Genes

28 pages, 2101 KiB

Open AccessArticle

Dissecting Selective Signatures and Candidate Genes in Grandparent Lines Subject to High Selection Pressure for Broiler Production and in a Local Russian Chicken Breed of Ushanka

by Michael N. Romanov, Alexey V. Shakhin, Alexandra S. Abdelmanova, Natalia A. Volkova, Dmitry N. Efimov, Vladimir I. Fisinin, Liudmila G. Korshunova, Dmitry V. Anshakov, Arsen V. Dotsev, Darren K. Griffin and Natalia A. Zinovieva

Genes 2024, 15(4), 524; https://doi.org/10.3390/genes15040524 - 22 Apr 2024

Cited by 6 | Viewed by 1666

Abstract

Breeding improvements and quantitative trait genetics are essential to the advancement of broiler production. The impact of artificial selection on genomic architecture and the genetic markers sought remains a key area of research. Here, we used whole-genome resequencing data to analyze the genomic [...] Read more.

Breeding improvements and quantitative trait genetics are essential to the advancement of broiler production. The impact of artificial selection on genomic architecture and the genetic markers sought remains a key area of research. Here, we used whole-genome resequencing data to analyze the genomic architecture, diversity, and selective sweeps in Cornish White (CRW) and Plymouth Rock White (PRW) transboundary breeds selected for meat production and, comparatively, in an aboriginal Russian breed of Ushanka (USH). Reads were aligned to the reference genome bGalGal1.mat.broiler.GRCg7b and filtered to remove PCR duplicates and low-quality reads using BWA-MEM2 and bcftools software; 12,563,892 SNPs were produced for subsequent analyses. Compared to CRW and PRW, USH had a lower diversity and a higher genetic distinctiveness. Selective sweep regions and corresponding candidate genes were examined based on ZF_ST, hapFLK, and ROH assessment procedures. Twenty-seven prioritized chicken genes and the functional projection from human homologs suggest their importance for selection signals in the studied breeds. These genes have a functional relationship with such trait categories as body weight, muscles, fat metabolism and deposition, reproduction, etc., mainly aligned with the QTLs in the sweep regions. This information is pivotal for further executing genomic selection to enhance phenotypic traits. Full article

(This article belongs to the Special Issue Poultry Genetics and Genomics—2nd Edition)

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The three chicken breeds examined in this study. (a) Cornish White (female, left; male, right); (b) Plymouth Rock White (male, front; females, back); and (c) Ushanka (female, left; male, right). Full article ">Figure 2
Genetic relationships among the three chicken breeds studied using genome-wide SNP genotyping. (a,b) PCA plots showing the distribution of breeds and individuals in the dimensions of two coordinates, i.e., the first (PC1; X-axis) and second (PC2; Y-axis; (a) or third (PC3; Y-axis; (b) principal components; (c) admixture-based bar plots illustrating the proportions of individual ancestry in the breeds under study at K = 2 (top) and K = 3 (bottom). Breeds: CRW, Cornish White; PRW, Plymouth Rock White; USH, Ushanka. Full article ">Figure 3
Search for signatures of selection in genomes of the studied breeds as revealed by the hapFLK analysis. Chicken autosomes are the values for the X-axis, and statistical significance values (−log10 p-values) are the values for the Y-axis. The red line that indicates the threshold of significance at p < 2.8 × 10−8 (i.e., −log10(p) > 7.55) was determined using the Bonferroni correction and defines the strongest hapFLK regions, while the blue line indicates the threshold of significance at p < 1 × 10−5 (i.e., −log10(p) > 5) and defines the putative hapFLK regions. Full article ">Figure 4
Descriptive statistics of the runs of homozygosity (ROHs) by ROH length class in the studied chicken breeds: (a) Overall mean length of ROHs (Y-axis) by ROH length class (X-axis; 0.5–2, 2–4 and 4–8 Mb). (b) Mean number of ROHs (Y-axis) by ROH length class (X-axis; 0.5–2, 2–4, and 4–8 Mb). Breeds: CRW, Cornish White; PRW, Plymouth Rock White; USH, Ushanka. Full article ">

25 pages, 7178 KiB

Open AccessArticle

Effects of Long-Term Cryopreservation on the Transcriptomes of Giant Grouper Sperm

by Xiaoyu Ding, Yongsheng Tian, Yishu Qiu, Pengfei Duan, Xinyi Wang, Zhentong Li, Linlin Li, Yang Liu and Linna Wang

Genes 2024, 15(4), 523; https://doi.org/10.3390/genes15040523 - 22 Apr 2024

Cited by 1 | Viewed by 1573

Abstract

The giant grouper fish (Epinephelus lanceolatus), one of the largest and rarest groupers, is a fast-growing economic fish. Grouper sperm is often used for cross-breeding with other fish and therefore sperm cryopreservation is important. However, freezing damage cannot be avoided. Herein, [...] Read more.

The giant grouper fish (Epinephelus lanceolatus), one of the largest and rarest groupers, is a fast-growing economic fish. Grouper sperm is often used for cross-breeding with other fish and therefore sperm cryopreservation is important. However, freezing damage cannot be avoided. Herein, we performed a transcriptome analysis to compare fresh and frozen sperm of the giant grouper with frozen storage times of 0, 23, 49, and 61 months. In total, 1911 differentially expressed genes (DEGs), including 91 in El-0-vs-El-23 (40 upregulated and 51 downregulated), 251 in El-0-vs-El-49 (152 upregulated and 69 downregulated), and 1569 in El-0-vs-El-61 (984 upregulated and 585 downregulated), were obtained in the giant grouper sperm. DEGs were significantly increased at 61 months of cryopreservation (p < 0.05). GO and KEGG enrichment analyses of the DEGs revealed significant enrichment in the pilus assembly, metabolic process, MAPK signaling pathway, apoptosis, and P53 signaling pathway. Time-series expression profiling of the DEGs showed that consistently upregulated modules were also significantly enriched in signaling pathways associated with apoptosis. Four genes, scarb1, odf3, exoc8, and atp5f1d, were associated with mitochondria and flagella in a weighted correlation network analysis. These genes may play an important role in the response to sperm freezing. The experimental results show that long-term cryopreservation results in freezing damage to the giant grouper sperm. This study provides rich data for studies of the mechanism underlying frozen fish sperm damage as well as a technical reference and evaluation index for the long-term cryopreservation of fish sperm. Full article

(This article belongs to the Special Issue Genetic Studies of Fish)

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15 pages, 1294 KiB

Open AccessArticle

HLA-B and C Expression Contributes to COVID-19 Disease Severity within a South African Cohort

by Lisa Naidoo, Thilona Arumugam and Veron Ramsuran

Genes 2024, 15(4), 522; https://doi.org/10.3390/genes15040522 - 22 Apr 2024

Viewed by 1351

Abstract

Globally, SARS-CoV-2 has negatively impacted many lives and industries due to its rapid spread, severe outcomes, and the need for the implementation of lockdown strategies across the world. SARS-CoV-2 disease severity varies among different populations. Host genetics have been associated with various diseases, [...] Read more.

