic theory on multivariate character evolution predicts that a population's response to directional selection is biased toward the major axis of the genetic covariance matrix G-the so-called genetic line of least resistance. Inferences on the genetic constraints in this sense have traditionally been made by measuring the angle of deviation of evolutionary trajectories from the major axis, or more recently by calculating the amount of genetic variance-the Hansen-Houle evolvability-available along the trajectories. However, there have not been clear practical guidelines on how these quantities can be interpreted, especially in a high-dimensional space. This study summarizes pertinent distribution theories for relevant quantities, pointing out that they can be written as ratios of quadratic forms in evolutionary trajectory vectors by taking G as a parameter. For example, a beta distribution with appropriate parameters can be used as a null distribution for squared cosine of the angle of deviation from a major axis or subspace. More general cases can be handled with the probability distribution of ratios of quadratic forms in normal variables. Apart from its use in hypothesis-testing, this latter approach could potentially be used as a heuristic tool for looking into various selection scenarios like directional and/or correlated selection as parameterized with mean and covariance of selection gradients.

Optimizing large-scale hydrogen storage: A novel hybrid genetic algorithm approach for efficient pipeline network design

As hydrogen production technologies continue to advance, efficient and high-capacity hydrogen storage solutions become increasingly crucial. To address the complex optimization challenges in the design of large-scale hydrogen storage pipeline networks, the study introduces a mixed integer nonlinear optimization model inspired by hydrogen pipeline design optimization theory. The model not only focuses on optimizing network design parameters but also aims to minimize investment costs. To achieve this, the study proposes an innovative hybrid genetic algorithm that combines the Modified Feasible Directions Method (MFDM) and Genetic Algorithm Theory (GAT), specifically targeting the optimization of pipeline diameter's discrete distribution challenges. Comparative analyses with SUMT and GA algorithms demonstrate the superiority of the approach. In continuous space, the algorithm achieves a lower convergence cost of 232.4437 × 104 Yuan, while in discrete space, the cost further decreases to 212.1636 × 104 Yuan. Additionally, the study delves into the sensitivity of the HGA-MFDM algorithm to ambient temperature and wellhead temperature in hydrogen storage facilities. The analysis reveals that wellhead temperature has a more significant impact on pipeline network investment, whereas ambient temperature exhibits a more pronounced effect on iteration curves. The findings provide valuable insights for the precise adjustment and optimization of hydrogen storage pipeline networks in practical applications.

Life and fate of Ervin Bauer (1890–1938), the eminent scholar and foundational theoretical biologist

Ervin Bauer (1890–1938) was the first to build a general molecular-based biological theory. He defined the basic principles of theoretical biology from a thermodynamic perspective, focusing on the capacity of biological systems to produce and support the state of sustainable non-equilibrium. His central work “Theoretical Biology” (1935) was written long before modern advances in molecular biology, genetics, and information theory. Ervin Bauer and his wife Stefánia were executed in Stalin's Great Terror. This paper presents a brief introduction to Ervin Bauer's life and includes his short biography.

A REVIEW OF THE CULTURAL LEVELS OF THE ARTISTIC CHARACTERISTICS OF YANGJIABU NEW YEAR WOODCUT PRINTS

YangJiaBu New Year woodcut prints, integral to China's intangible cultural heritage, encapsulate the nation's rich folk traditions and artistic expressions. This study investigates their evolving cultural significance in the context of global cultural shifts. It adopts the method of literature analysis to explore in depth the inheritance and innovative application of these prints, offering insights into their historical background, development patterns, and cultural values. The research draws on interdisciplinary perspectives to articulate the cultural evolution of these prints and their implications for cultural attributes, artistic aesthetics, and innovation direction. The YangJiaBu prints, embodying traditional Chinese culture's ethos, have undergone significant transformations across dynasties, reflecting the changing societal values and aspirations. This paper presents a tiered analysis using cultural genetics and cultural level theories, examining the prints' role in enhancing social connections and individual life experiences. It emphasizes their potential in design innovation, cultural heritage preservation, and fostering societal progress. The study also explores the interplay between art and technology, proposing a systematic design paradigm to integrate traditional culture into modern contexts. This synopsis retraces YangJiaBu prints' historical and cultural journey, highlighting their potential to enrich modern design and cultural innovation.

Ecological characteristics explain neutral genetic variation of three coastal sparrow species.

