Hasil untuk "Genetics"

D. Falk, K. Holsinger

P. Stragier, R. Losick

D. Rimoin

VOLUME 1 PART 1 BASIC PRINCIPLES: History of Medical Genetics. Nature and Frequency of Genetic Disease. Gene Structure and Function. Mutations in Human Diseases: Nature and Consequences . Molecular Methodology. Mendelian Inheritance. Segregation Analysis. Analysis of Genetic Linkage. Genomics. Morbid Anatomy of the Human Genome. Chromosomal Basis of Inheritance. Cytogenetic Analysis. Mitochondrial Genetics. Multifactorial Inheritance and Genetic Analysis of Multifactorial Disease. Population Genetics. Pathogenesis of Genetic Disease. Genetic Epidemiology. Human Malformations. Twins and Twinning. The Molecular Biology of Cancer. The Biologic Basis of Ageing: Implications for Medical Genetics. Pharmacogenetics. The Human Major Histocompatibility Complex and Disease Susceptibility. PART II CLINICAL APPLICATIONS: GENERAL PRINCIPLES: Genetic Assessment and Pedigree Analysis. Risk Estimation in Genetic Counseling. Carrier Screening. Prenatal Screening for Neural Tube Defects and Down Syndrome. Prenatal Diagnosis. Neonatal Screening. Genetic Counseling. Strategies for the Treatment of Genetic Disease. Ethical Aspects of Genetic Screening and Diagnosis. Legal Issues in Genetics. APPROACHES to COMMON CLINICAL PROBLEMS: Infertility. Fetal Loss. A Clinical Approach to the Dysmorphic Child. Human Teratology. Abnormal Mental Development. Abnormal Body Size and Proportion. Transplantation Genetics. APPROACHES to SPECIFIC DISORDERS:: Cardiovascular Disorders: Congenital Heart Disease. Common Generic Determinants of Coagulation and Fibrinolysis. Cardiomyopathies. Familial Dysrhythmias. Molecular Genetics of Hypertension. Pre-Eclampsia. Chromosome Disorders: Down Syndrome and Other Autosomal Trisomies. Sex Chromosome Abnormalities. Deletions and Other Structural Abnormalities of the Autosomes. Connective Tissue Disorders: Marfan Syndrome and Other Disorders of Fibrillin. Ehlers-Danlos Syndrome. Pseudoxanthoma Elasticu M, Cutix Laxa, And Other Disorders of Elastic Tissue. Craniofacial Disorders: Craniofacial Disorders. Deafn

D. Kimbrell, B. Beutler

Laura Navarro, Laura Navarro, Laura Navarro et al.

Brain damage (BD) caused by stroke, traumatic brain injury (TBI), or neurodegenerative conditions often results in persistent cognitive, motor, and emotional impairments. Music-based interventions (MI) have been explored as adjunctive rehabilitation strategies; however, the evidence remains fragmented. This systematic review and meta-analysis synthesize available research on the effects of MI on functional recovery following BD, due to acquired brain injury (ABI), including both TBI and non-TBI. From a total of 868 publications screened in PubMed, Embase, Scopus, Cochrane Library, Web of Science, and ClinicalTrials.gov, 90 were included, of which 41 met the criteria for quantitative evaluation and meta-analysis, to assess the state-of-the-art of research on music and BD in the fields of neuropsychology and cognitive sciences. The reviewed studies span a range of methodologies, including randomized controlled trials and qualitative research, and incorporate diverse MI strategies, such as active music-making, structured listening, and improvisational techniques. The findings indicate that music supports recovery across motor, cognitive, and, albeit to a lesser extent, communicative and psychosocial domains. The findings suggest beneficial effects of MI, particularly in gait function (z = 3.46, P < 0.01), upper extremity function (z = 6.11, P < 0.01; UEF), communication (z = 3.21, P < 0.01), cognitive rehabilitation (z = 3.29, P < 0.01), and emotional, behavioral, and social outcomes (z = 2.35, P = 0.02); notably, these effects were often supported by consistent statistical significance across multiple subgroup analyses (e.g., gait, UEF). This study highlights the therapeutic potential of music in neurorehabilitation and supports its integration into multidisciplinary treatment programs. Despite these promising findings, methodological heterogeneity, small sample sizes, and short intervention durations limit the generalizability of results. The evidence suggests that music may modulate key neurobiological pathways in BD, supporting its integration into evidence-based neurorehabilitation programs.