Globally, SARS-CoV-2 has negatively impacted many lives and industries due to its rapid spread, severe outcomes, and the need for the implementation of lockdown strategies across the world. SARS-CoV-2 disease severity varies among different populations. Host genetics have been associated with various diseases, and their ability to alter disease susceptibility and severity. In addition, Human Leukocyte Antigen (HLA) expression levels and alleles vary significantly among ethnic groups, which might impact the host’s response to SARS-CoV-2. Our previous study highlighted that HLA-A might have an effect on COVID-19 disease severity across ethnicities. Therefore, in this study, we aim to examine the effect of HLA-B and C expression levels on COVID-19 disease severity. To achieve this, we used real-time PCR to measure the HLA mRNA expression levels of SARS-CoV-2-infected individuals from a South African cohort and compared them across ethnic groups, disease outcomes, gender, comorbidities, and age. Our results show (1) that the effect of HLA-B mRNA expression levels was associated with differences in disease severity when we compare symptomatic vs. asymptomatic (p < 0.0001). While HLA-C mRNA expression levels were not associated with COVID-19 disease severity. (2) In addition, we observed that HLA-B and HLA-C mRNA expression levels were significantly different between South African Black individuals and South African Indian individuals (p < 0.0001, p < 0.0001). HLA-B mRNA expression levels among symptomatic South African Black individuals were significantly higher than symptomatic South African Indian individuals (p < 0.0001). In addition, the HLA-B mRNA expression levels of symptomatic South African Black individuals were significantly higher than asymptomatic South African Black individuals (p > 0.0001). HLA-C mRNA expression levels among symptomatic South African Black individuals were significantly higher than among symptomatic South African Indian individuals (p = 0.0217). (3) HLA-C expression levels were significantly different between males and females (p = 0.0052). In addition, the HLA-C expression levels of asymptomatic males are higher than asymptomatic females (p = 0.0375). (4) HLA-B expression levels were significantly different between individuals with and without comorbidities (p = 0.0009). In addition, we observed a significant difference between individuals with no comorbidities and non-communicable diseases (p = 0.0034), in particular, hypertension (p = 0.0487). (5) HLA-B expression levels were significantly different between individuals between 26–35 and 56–65 years (p = 0.0380). Our work is expected to strengthen the understanding of the relationship between HLA and COVID-19 by providing insights into HLA-B and C expression levels across ethnic populations in South Africa among COVID-19-symptomatic and asymptomatic individuals. Our results highlight that HLA-B mRNA expression levels contribute to COVID-19 severity as well as variation in ethnicities associated with COVID-19. Further studies are needed to examine the effect of HLA expression levels across various ethnic groups with contributing factors. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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14 pages, 4099 KiB

Open AccessArticle

Contradiction in Star-Allele Nomenclature of Pharmacogenes between Common Haplotypes and Rare Variants

by Se Hwan Ahn, Yoomi Park and Ju Han Kim

Genes 2024, 15(4), 521; https://doi.org/10.3390/genes15040521 - 22 Apr 2024

Viewed by 1645

Abstract

The nomenclature of star alleles has been widely used in pharmacogenomics to enhance treatment outcomes, predict drug response variability, and reduce adverse reactions. However, the discovery of numerous rare functional variants through genome sequencing introduces complexities into the star-allele system. This study aimed [...] Read more.

The nomenclature of star alleles has been widely used in pharmacogenomics to enhance treatment outcomes, predict drug response variability, and reduce adverse reactions. However, the discovery of numerous rare functional variants through genome sequencing introduces complexities into the star-allele system. This study aimed to assess the nature and impact of the rapid discovery of numerous rare functional variants in the traditional haplotype-based star-allele system. We developed a new method to construct haplogroups, representing a common ancestry structure, by iteratively excluding rare and functional variants of the 25 representative pharmacogenes using the 2504 genomes from the 1000 Genomes Project. In total, 192 haplogroups and 288 star alleles were identified, with an average of 7.68 ± 4.2 cross-ethnic haplogroups per gene. Most of the haplogroups (70.8%, 136/192) were highly aligned with their corresponding classical star alleles (VI = 1.86 ± 0.78), exhibiting higher genetic diversity than the star alleles. Approximately 41.3% (N = 119) of the star alleles in the 2504 genomes did not belong to any of the haplogroups, and most of them (91.3%, 105/116) were determined by a single variant according to the allele-definition table provided by CPIC. These functional single variants had low allele frequency (MAF < 1%), high evolutionary conservation, and variant deleteriousness, which suggests significant negative selection. It is suggested that the traditional haplotype-based naming system for pharmacogenetic star alleles now needs to be adjusted by balancing both traditional haplotyping and newly emerging variant-sequencing approaches to reduce naming complexity. Full article

(This article belongs to the Section Pharmacogenetics)