Eco-phylogeographic approaches to comparative population genetic analyses allow for the inclusion of intrinsic influences as drivers of intraspecific genetic structure. This insight into microevolutionary processes, including changes within a species or lineage, provides better mechanistic understanding of species-specific interactions and enables predictions of evolutionary responses to environmental change. In this study, we used single nucleotide polymorphisms (SNPs) identified from reduced representation sequencing to compare neutral population structure, isolation by distance (IBD), genetic diversity and effective population size (Ne) across three closely related and co-distributed saltmarsh sparrow species differing along a specialization gradient-Nelson's (Ammospiza nelsoni subvirgata), saltmarsh (A. caudacuta) and seaside sparrows (A. maritima maritima). Using an eco-phylogeographic lens within a conservation management context, we tested predictions about species' degree of evolutionary history and ecological specialization to tidal marshes, habitat, current distribution and population status on population genetic metrics. Population structure differed among the species consistent with their current distribution and habitat factors, rather than degree of ecological specialization: seaside sparrows were panmictic, saltmarsh sparrows showed hierarchical structure and Nelson's sparrows were differentiated into multiple, genetically distinct populations. Neutral population genetic theory and demographic/evolutionary history predicted patterns of genetic diversity and Ne rather than degree of ecological specialization. Patterns of population variation and evolutionary distinctiveness (Shapely metric) suggest different conservation measures for long-term persistence and evolutionary potential in each species. Our findings contribute to a broader understanding of the complex factors influencing genetic variation, beyond specialist-generalist status and support the role of an eco-phylogeographic approach in population and conservation genetics.

The fundamental theorem of natural selection: the end of a story.

The direction of research in population genetics theory is currently, and correctly, retrospective, that is directed toward the past. What events in the past have led to the presently observed genetic constitution of a population? This direction is inspired, first, by the large volumes of genomic data now available and, second, by the success of the classical prospective theory in validating the Darwinian theory in terms of Mendelian genetics. However, the prospective theory should not be forgotten, and in that theory, perhaps the most interesting and certainly the most controversial, is Fisher's so-called "Fundamental Theorem of Natural Selection." This article describes the history and the current status of that theorem.

A comprehensive review on the development of sporadic cerebral arteriovenous malformations: from Padget to next-generation sequencing.

Cerebral arteriovenous malformations (AVMs) are a leading cause of intracerebral hemorrhage in both children and young adults. With the continued advancement of science and technology, the understanding of the pathophysiology behind the development of these lesions has evolved. From early theory published by Harvey Cushing and Percival Bailey in 1928, Tumors Arising from the Blood-vessels of the Brain: Angiomatous Malformations and Hemangioblastoma, which regarded AVMs as tumors arising from blood vessels, to the meticulous artistry of Dorcas Padget's embryological cataloguing of the cerebral vasculature in 1948, to the proliferative capillaropathy theory of Yaşargil in 1987, to Ramey's 2014 hierarchical model of vascular development, there have been multiple hypotheses of congenital, developmental, and genetic two-hit theories in the pathogenesis of AVMs. Most recent evidence implicates somatic KRAS mutations in the cerebral endothelium, producing an important understanding of the pathogenesis of this disease, which is critical to the development of targeted therapeutics. The authors present the historical progression of their understanding of AVM pathogenesis. They focus on the foundation laid by early pioneers, discussing embryological anatomy and vasculogenesis, the prominent theories of AVM development that have emerged over time, and culminate in an overview of the most current understanding of the pathogenesis of these complex vascular lesions and the clinical implications of our scientific progress.

A unified framework for evolutionary genetic and physiological theories of aging.

Why and how we age are 2 intertwined questions that have fascinated scientists for many decades. However, attempts to answer these questions remain compartmentalized, preventing a comprehensive understanding of the aging process. We argue that the current lack of knowledge about the evolution of aging mechanisms is due to a lack of clarity regarding evolutionary theories of aging that explicitly involve physiological processes: the disposable soma theory (DST) and the developmental theory of aging (DTA). In this Essay, we propose a new hierarchical model linking genes to vital rates, enabling us to critically reevaluate the DST and DTA in terms of their relationship to evolutionary genetic theories of aging (mutation accumulation (MA) and antagonistic pleiotropy (AP)). We also demonstrate how these 2 theories can be incorporated in a unified hierarchical framework. The new framework will help to generate testable hypotheses of how the hallmarks of aging are shaped by natural selection.