John Quackenbush

J. Coyne, H. Orr

Ritabrata Dutta, Yuehao Xu, Sherman Khoo et al.

In population genetics, there is often interest in inferring selection coefficients. This task becomes more challenging if multiple linked selected loci are considered simultaneously. For such a situation, we propose a novel generalized Bayesian framework where we compute a scoring rule posterior for the selection coefficients in multi-locus temporal population genetics models. As we consider trajectories of allele frequencies over time as our data, we choose to use a signature kernel scoring rule - a kernel scoring rule defined for high-dimensional time-series data using iterated path integrals of a path (called signatures). We can compute an unbiased estimate of the signature kernel score using model simulations. This enables us to sample asymptotically from the signature kernel scoring rule posterior of the selection coefficients using pseudo-marginal MCMC-type algorithms. Through a simulation study, we were able to show the inferential efficacy of our method compared to existing benchmark methods for two and three selected locus scenarios under the standard Wright-Fisher model with recombination and selection. We also consider a negative frequency-dependent selection model for one and two locus scenarios, and also joint inference of selection coefficients and initial haplotype frequencies under the standard Wright-Fisher model. Finally, we illustrate the application of our inferential method for two real-life dataset. More specifically, we consider a data set on Yeast, as well as data from an Evolve and Resequence (E\&R) experiment on {\em Drosophila simulans}.

Yudam Seo, Tsvi Tlusty, Junghyo Jo

The origin and organizing principles of the genetic code remain fundamental puzzles in life science. The vanishingly low probability of the natural codon-to-amino acid mapping arising by chance has spurred the hypothesis that its structure is a solution optimized for robustness against mutations and translational errors. For the construction of effective molecular machines, the dictionary of encoded amino acids must also be diverse enough in physicochemical features. Here, we examine whether the standard genetic code can be understood as a near-optimal solution balancing these two objectives: minimizing error load and aligning codon assignments with the naturally occurring amino acid composition. Using simulated annealing, we explore this trade-off across a broad range of parameters. We find that the standard genetic code lies near local optima within the multidimensional parameter space. It is a highly effective solution that balances fidelity against resource availability constraints. These results suggest that the present genetic code reflects coevolution under conflicting pressures of fidelity and diversity, offering new insight into its emergence and evolution.

Mariana A. Londe, Luciana S. Pessoa, Carlos E. Andrade et al.

A random-key genetic algorithm is an evolutionary metaheuristic for discrete and global optimization. Each solution is encoded as a vector of N random keys, where a random key is a real number randomly generated in the continuous interval [0, 1). A decoder maps each vector of random keys to a solution of the optimization problem being solved and computes its cost. The benefit of this approach is that all genetic operators and transformations can be maintained within the unitary hypercube, regardless of the problem being addressed. This enhances the productivity and maintainability of the core framework. The algorithm starts with a population of P vectors of random keys. At each iteration, the vectors are partitioned into two sets: a smaller set of high-valued elite solutions and the remaining non-elite solutions. All elite elements are copied, without change, to the next population. A small number of random-key vectors (the mutants) is added to the population of the next iteration. The remaining elements of the population of the next iteration are generated by combining, with the parametrized uniform crossover of Spears and DeJong (1991), pairs of solutions. This chapter reviews random-key genetic algorithms and describes an effective variant called biased random-key genetic algorithms.

Han Shen, Xiaoxuan Sun, Ziqi Wang et al.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability. Nevertheless, the involvement of genetic variants in ASDs is not fully understood. One gene of interest is TRIO, which encodes a large protein that aids in GDP-to-GTP exchange as a Ras homologous (Rho) guanine nucleotide exchange factor (GEF), facilitating cytoskeleton reorganization. Thus, it plays crucial roles in neuronal migration, neurite outgrowth, and synaptic transmission. De novo mutations in TRIO have been extensively reported in the pathogenesis of ASDs. However, no evidence currently supports the genetic association between common variants in TRIO and ASDs. To investigate the role of common genetic variations in autism risk, we analyzed 12 tagging single-nucleotide polymorphisms (SNPs) in the TRIO gene. These tagging SNPs captured an average of 75% of all common variations in TRIO with a minor allele frequency (MAF) > 5%. Using the family-based association study in 239 Chinese Han autism trios, we identified the significant association of three SNPs (rs32593, rs33005, and rs27479) with autism. To confirm the association, the sample size was expanded to 427 trios by recruiting 188 additional trios. Our findings across all 427 trios confirmed that A allele of rs32593, G allele of rs33005, and C allele of rs27479 showed a preferential transmission to the affected offspring (rs32593: A > G, Z = 2.600, p=0.0093; rs33005: G > T, Z = 2.978, p=0.0029; rs27479: C > A, Z = 3.214, p=0.0013) after Bonferroni’s correction (p<0.0042). Haplotype analyses showed that one haplotype (A-G) constructed from rs32593 and rs33005 was significantly associated with autism (p=0.0064; Global p=0.022). These results suggested that the common variants in TRIO might be involved in the susceptibility to autism in the Chinese Han population.