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Process for constructing haplogroups for each pharmacogene. Initially, a matrix is created, with each row representing a phased allele sequence (haplotype, hn) and each column representing all observed variants, including coding and non-coding variants, within a gene. During the haplotype collapsing step, all identical haplotype sequences are combined into a single entity. Then, the variant with the lowest minor allele frequency (MAF) is removed from the matrix (variant collapsing). These two steps are repeated until the stopping condition. The stopping condition is the MAF. Full article ">Figure 2
The number of haplogroups, singletons, and variants across iterations until the minor allele frequency (MAF) satisfies the stopping condition. Full article ">Figure 3
Distribution of star alleles in the 1KGP. The frequency of star alleles observed within the 1KGP dataset of 25 pharmacogenes was assigned using PyPGx (version 0.20.0). (A) Allele frequencies of reference star alleles of each gene are shown. (B) Allele frequencies of non-reference star alleles are shown. Full article ">Figure 4
The heatmaps of Nei’s standard genetic distance for 25 pharmacogenes across five populations. In each panel, the upper triangular part of the matrix shows the results from star alleles, while the lower triangular part shows the results from haplogroups. AFR, African; AMR, American; EUR, European; EAS, East Asian; SAS, South Asian. Full article ">Figure 5
The percentage of star alleles and haplogroups that have a significant association in the 1KGP. (A) The percentage of star alleles that have a significant association with at least one haplogroup in the 1KGP. (B) The percentage of haplotypes representing respective star alleles. (C) The percentage of haplogroups that have a significant association with at least one star allele. (D) The proportion of haplotypes respective haplogroups. Only the values under 100% are represented. SA, star alleles that have a significant association with haplogroups; SI, star alleles that are independent of haplogroups. Full article ">Figure 6
Genomic characterization of star alleles that are significantly associated with haplogroups (SA) and star alleles that are independent of haplogroups (SI) with the six genetic molecular features. (A) The number of variants defining star alleles. (B) The frequency of star alleles in the 1KGP. (C–F) GERP++, SIFT, PolyPhen2, and CADD score. * p < 0.05; ** p < 0.01; **** p < 0.0001 by the Wilcoxon test. Full article ">

18 pages, 1355 KiB

Open AccessCommentary

DNA Damage, Genome Stability, and Adaptation: A Question of Chance or Necessity?

by John Herrick

Genes 2024, 15(4), 520; https://doi.org/10.3390/genes15040520 - 21 Apr 2024

Viewed by 2085

Abstract

DNA damage causes the mutations that are the principal source of genetic variation. DNA damage detection and repair mechanisms therefore play a determining role in generating the genetic diversity on which natural selection acts. Speciation, it is commonly assumed, occurs at a rate [...] Read more.

DNA damage causes the mutations that are the principal source of genetic variation. DNA damage detection and repair mechanisms therefore play a determining role in generating the genetic diversity on which natural selection acts. Speciation, it is commonly assumed, occurs at a rate set by the level of standing allelic diversity in a population. The process of speciation is driven by a combination of two evolutionary forces: genetic drift and ecological selection. Genetic drift takes place under the conditions of relaxed selection, and results in a balance between the rates of mutation and the rates of genetic substitution. These two processes, drift and selection, are necessarily mediated by a variety of mechanisms guaranteeing genome stability in any given species. One of the outstanding questions in evolutionary biology concerns the origin of the widely varying phylogenetic distribution of biodiversity across the Tree of Life and how the forces of drift and selection contribute to shaping that distribution. The following examines some of the molecular mechanisms underlying genome stability and the adaptive radiations that are associated with biodiversity and the widely varying species richness and evenness in the different eukaryotic lineages. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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Species richness and evenness in Urodela. The black triangles represent species richness in the 10 salamander families. Species richness varies widely across the respective salamander lineages and their distributions are highly uneven. The numbers refer to family average genome size. Families with smaller average genome size (less than 40 pg) are more speciose than families with larger genome size (greater than 40 pg), independent of being sister clades (e.g., Hynobiidae–Cryptobranchidae and Amphiumidae–Plethodontidae). Full article ">Figure 2
Salamanders have relatively slower rates of molecular evolution compared to frogs and fish. Units of evolutionary period (UEP: million years per 1% difference in the POMC gene in different lineages) reflect evolutionary rates. The box plots reveal an increase with the genome size, indicating that lineages associated with larger genomes have correspondingly slower rates of evolution. The box corresponds to the middle 50% of the data and the whiskers to 80%; the small square corresponds to the mean and the line to the median. Mean UEP values are significantly different (p < 0.05) for the pairs 1.3 to 2.2 pg (fish–fish), 4.5 to 6 pg (frog–fish), 4.5 to 35 pg (frog–salamander), and 6 to 35 pg (fish–salamander). Recently diverged salamanders (far right: rec div sal) appear to be evolving faster than other salamanders that diverged earlier; recently, diverged fish (2.2 fish, Salmonidae) are also evolving faster than other fish that diverged earlier. Note, however, that salamanders are evolving more slowly than Salmonidae, despite the lineages having diverged at about the same time. A clear trend of slower rates of evolution in older lineages is apparent in each group. Lineage-specific effects on evolutionary rates are also apparent independently of the genome size: Salmonidae (C-value 2.2 pg) are evolving at a faster rate than other fish lineages. Likewise, cartilaginous fish (Heterodontus francisci) and different members of the Actinoptergyii class (C-value between 5 and 7 pg) are evolving much more slowly than the other lineages. It should be noted that phylogenetic relatedness within each taxon is not specified. The plots therefore represent the non-phylogenetic relationship between the genome size and the divergence rate across the fish, anurans, and urodeles: genome size, independently of lineage, correlates with divergence rate when compared across the three different vertebrate groups. Full article ">Figure 3
Rates of molecular evolution in the fish lineage. The box plots represent silent site substitutions in codons per million years (ds/Myr). Genetic distances were obtained from aligned sequences, and divergence times ascertained from the literature. Analyses were performed on Tetraodontiformes (T) (average C-value: 0.5 pg), Cypriniformes (1.5 pg), skates and rays (SR) (4 pg), and lantern sharks (S) (12 pg). A clear difference in evolutionary rates associated with the genome size is apparent. Note that skates, rays, and sharks all have exceptionally low and similar evolutionary rates. Inset: log-transformed data indicate a power law relationship between evolutionary rates and the genome size across these samples. The exponent is −0.39, suggesting significantly different modes of evolution in fish with small genomes compared to fish with larger genomes, perhaps because of the slower rates of DNA loss in species with larger genomes and a corresponding differential dependence on DNA repair systems between species with large versus small genomes (small C-value: HR > NHEJ; large C-value: HR < NHEJ). See [<a href="#B115-genes-15-00520" class="html-bibr">115</a>]. Full article ">Figure 4
Hypothetical biphasic model of stem and crown group dynamics. The black triangles represent extant crown group family species richness (salamanders). The dotted triangles represent extinct stem group species richness. The Cryptobranchidae, for example, are evolving more slowly over evolutionary time (slope of dotted line; stem to crown age) than the sister clade of Hynobiidae. It is assumed in this case that speciation occurs in a predominantly neutral niche mode (neutral adaptive radiation) in the ancestral population until an environmental crisis, or shift, drives ecological speciation (adaptive radiation). Both drift and selection, however, are expected to shape simultaneously evolutionary paths. If karyotype diversity evolves neutrally (genetic drift) during an ancestral phase of evolution (dotted triangles), the rate of karyotype diversification might be greater than or at least equal to the rate of genetic diversification (rate KD ≥ rate GD): more than one genotype, for example, specifying a single phenotype. If an environmental shift applies selection pressure on the diversified karyotypes, a transition might take place where selection pressure acts principally, but not exclusively, on genes (rate of GD > rate of KD). The figure depicts one of multiple cycles generating extant species richness during the evolution of a lineage (crown group). The ancestral karyotypes surviving the post-crisis/shift will contribute proportionally to the karyotype diversity in the crown group until those ancestors become extinct (Gause’s principle). It should be noted that “living fossils”—the notion that stem group species persist into extant crown group species—is not assumed in this model: the rates of molecular evolution over time (molecular clock) will result in crown group species that are descended—and genetically distinct—from extinct stem group species, even in the absence of identifiable morphological or phenotypic change. Figure adapted from [<a href="#B127-genes-15-00520" class="html-bibr">127</a>]. Full article ">