A Community-Based Framework Integrates Interspecific Interactions into Forest Genetic Conservation

Forest genetic conservation is typically species-specific and does not integrate interspecific interaction and community structure. It mainly focuses on the theories of population and quantitative genetics. This approach depicts the intraspecific patterns of population genetic structure derived from genetic markers and the genetic differentiation of adaptive quantitative traits in provenance trials. However, it neglects possible interspecific interaction in natural forests and overlooks natural hybridization or subspeciation. We propose that the genetic diversity of a given species in a forest community is shaped by both intraspecific population and interspecific community evolutionary processes, and expand the traditional forest genetic conservation concept under the community ecology framework. We show that a community-specific phylogeny derived from molecular markers would allow us to explore the genetic mechanisms of a tree species interacting with other resident species. It would also facilitate the exploration of a species’ ecological role in forest community assembly and the taxonomic relationship of the species with other species specific to its resident forest community. Phylogenetic β-diversity would assess the similarities and differences of a tree species across communities regarding ecological function, the strength of selection pressure, and the nature and extent of its interaction with other species. Our forest genetic conservation proposal that integrates intraspecific population and interspecific community genetic variations is suitable for conserving a taxonomic species complex and maintaining its evolutionary potential in natural forests. This provides complementary information to conventional population and quantitative genetics-based conservation strategies.

Measures of genetic diversification in somatic tissues at bulk and single-cell resolution.

Intra-tissue genetic heterogeneity is universal to both healthy and cancerous tissues. It emerges from the stochastic accumulation of somatic mutations throughout development and homeostasis. By combining population genetics theory and genomic information, genetic heterogeneity can be exploited to infer tissue organization and dynamics in vivo. However, many basic quantities, for example the dynamics of tissue-specific stem cells remain difficult to quantify precisely. Here, we show that single-cell and bulk sequencing data inform on different aspects of the underlying stochastic processes. Bulk-derived variant allele frequency spectra (VAF) show transitions from growing to constant stem cell populations with age in samples of healthy esophagus epithelium. Single-cell mutational burden distributions allow a sample size independent measure of mutation and proliferation rates. Mutation rates in adult hematopietic stem cells are higher compared to inferences during development, suggesting additional proliferation-independent effects. Furthermore, single-cell derived VAF spectra contain information on the number of tissue-specific stem cells. In hematopiesis, we find approximately 2 × 105 HSCs, if all stem cells divide symmetrically. However, the single-cell mutational burden distribution is over-dispersed compared to a model of Poisson distributed random mutations. A time-associated model of mutation accumulation with a constant rate alone cannot generate such a pattern. At least one additional source of stochasticity would be needed. Possible candidates for these processes may be occasional bursts of stem cell divisions, potentially in response to injury, or non-constant mutation rates either through environmental exposures or cell-intrinsic variation.

Measures of genetic diversification in somatic tissues at bulk and single-cell resolution

Intra-tissue genetic heterogeneity is universal to both healthy and cancerous tissues. It emerges from the stochastic accumulation of somatic mutations throughout development and homeostasis. By combining population genetics theory and genomic information, genetic heterogeneity can be exploited to infer tissue organization and dynamics in vivo. However, many basic quantities, for example the dynamics of tissue-specific stem cells remain difficult to quantify precisely. Here, we show that single-cell and bulk sequencing data inform on different aspects of the underlying stochastic processes. Bulk-derived variant allele frequency spectra (VAF) show transitions from growing to constant stem cell populations with age in samples of healthy esophagus epithelium. Single-cell mutational burden distributions allow a sample size independent measure of mutation and proliferation rates. Mutation rates in adult hematopietic stem cells are higher compared to inferences during development, suggesting additional proliferation-independent effects. Furthermore, single-cell derived VAF spectra contain information on the number of tissue-specific stem cells. In hematopiesis, we find approximately 2 × 105 HSCs, if all stem cells divide symmetrically. However, the single-cell mutational burden distribution is over-dispersed compared to a model of Poisson distributed random mutations. A time-associated model of mutation accumulation with a constant rate alone cannot generate such a pattern. At least one additional source of stochasticity would be needed. Possible candidates for these processes may be occasional bursts of stem cell divisions, potentially in response to injury, or non-constant mutation rates either through environmental exposures or cell-intrinsic variation.

[Genetic characteristic analysis of slight-to-moderate sensorineural hearing loss in children].