Diana Luise, Silvia Carta, Paola Cremonesi et al.

The introduction of advanced sequencing platforms has redefined our understanding of microbial communities, revealing their presence in environments long assumed to be sterile. This literature review explores the complex microbiota of colostrum and milk, emphasising its importance for animal health and dairy production. It examines the methods and protocols for sampling and sequencing the milk microbial community. In addition, the review discusses the potential origins of the milk microbial community as well as intrinsic and extrinsic factors like host genetics and feeding strategies that can drive changes in the milk microbial community of livestock. Factors such as nutritional and feeding interventions, along with genetic predisposition, significantly influence milk microbiota, impacting feed efficiency and disease resistance. Despite these findings, the review underscores the paucity of studies and points out technical and methodological limitations, including the lack of standardised protocols for DNA extraction and sequencing and issues with sample contamination. Future research using a multi-omics approach is essential to enhance our understanding and develop strategies to improve livestock health, productivity, and sustainability.

Shan Gao, Dahai Wang, Xingmei Ding et al.

BackgroundThe Wilms Tumour gene 1 (WT1, NM_024426.6) holds significant importance in the developmental processes of the kidneys and gonads. Herein, we report a case of nephrotic syndrome and differences of sex development in a patient with novel mutations in WT1 gene.MethodsThe child, identified as female based on social gender, exhibited symptoms at 6 years of age and was diagnosed with steroid-resistant nephrotic syndrome (SRNS). Renal biopsy findings indicated focal segmental glomerulosclerosis. Whole-exome sequencing unveiled a novel variant, c.1447 + 6(IVS9)T &gt; C, in the WT1 gene, and karyotypic analysis revealed 46, XY, aligning with the phenotypic presentation of Frasier syndrome (FS, OMIM#136680) associated with WT1 gene mutation. The influence of gene variants on mRNA splicing was examined using in vitro minigene assays.ResultsThe variant was classified as likely pathogenic (PS2 + PM2_Supporting + PP3) in accordance with American College of Medical Genetics and Genomics (ACMG) guidelines. in vitro minigene experiments demonstrated that the c.1447 + 6(IVS9)T &gt; C variant altered the splicing pattern of exon 9 in the WT1 gene from two isoforms to a single form, thereby supporting its pathogenicity.ConclusionThrough high-throughput sequencing and in vitro minigene splicing experiments, the c.1447 + 6T &gt; C variant in the WT1 gene was supported as the underlying genetic cause in the child patient, thereby expanding the spectrum of gene variants of WT1 gene and enhancing our comprehension of the molecular pathogenesis of this disorder.

Cella Florescu, Marc Kaufmann, Johannes Lengler et al.

The compact Genetic Algorithm (cGA), parameterized by its hypothetical population size $K$, offers a low-memory alternative to evolving a large offspring population of solutions. It evolves a probability distribution, biasing it towards promising samples. For the classical benchmark OneMax, the cGA has to two different modes of operation: a conservative one with small step sizes $Θ(1/(\sqrt{n}\log n))$, which is slow but prevents genetic drift, and an aggressive one with large step sizes $Θ(1/\log n)$, in which genetic drift leads to wrong decisions, but those are corrected efficiently. On OneMax, an easy hill-climbing problem, both modes lead to optimization times of $Θ(n\log n)$ and are thus equally efficient. In this paper we study how both regimes change when we replace OneMax by the harder hill-climbing problem DynamicBinVal. It turns out that the aggressive mode is not affected and still yields quasi-linear runtime $O(n\cdot polylog (n))$. However, the conservative mode becomes substantially slower, yielding a runtime of $Ω(n^2)$, since genetic drift can only be avoided with smaller step sizes of $O(1/n)$. We complement our theoretical results with simulations.

Lei Xu, Lei Xu, Lei Xu et al.