21 pages, 4938 KiB

Open AccessArticle

Single-Nucleus Transcriptome Profiling from the Hippocampus of a PTSD Mouse Model and CBD-Treated Cohorts

by Guanbo Xie, Yihan Qin, Ning Wu, Xiao Han and Jin Li

Genes 2024, 15(4), 519; https://doi.org/10.3390/genes15040519 - 21 Apr 2024

Cited by 1 | Viewed by 2094

Abstract

Post-traumatic stress disorder (PTSD) is the most common psychiatric disorder after a catastrophic event; however, the efficacious treatment options remain insufficient. Increasing evidence suggests that cannabidiol (CBD) exhibits optimal therapeutic effects for treating PTSD. To elucidate the cell-type-specific transcriptomic pathology of PTSD and [...] Read more.

Post-traumatic stress disorder (PTSD) is the most common psychiatric disorder after a catastrophic event; however, the efficacious treatment options remain insufficient. Increasing evidence suggests that cannabidiol (CBD) exhibits optimal therapeutic effects for treating PTSD. To elucidate the cell-type-specific transcriptomic pathology of PTSD and the mechanisms of CBD against this disease, we conducted single-nucleus RNA sequencing (snRNA-seq) in the hippocampus of PTSD-modeled mice and CBD-treated cohorts. We constructed a mouse model by adding electric foot shocks following exposure to single prolonged stress (SPS+S) and tested the freezing time, anxiety-like behavior, and cognitive behavior. CBD was administrated before every behavioral test. The PTSD-modeled mice displayed behaviors resembling those of PTSD in all behavioral tests, and CBD treatment alleviated all of these PTSD-like behaviors (n = 8/group). Three mice with representative behavioral phenotypes were selected from each group for snRNA-seq 15 days after the SPS+S. We primarily focused on the excitatory neurons (ExNs) and inhibitory neurons (InNs), which accounted for 68.4% of the total cell annotations. A total of 88 differentially upregulated genes and 305 differentially downregulated genes were found in the PTSD mice, which were found to exhibit significant alterations in pathways and biological processes associated with fear response, synaptic communication, protein synthesis, oxidative phosphorylation, and oxidative stress response. A total of 63 overlapping genes in InNs were identified as key genes for CBD in the treatment of PTSD. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the anti-PTSD effect of CBD was related to the regulation of protein synthesis, oxidative phosphorylation, oxidative stress response, and fear response. Furthermore, gene set enrichment analysis (GSEA) revealed that CBD also enhanced retrograde endocannabinoid signaling in ExNs, which was found to be suppressed in the PTSD group. Our research may provide a potential explanation for the pathogenesis of PTSD and facilitate the discovery of novel therapeutic targets for drug development. Moreover, it may shed light on the therapeutic mechanisms of CBD. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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9 pages, 795 KiB

Open AccessArticle

22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity

by Melissa Bittencourt de Wallau, Ana Carolina Xavier, Carolina Araújo Moreno, Chong Ae Kim, Elaine Lustosa Mendes, Erlane Marques Ribeiro, Amanda Oliveira, Têmis Maria Félix, Agnes Cristina Fett-Conte, Luciana Cardoso Bonadia, Gabriela Roldão Correia-Costa, Isabella Lopes Monlleó, Vera Lúcia Gil-da-Silva-Lopes and Társis Paiva Vieira

Genes 2024, 15(4), 518; https://doi.org/10.3390/genes15040518 - 21 Apr 2024

Viewed by 1949

Abstract

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA [...] Read more.

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings. Full article

(This article belongs to the Special Issue Phenotype and Pathogenetic Mechanisms in 22q11.2 Deletion/DiGeorge Syndrome)

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18 pages, 1238 KiB

Open AccessArticle

Information Provision Regarding Health-Related Direct-to-Consumer Genetic Testing for Dutch Consumers: An in-Depth Content Analysis of Sellers’ Websites

by Danny Bruins, Suzanne M. Onstwedder, Martina C. Cornel, Margreet G. E. M. Ausems, Marc H. W. van Mil and Tessel Rigter

Genes 2024, 15(4), 517; https://doi.org/10.3390/genes15040517 - 20 Apr 2024

Cited by 2 | Viewed by 2242

Abstract

Background: Previous studies have suggested that information offered by sellers of health-related direct-to-consumer genetic tests (DTC-GTs) is often incomplete, unbalanced, or too difficult to understand. The extent to which this is the case for sellers accessible to Dutch consumers has not previously [...] Read more.