Objective:To analyze genetic factors and phenotype characteristics in pediatric population with slight-to-moderate sensorineural hearing loss. Methods:Children with slight-to-moderate sensorineural hearing loss of and their parents, enrolled from the Chinese Deafness Genome Project, were studied. Hearing levels were assessed using pure tone audiometry, behavioral audiometry, auditory steady state response（ASSR）, auditory brainstem response（ABR） thresholds, and deformed partial otoacoustic emission（DPOAE）. Classification of hearing loss is according to the 2022 American College of Medical Genetics and Genomics（ACMG） Clinical Practice Guidelines for Hearing Loss. Whole exome sequencing（WES） and deafness gene Panel testing were performed on peripheral venous blood from probands and validations were performed on their parents by Sanger sequencing. Results:All 134 patients had childhood onset, exhibiting bilateral symmetrical slight-to-moderate sensorineural hearing loss, as indicated by audiological examinations. Of the 134 patients, 29（21.6%） had a family history of hearing loss, and the rest were sporadic patients. Genetic causative genes were identified in 66（49.3%） patients. A total of 11 causative genes were detected, of which GJB2 was causative in 34 cases（51.5%）, STRC in 10 cases（15.1%）, MPZL2 gene in six cases（9.1%）, and USH2A in five cases（7.6%）.The most common gene detected in slight-to-moderate hearing loss was GJB2, with c. 109G>A homozygous mutation found in 16 cases（47.1%） and c. 109G>A compound heterozygous mutation in 9 cases（26.5%）. Conclusion:This study provides a crucial genetic theory reference for early screening and detection of mild to moderate hearing loss in children, highlighting the predominance of recessive inheritance and the significance of gene like GJB2, STRC, MPZL2, USH2A.

The difficulty of detecting inbreeding depression and its effect on conservation decisions.

Statistical inferences about inbreeding depression are often derived from analyses with low power and a high risk of failing to detect inbreeding depression. That risk is widely appreciated by scientists familiar with the relevant statistical and genetical theory, but may be overlooked and underappreciated by decision-makers. Consequently, there is value in demonstrating this risk using a real example. We use data from the wolf population on Isle Royale to demonstrate the difficulty of making reliable statistical inferences about inbreeding depression. This wolf population is known - by other methods - to have gone effectively extinct due to deleterious genetic processes associated with inbreeding. Beyond that demonstration, we use two case studies - wolves on Isle Royale and vaquita (porpoises) from the Gulf of California, Mexico - to show how statistical inferences about inbreeding depression can affect conservation decisions. According to most decision theory, decisions depend importantly on (i) probabilities that certain states exist (e.g., inbreeding depression is present) and (ii) the utility assigned to various outcomes (e.g., the value of acting to mitigate inbreeding when it is present). The probabilities are provided by statistical inference; whereas utilities are almost entirely determined by normative values and judgement. Our analysis suggests that decisions to mitigate inbreeding depression are often driven more by utilities (normative values) than probabilities (statistical inferences). As such, advocates for mitigating inbreeding depression will benefit from better communicating to decision-makers the value of populations persisting and the extent to which decisions should depend on normative values.

Never-ending story of Brachyury: From short-tailed mice to tailless primates

The history of developmental biology starts from the almost simultaneous discoveries of the Organizer of axial structures in amphibians by Spemann and Mangold in Freiburg and of the Brachyury mutant in mammals by the Dobrovolskaya-Zavadskaya laboratory at the Curie Institute and its follow-up studies in the Leslie Dunn laboratory at Columbia University. Following the Organizer's discovery, the inductive activity of several other embryonic tissues was found, including that of the ear primordium by Boris Balinsky in Kiev. Initially, the experimental embryological and genetic lines of research existed independently of each other, but after they met at the bench of Salome Gluecksohn, they strengthened and cross-fertilized each other, eventually leading to developmental genetics, which later became known as developmental biology. It appears that the regulatory activities of Brachyury and related T-box proteins in general are at the heart of the development of all vertebrates. These activities are fundamental and have been discovered in several model organisms subjected to mutagenesis, exemplified by the story of George Streisinger's discovery of the no tail mutant in zebrafish. This essay describes the history of Brachyury studies, their connection to an idea of embryonic induction by Organizer, and an impact of Brachyury and related genes on various fields of research from embryology and cell biology to medical genetics and evolutionary theory.

How chromosomal inversions reorient the evolutionary process.