Grasping the genetic structure of marine fish populations is vital for comprehending species connectivity patterns and determining the appropriate spatiotemporal scales for conservation management strategies. Here, we analyzed the population genetics of the Orangefin Ponyfish (Photopectoralis bindus Valenciennes, 1835) by examining a portion of the gene coding for the mitochondrial cytochrome c oxidase subunit I. The aim was to evaluate the haplotype pattern, genetic structure, demographic history, as well as the influence of ecological connectivity through the Qiongzhou Strait on the distribution patterns of this species in the northern South China Sea and the Beibu Gulf. In total, 257 specimens yielded only 13 haplotypes, with the predominant haplotype present at all sampling locations. The analysis revealed a “star-like” haplotype pattern, indicating low levels of both haplotype and nucleotide diversity. Additionally, a small but significant genetic structure was observed between the coastal regions flanking the Leizhou Peninsula. These patterns in the haplotype network and genetic structure may be significantly influenced by contemporary currents, particularly through the connectivity of the Qiongzhou Strait. Tajima’s D and Fu’s Fs demonstrated pronouncedly negative values, along with a unimodal mismatch distribution, suggested a recent demographic expansion of Photopectoralis bindus during the late Pleistocene, likely influenced by fluctuations in sea levels.

A. Beaumont

L. Andersson, M. Georges

Jisu Oh, Amy E. Riek, Kevin T. Bauerle et al.

Abstract Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Uzair Muhammad Khan, Iqrar Ahmad Rana, Nabeel Shaheen et al.

Abstract Very long-chain fatty acids (VLCFAs) possess more than twenty carbon atoms and are the major components of seed storage oil, wax, and lipids. FAE (Fatty Acid Elongation) like genes take part in the biosynthesis of VLCFAs, growth regulation, and stress responses, and are further comprised of KCS (Ketoacyl-CoA synthase) and ELO (Elongation Defective Elongase) sub-gene families. The comparative genome-wide analysis and mode of evolution of KCS and ELO gene families have not been investigated in tetraploid Brassica carinata and its diploid progenitors. In this study, 53 KCS genes were identified in B. carinata compared to 32 and 33 KCS genes in B. nigra and B. oleracea respectively, which suggests that polyploidization might has impacted the fatty acid elongation process during Brassica evolution. Polyploidization has also increased the number of ELO genes in B. carinata (17) over its progenitors B. nigra (7) and B. oleracea (6). Based on comparative phylogenetics, KCS, and ELO proteins can be classified into eight and four major groups, respectively. The approximate date of divergence for duplicated KCS and ELO genes varied from 0.03 to 3.20 million years ago (MYA). Gene structure analysis indicated that the maximum number of genes were intron-less and remained conserved during evolution. The neutral type of selection seemed to be predominant in both KCS and ELO genes evolution. String-based protein-protein interaction analysis suggested that bZIP53, a transcription factor might be involved in the activation of transcription of ELO/KCS genes. The presence of biotic and abiotic stress-related cis-regulatory elements in the promoter region suggests that both KCS and ELO genes might also play their role in stress tolerance. The expression analysis of both gene family members reflect their preferential seed-specific expression, especially during the mature embryo development stage. Furthermore, some KCS and ELO genes were found to be specifically expressed under heat stress, phosphorus starvation, and Xanthomonas campestris infection. The current study provides a basis to understand the evolution of both KCS and ELO genes in fatty acid elongation and their role in stress tolerance.

Jungin Kwon, Yu-Sheng Yeh, Satoko Kawarasaki et al.

Summary: The high thermogenic activity of brown adipose tissue (BAT) has received considerable attention. Here, we demonstrated the role of the mevalonate (MVA) biosynthesis pathway in the regulation of brown adipocyte development and survival. The inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the MVA pathway and the molecular target of statins, suppressed brown adipocyte differentiation by suppressing protein geranylgeranylation-mediated mitotic clonal expansion. The development of BAT in neonatal mice exposed to statins during the fetal period was severely impaired. Moreover, statin-induced geranylgeranyl pyrophosphate (GGPP) deficiency led to the apoptosis of mature brown adipocytes. Brown adipocyte-specific Hmgcr knockout induced BAT atrophy and disrupted thermogenesis. Importantly, both genetic and pharmacological inhibition of HMGCR in adult mice induced morphological changes in BAT accompanied by an increase in apoptosis, and statin-treated diabetic mice showed worsened hyperglycemia. These findings revealed that MVA pathway-generated GGPP is indispensable for BAT development and survival.