Background: Previous studies have suggested that information offered by sellers of health-related direct-to-consumer genetic tests (DTC-GTs) is often incomplete, unbalanced, or too difficult to understand. The extent to which this is the case for sellers accessible to Dutch consumers has not previously been studied. Methods and Goals: The present study aimed to assess the completeness, balance, readability, and findability of informational content on a selection of websites from several health-related DTC-GT sellers accessible to Dutch consumers. An in-depth content analysis was performed based on a recently published checklist outlining key items for policy guidance regarding DTC-GT services. Results: The information provided by sellers did not equally cover all aspects relevant to health-related DTC-GT service provision. The provided information was slightly unbalanced, with benefits of health-related DTC-GT usage being overemphasized compared to its risks and limitations. The readability of the provided information was low, on average requiring college education for proper understanding. A findability analysis showed that information concerning all themes is overall relatively evenly distributed across analyzed sellers’ websites. Conclusions: Information provision by assessed health-related DTC-GT sellers is suboptimal regarding completeness, balance, and readability. To better empower potential consumers to make an informed decision regarding health-related DTC-GT usage, we advocate industry-wide enhancement of information provision. Full article

(This article belongs to the Special Issue Human Genetics: Diseases, Community, and Counseling)

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Visual representation of content analysis workflow. Pieces of information on each website were systematically coded to examine the completeness, balance, readability, and findability of information provided by selected sellers. For details on the codebook: see <a href="#app1-genes-15-00517" class="html-app">Supplementary Materials Document S2, Table S2</a>. Full article ">Figure 2
Overview of workflow regarding assessment of completeness of information provision per seller. Code usage per main theme across all coded pieces of information was assessed and visualized guided by median of observations. Full article ">Figure 3
Visual representation of findability assay methodology. Coded pieces of information were categorized per seller as poorly findable or easily findable per Likert scale based on their assigned scores. As such, a total of six categories (three easily findable categories and three poorly findable categories) were defined. Subsequently, for each of the six categories, main theme usage was then compared between the easily findable and poorly findable categories and the overall information provision (resulting from the ‘completeness of information’ assessment). These comparisons revealed the distribution of themes associated with easily findable or poorly findable information on the sellers’ websites. Subsequently, code usage at the subcode level was utilized to interpret these differences. Note that the figure shows the ‘easily findable’ and ‘poorly findable’ categories for two different Likert scales. ↑: information corresponding to a theme more represented in a respective findability category (poorly or easily findable) compared to the overall information provision. ↓: information corresponding to a theme less represented in a respective findability category (poorly or easily findable) compared to the overall information provision. Full article ">

13 pages, 1404 KiB

Open AccessCase Report

Syndromic Retinitis Pigmentosa: A 15-Patient Study

by Ianne Pessoa Holanda, Priscila Hae Hyun Rim, Rare Genomes Project Consortium, Mara Sanches Guaragna, Vera Lúcia Gil-da-Silva-Lopes and Carlos Eduardo Steiner

Genes 2024, 15(4), 516; https://doi.org/10.3390/genes15040516 - 20 Apr 2024

Cited by 3 | Viewed by 2369

Abstract

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in [...] Read more.

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet–Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)

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10 pages, 2078 KiB

Open AccessArticle

Identification of Crucial Modules and Genes Associated with Bt Gene Expression in Cotton

by Guiyuan Zhao, Zhao Geng, Jianguang Liu, Haiyan Tian, Xu Liu, Zetong An, Ning Zhao, Hanshuang Zhang, Liqiang Wu, Xingfen Wang, Yongqiang Wang and Guiyin Zhang

Genes 2024, 15(4), 515; https://doi.org/10.3390/genes15040515 - 19 Apr 2024

Viewed by 1482

Abstract

The expression of Bacillus thuringiensis (Bt) toxins in transgenic cotton confers resistance to insect pests. However, it has been demonstrated that its effectiveness varies among cotton cultivars and different tissues. In this study, we evaluated the expression of Bt protein in 28 cotton [...] Read more.

The expression of Bacillus thuringiensis (Bt) toxins in transgenic cotton confers resistance to insect pests. However, it has been demonstrated that its effectiveness varies among cotton cultivars and different tissues. In this study, we evaluated the expression of Bt protein in 28 cotton cultivars and selected 7 cultivars that differed in Bt protein expression for transcriptome analysis. Based on their Bt protein expression levels, the selected cultivars were categorized into three groups: H (high Bt protein expression), M (moderate expression), and L (low expression). In total, 342, 318, and 965 differentially expressed genes were detected in the H vs. L, M vs. L, and H vs. M comparison groups, respectively. And three modules significantly associated with Bt protein expression were identified by weighted gene co-expression network analysis. Three hub genes were selected to verify their relationships with Bt protein expression using virus-induced gene silencing (VIGS). Silencing GhM_D11G1176, encoding an MYC transcription factor, was confirmed to significantly decrease the expression of Bt protein. The present findings contribute to an improved understanding of the mechanisms that influence Bt protein expression in transgenic cotton. Full article

(This article belongs to the Special Issue Cotton Genes, Genetics, and Genomics)

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Bt protein contents of 28 cultivars in 2021 and 2022. Full article ">Figure 2
RNA-seq analysis of comparisons between different Bt contents of varieties (L vs. H, L vs. M, and M vs. H). (A) A Venn diagram showing upregulated DEGs of different comparisons. (B) A Venn diagram showing downregulated DEGs of different comparisons. (C,D) KEGG and GO enrichment analyses of DEGs of different comparisons. Full article ">Figure 3
Construction and identification of co-expression modules. (A) Correlation heatmap of modules and Bt contents. The adjusted p-value and correlation coefficient are shown in each cell. (B) Networks of hub genes in the midnight blue module. (C) Networks of hub genes in the white module. (D) Networks of hub genes in the dark turquoise module. Full article ">Figure 4
Silencing of GhM_D11G1176 by VIGS. (A) Phenotypes of the VIGS-GhM_D11G1176 and control cotton plants. (B) The expression of GhM_D11G1176 was determined by qRT-PCR after the VIGS injection. (C) The Bt contents in control and VIGS-GhM_D11G1176 cotton plants. Significance was determined by t-test (** p < 0.01). Full article ">

14 pages, 3118 KiB

Open AccessArticle

A High-Quality Assembly and Comparative Analysis of the Mitogenome of Actinidia macrosperma

by Jiangmei Gong, Jun Yang, Yan Lai, Tengfei Pan and Wenqin She

Genes 2024, 15(4), 514; https://doi.org/10.3390/genes15040514 - 19 Apr 2024

Cited by 1 | Viewed by 1510

Abstract

The mitochondrial genome (mitogenome) of Actinidia macrosperma, a traditional medicinal plant within the Actinidia genus, remains relatively understudied. This study aimed to sequence the mitogenome of A. macrosperma, determining its assembly, informational content, and developmental expression. The results revealed that the [...] Read more.