Inversions are structural mutations that reverse the sequence of a chromosome segment and reduce the effective rate of recombination in the heterozygous state. They play a major role in adaptation, as well as in other evolutionary processes such as speciation. Although inversions have been studied since the 1920s, they remain difficult to investigate because the reduced recombination conferred by them strengthens the effects of drift and hitchhiking, which in turn can obscure signatures of selection. Nonetheless, numerous inversions have been found to be under selection. Given recent advances in population genetic theory and empirical study, here we review how different mechanisms of selection affect the evolution of inversions. A key difference between inversions and other mutations, such as single nucleotide variants, is that the fitness of an inversion may be affected by a larger number of frequently interacting processes. This considerably complicates the analysis of the causes underlying the evolution of inversions. We discuss the extent to which these mechanisms can be disentangled, and by which approach.

A current view on atrophic scars pathogenesis

The main theories of striae pathogenesis are the following: mechanical — an atrophic scar as a result of excessive skin stretching, hormonal — increased expression of genes for receptors of various hormones, and genetic theory — striae as a consequence of congenital structural disorders in the formation of epidermal and dermal structures of the skin. Purpose of the study: to analyze the increased risk of formation of hormone-dependent atrophic scars by studying the polymorphism of the genes for estrogen receptor 1, matrix metalloproteinase type-3, and COL1A1. Material and methods. In order to identify genetic factors of increased risk of striae formation, 20 patients with atrophic scars and 15 healthy patients were examined. The work examined the polymorphism of the COL1A1, ESR1, and MMP-3 genes. Results. Comparative analysis of gene polymorphism in patients with hormone-dependent scars determined a statistically significant difference in the distribution of alleles compared to the control group and showed high values of high-risk TT genotypes for COL1A1 (rs1800012). High values of the mutation / mutation allele CC for ESR1 (rs 2234693) were observed, as well as high values of intermediate risk genotypes 5A / 6A for MMP-3 (rs3025058) were detected. The data obtained can be considered as potential risk factors for the development of atrophic scars of the striae phenotype.

Identification of Multiple Genetic Loci Related to Low-Temperature Tolerance during Germination in Maize (Zea maize L.) through a Genome-Wide Association Study.

Low-temperature stress during the germination stage is an important abiotic stress that affects the growth and development of northern spring maize and seriously restricts maize yield and quality. Although some quantitative trait locis (QTLs) related to low-temperature tolerance in maize have been detected, only a few can be commonly detected, and the QTL intervals are large, indicating that low-temperature tolerance is a complex trait that requires more in-depth research. In this study, 296 excellent inbred lines from domestic and foreign origins (America and Europe) were used as the study materials, and a low-coverage resequencing method was employed for genome sequencing. Five phenotypic traits related to low-temperature tolerance were used to assess the genetic diversity of maize through a genome-wide association study (GWAS). A total of 14 SNPs significantly associated with low-temperature tolerance were detected (-log10(P) > 4), and an SNP consistently linked to low-temperature tolerance in the field and indoors during germination was utilized as a marker. This SNP, 14,070, was located on chromosome 5 at position 2,205,723, which explained 4.84-9.68% of the phenotypic variation. The aim of this study was to enrich the genetic theory of low-temperature tolerance in maize and provide support for the innovation of low-temperature tolerance resources and the breeding of new varieties.

Stem Cell Theory of Cancer: Clinical Implications of Epigenomic versus Genomic Biomarkers in Cancer Care

Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would be a holy grail of cancer research and therapy. We propose that a stem cell versus genetic theory of cancer may not only enable us to track and trace the biological evolution of cancer but also empower us to attenuate its clinical course and optimize the clinical outcome of patients with cancer. Hence, a biomarker that identifies cancer stem cells (CSCs) and distinguishes them from non-CSCs may serve to elucidate inter-tumoral and intra-tumoral heterogeneity, elevate the values and utility of current prognostic and predictive tests, and enhance drug versus therapy development in cancer care. From this perspective, we focus on CSC biomarkers and discuss stemness or stem-like biomarkers in the context of a unified theory and a consideration of stem cell versus genetic origin. We review their role in primary and mixed tumors, in the elaboration of tumor subtypes, and in the imaging and monitoring of minimal residual diseases. We investigate how scientific theories influence the direction of scientific research and interpretation of experimental results, and how genomics and epigenomics affect the dynamics and trajectories of biomarkers in the conduct of cancer research and in the practice of cancer care.