The mitochondrial genome (mitogenome) of Actinidia macrosperma, a traditional medicinal plant within the Actinidia genus, remains relatively understudied. This study aimed to sequence the mitogenome of A. macrosperma, determining its assembly, informational content, and developmental expression. The results revealed that the mitogenome of A. macrosperma is circular, spanning 752,501 bp with a GC content of 46.16%. It comprises 63 unique genes, including 39 protein-coding genes (PCGs), 23 tRNA genes, and three rRNA genes. Moreover, the mitogenome was found to contain 63 SSRs, predominantly mono-nucleotides, as well as 25 tandem repeats and 650 pairs of dispersed repeats, each with lengths equal to or greater than 60, mainly comprising forward repeats and palindromic repeats. Moreover, 53 homologous fragments were identified between the mitogenome and chloroplast genome (cp-genome), with the longest segment measuring 4296 bp. This study represents the initial report on the mitogenome of the A. macrosperma, providing crucial genetic materials for phylogenetic research within the Actinidia genus and promoting the exploitation of species genetic resources. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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The circular representation of the A. macrosperma mitogenome depicting its genomic characteristics, with the genes transcribed in a clockwise direction depicted inside the circle, while those transcribed counterclockwise were illustrated on the outside. The color scheme was assigned based on the functional classification of the genes. The innermost blue numbers represent the mitogenome scale. Full article ">Figure 2
The examination of repeats within the A. macrosperma mitogenomes was depicted as follows: Circle1 (C1) illustrated the dispersed repeats, where the connected blue arcs denoted forward repeats, while the pink arcs represented palindromic repeats. C2 showcased the A. macrosperma mitogenomes, with a scale of 50 kb on C3. Tandem repeats were visualized as short bars in C4. Microsatellite sequences detected by MISA were delineated in C5. Full article ">Figure 3
An examination was undertaken regarding the transfer of mitogenome sequences from A. macrosperma cp-genomes. The outer arcs, represented in yellow and green, corresponded to the mitogenome and cp-genome, respectively, while the inner arcs depicted homologous DNA fragments. Fragments with alignment lengths exceeding 1000 bp were denoted in dark blue, those below 100 bp were depicted in jade-green, and fragments falling within this range were shown in orange. The outer arcs exhibited a scale at 50 kb intervals. Full article ">Figure 4
The diagrams delineate collinear regions observed among disparate mitogenomes in additional Actinidia species when compared to A. macrosperma ((A): Actinidia arguta; (B): Actinidia chinensis; (C): Actinidia deliciosas; (D): Actinidia eriantha; (E): Actinidia latifolia; (F): Actinidia valvata). The outer frame colors represent the orientation of the mitogenomes sequences (orange indicating the forward direction and blue indicating the reverse direction), while the fill colors represent the alignment status (orange indicating forward alignment and blue indicating reverse alignment). Full article ">Figure 5
The analysis delved into the phylogenetic relationships involving A. macrosperma and other species. Utilizing twelve core genes from the mitogenomes, a phylogenetic tree was constructed based on protein sequences. The mitogenomes under study were highlighted in a red font, while variously colored backgrounds were employed to denote the taxonomic classification of orders within the investigated species. The bootstrap values were denoted by the red numbers positioned on the branches of the phylogenetic tree. Full article ">Figure 6
The Ka/Ks values for the individual mitochondrial genes in seven species of Actinidia are illustrated in the box diagram. The x-axis and y-axis represent protein-coding genes and Ka/Ks values, respectively. Full article ">Figure 7
Codon usage bias was observed in the mitochondrial PCGs of A. macrosperma. The term RSCU denotes relative synonymous codon usage. Full article ">

10 pages, 1759 KiB

Open AccessCase Report

Genome Sequencing in an Individual Presenting with 22q11.2 Deletion Syndrome and Juvenile Idiopathic Arthritis

by Ruy Pires de Oliveira-Sobrinho, Simone Appenzeller, Ianne Pessoa Holanda, Júlia Lôndero Heleno, Josep Jorente, on behalf of the Rare Genomes Project Consortium, Társis Paiva Vieira and Carlos Eduardo Steiner

Genes 2024, 15(4), 513; https://doi.org/10.3390/genes15040513 - 19 Apr 2024

Viewed by 1859

Abstract

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a [...] Read more.

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the MIF gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome. Full article

(This article belongs to the Special Issue Phenotype and Pathogenetic Mechanisms in 22q11.2 Deletion/DiGeorge Syndrome)

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11 pages, 256 KiB

Open AccessArticle

Association between MCU Gene Polymorphisms with Obesity: Findings from the All of Us Research Program

by Jade Avery, Tennille Leak-Johnson and Sharon C. Francis

Genes 2024, 15(4), 512; https://doi.org/10.3390/genes15040512 - 19 Apr 2024

Cited by 1 | Viewed by 1874

Abstract

Obesity is a public health crisis, and its prevalence disproportionately affects African Americans in the United States. Dysregulation of organelle calcium homeostasis is associated with obesity. The mitochondrial calcium uniporter (MCU) complex is primarily responsible for mitochondrial calcium homeostasis. Obesity is [...] Read more.

Obesity is a public health crisis, and its prevalence disproportionately affects African Americans in the United States. Dysregulation of organelle calcium homeostasis is associated with obesity. The mitochondrial calcium uniporter (MCU) complex is primarily responsible for mitochondrial calcium homeostasis. Obesity is a multifactorial disease in which genetic underpinnings such as single-nucleotide polymorphisms (SNPs) may contribute to disease progression. The objective of this study was to identify genetic variations of MCU with anthropometric measurements and obesity in the All of Us Research Program. Methods: We used an additive genetic model to assess the association between obesity traits (body mass index (BMI), waist and hip circumference) and selected MCU SNPs in 19,325 participants (3221 normal weight and 16,104 obese). Eleven common MCU SNPs with a minor allele frequency ≥ 5% were used for analysis. Results: We observed three MCU SNPs in self-reported Black/African American (B/AA) men, and six MCU SNPs in B/AA women associated with increased risk of obesity, whereas six MCU SNPs in White men, and nine MCU SNPs in White women were protective against obesity development. Conclusions: This study found associations of MCU SNPs with obesity, providing evidence of a potential predictor of obesity susceptibility in B/AA adults. Full article

(This article belongs to the Special Issue Genetics of Obesity)

16 pages, 16398 KiB

Open AccessArticle

An R2R3-MYB Transcriptional Factor LuMYB314 Associated with the Loss of Petal Pigmentation in Flax (Linum usitatissimum L.)

by Dongliang Guo, Haixia Jiang and Liqiong Xie

Genes 2024, 15(4), 511; https://doi.org/10.3390/genes15040511 - 18 Apr 2024

Cited by 1 | Viewed by 1477

Abstract

The loss of anthocyanin pigments is one of the most common evolutionary transitions in petal color, yet the genetic basis for these changes in flax remains largely unknown. In this study, we used crossing studies, a bulk segregant analysis, genome-wide association studies, a [...] Read more.

The loss of anthocyanin pigments is one of the most common evolutionary transitions in petal color, yet the genetic basis for these changes in flax remains largely unknown. In this study, we used crossing studies, a bulk segregant analysis, genome-wide association studies, a phylogenetic analysis, and transgenic testing to identify genes responsible for the transition from blue to white petals in flax. This study found no correspondence between the petal color and seed color, refuting the conclusion that a locus controlling the seed coat color is associated with the petal color, as reported in previous studies. The locus controlling the petal color was mapped using a BSA-seq analysis based on the F₂ population. However, no significantly associated genomic regions were detected. Our genome-wide association study identified a highly significant QTL (BP4.1) on chromosome 4 associated with flax petal color in the natural population. The combination of a local Manhattan plot and an LD heat map identified LuMYB314, an R2R3-MYB transcription factor, as a potential gene responsible for the natural variations in petal color in flax. The overexpression of LuMYB314 in both Arabidopsis thaliana and Nicotiana tabacum resulted in anthocyanin deposition, indicating that LuMYB314 is a credible candidate gene for controlling the petal color in flax. Additionally, our study highlights the limitations of the BSA-seq method in low-linkage genomic regions, while also demonstrating the powerful detection capabilities of GWAS based on high-density genomic variation mapping. This study enhances our genetic insight into petal color variations and has potential breeding value for engineering LuMYB314 to develop colored petals, bast fibers, and seeds for multifunctional use in flax. Full article

(This article belongs to the Special Issue Advances in Genetics and Genomics of Plants)

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Variations in petal color and seed coat color in several representative varieties in flax. The figure displays the variety names at the top, with each variety’s flowers (top) and seeds (bottom) showing a one-to-one correspondence. Full article ">Figure 2
Bulk segregation analyses of the petal coloration in the F2 segregating population. The horizontal axis indicates the physical positions of 15 chromosomes in flax and the vertical axis indicates the SNP/indel index or ΔSNP/Δindel index. Each SNP/indel site is plotted as a colored dot, and the black lines represent the fitting results. (A,B) SNP index values of the white petal pool (A) and blue petal pool (B). (C) The ΔSNP index. (D,E) Indel index values of the white petal pool (D) and blue petal pool (E). (F) The ΔIndel index. The red dotted lines indicate the association threshold (0.667). Full article ">Figure 3
Genome-wide association study of petal coloration in flax. (A) Manhattan plots illustrating a significantly associated signal for petal coloration using the compressed mixed linear model (MLM). The blue horizontal dash-dot line indicates the genome-wide significant threshold (1.53 × 10−8). The vertical axis indicated the −log10(P) value. (B) Local Manhattan plot of petal coloration surrounding the associated signal peaks on chromosome 4. The three red labelled points indicate SNPs above the threshold. (C) LD heat map drawn around the peak on chromosome 4. Representations of the pairwise r2 values among all SNPs in the genomic region corresponding to (B). (D) Detailed annotation information for three significant SNPs. Full article ">Figure 4
Multiple alignments of the amino acid sequences in the R2R3 region of LuMYB314 (Lus10028514) and its homologous proteins in plant species ranging from Rhodophyta to angiosperms. Taxon names are abbreviated as follows: Lu, Linum usitatissimum; At, Arabidopsis thaliana; Os, Oryza sativa; Amt, Amborella trichopoda; Sm, Selaginella moellendorffii; Spm, Sphagnum magellanicum; Cr, Chlamydomonas reinhardtii; Pu, Porphyra umbilicalis. Full article ">Figure 5
Phylogenetic tree of LuMYB314 homologs in plants. Amino acid sequences of LuMYB314 homologs from various plants were collected using BLAST in NCBI. This phylogenetic tree was constructed using the maximum likelihood method. A bootstrap analysis was performed with 1000 replications and the values are expressed as percentages. The proteins marked in bold on the evolutionary tree correspond to LuMYB314 identified in this study. Scale bar indicates the distances in substitutions per amino acid. Full article ">Figure 6
Overexpression of LuMYB314 increased anthocyanin accumulation in Nicotiana tabacum and Arabidopsis. (A) Anthocyanin deposition phenotype of wild-type Nicotiana NC89 and three independent 35S:LuMYB314NC89 transgenic Nicotiana tissue culture seedlings. (B–E) Anthocyanin deposition phenotype of wild-type (Col-0) and three independent 35S:LuMYB314Col-0 transgenic Arabidopsis samples. (B) Seedlings. (C) Rosette leaf (scale bar, 5 cm). (D) A close-up of the rosette leaf. (E) Mature seeds. Full article ">

13 pages, 1907 KiB

Open AccessArticle

Biogeographical Ancestry Analyses Using the ForenSeq^TM DNA Signature Prep Kit and Multiple Prediction Tools

by Nina Mjølsnes Salvo, Gunn-Hege Olsen, Thomas Berg and Kirstin Janssen

Genes 2024, 15(4), 510; https://doi.org/10.3390/genes15040510 - 18 Apr 2024

Cited by 1 | Viewed by 1517

Abstract

The inference of biogeographical ancestry (BGA) can assist in police investigations of serious crime cases and help to identify missing people and victims of mass disasters. In this study, we evaluated the typing performance of 56 ancestry-informative SNPs in 177 samples using the [...] Read more.

The inference of biogeographical ancestry (BGA) can assist in police investigations of serious crime cases and help to identify missing people and victims of mass disasters. In this study, we evaluated the typing performance of 56 ancestry-informative SNPs in 177 samples using the ForenSeq™ DNA Signature Prep Kit on the MiSeq FGx system. Furthermore, we compared the prediction accuracy of the tools Universal Analysis Software v1.2 (UAS), the FROG-kb, and GenoGeographer when inferring the ancestry of 503 Europeans, 22 non-Europeans, and 5 individuals with co-ancestry. The kit was highly sensitive with complete aiSNP profiles in samples with as low as 250pg input DNA. However, in line with others, we observed low read depth and occasional drop-out in some SNPs. Therefore, we suggest not using less than the recommended 1ng of input DNA. FROG-kb and GenoGeographer accurately predicted both Europeans (99.6% and 91.8% correct, respectively) and non-Europeans (95.4% and 90.9% correct, respectively). The UAS was highly accurate when predicting Europeans (96.0% correct) but performed poorer when predicting non-Europeans (40.9% correct). None of the tools were able to correctly predict individuals with co-ancestry. Our study demonstrates that the use of multiple prediction tools will increase the prediction accuracy of BGA inference in forensic casework. Full article

(This article belongs to the Special Issue State-of-the-Art in Forensic Genetics Volume II)

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13 pages, 770 KiB

Open AccessReview

Research Progress and Applications of Bovine Genome in the Tribe Bovini

by Xingjie Du, Yu Sun, Tong Fu, Tengyun Gao and Tianliu Zhang

Genes 2024, 15(4), 509; https://doi.org/10.3390/genes15040509 - 18 Apr 2024

Viewed by 1810

Abstract

Various bovine species have been domesticated and bred for thousands of years, and they provide adequate animal-derived products, including meat, milk, and leather, to meet human requirements. Despite the review studies on economic traits in cattle, the genetic basis of traits has only [...] Read more.

Various bovine species have been domesticated and bred for thousands of years, and they provide adequate animal-derived products, including meat, milk, and leather, to meet human requirements. Despite the review studies on economic traits in cattle, the genetic basis of traits has only been partially explained by phenotype and pedigree breeding methods, due to the complexity of genomic regulation during animal development and growth. With the advent of next-generation sequencing technology, genomics projects, such as the 1000 Bull Genomes Project, Functional Annotation of Animal Genomes project, and Bovine Pangenome Consortium, have advanced bovine genomic research. These large-scale genomics projects gave us a comprehensive concept, technology, and public resources. In this review, we summarize the genomics research progress of the main bovine species during the past decade, including cattle (Bos taurus), yak (Bos grunniens), water buffalo (Bubalus bubalis), zebu (Bos indicus), and gayal (Bos frontalis). We mainly discuss the development of genome sequencing and functional annotation, focusing on how genomic analysis reveals genetic variation and its impact on phenotypes in several bovine species. Full article

(This article belongs to the Special Issue Research on Genetics and Genomics of Cattle)

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11 pages, 734 KiB

Open AccessArticle

Spectrum of ERCC6-Related Cockayne Syndrome (Type B): From Mild to Severe Forms

by Jacopo Sartorelli, Lorena Travaglini, Marina Macchiaiolo, Giacomo Garone, Michaela Veronika Gonfiantini, Davide Vecchio, Lorenzo Sinibaldi, Flaminia Frascarelli, Viola Ceccatelli, Sara Petrillo, Fiorella Piemonte, Gabriele Piccolo, Antonio Novelli, Daniela Longo, Stefano Pro, Adele D’Amico, Enrico Silvio Bertini and Francesco Nicita

Genes 2024, 15(4), 508; https://doi.org/10.3390/genes15040508 - 18 Apr 2024

Cited by 1 | Viewed by 1961

Abstract

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed [...] Read more.

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity. Full article

(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)

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17 pages, 6104 KiB

Open AccessArticle

Assessment of the Effect of Leonurine Hydrochloride in a Mouse Model of PCOS by Gene Expression Profiling

by Mengmeng Wang, Li Yang, Guojie Sun, Yongbin Shao, Yuran Liu, Huiying Yang, Yan Wang, Mengyuan Zhang, Yunxia Shang and Xinli Gu

Genes 2024, 15(4), 507; https://doi.org/10.3390/genes15040507 - 18 Apr 2024

Cited by 2 | Viewed by 1712

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disease commonly associated with metabolic disorders in females. Leonurine hydrochloride (Leo) plays an important role in regulating immunity, tumours, uterine smooth muscle, and ovarian function. However, the effect of Leo on PCOS has not been reported. [...] Read more.

Polycystic ovary syndrome (PCOS) is an endocrine disease commonly associated with metabolic disorders in females. Leonurine hydrochloride (Leo) plays an important role in regulating immunity, tumours, uterine smooth muscle, and ovarian function. However, the effect of Leo on PCOS has not been reported. Here, we used dehydroepiandrosterone to establish a mouse model of PCOS, and some mice were then treated with Leo by gavage. We found that Leo could improve the irregular oestros cycle of PCOS mice, reverse the significantly greater serum testosterone (T) and luteinising hormone (LH) levels, significantly reduce the follicle-stimulating hormone (FSH) level, and significantly increase the LH/FSH ratio of PCOS mice. Leo could also change the phenomenon of ovaries in PCOS mice presented with cystic follicular multiplication and a lacking corpus luteum. Transcriptome analysis identified 177 differentially expressed genes related to follicular development between the model and Leo groups. Notably, the cAMP signalling pathway, neuroactive ligand-receptor interactions, the calcium signalling pathway, the ovarian steroidogenesis pathway, and the Lhcgr, Star, Cyp11a, Hsd17b7, Camk2b, Calml4, and Phkg1 genes may be most related to improvements in hormone levels and the numbers of ovarian cystic follicles and corpora lutea in PCOS mice treated by Leo, which provides a reference for further study of the mechanism of Leo. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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11 pages, 2798 KiB

Open AccessArticle

Complete Mitochondrial Genome for Lucilia cuprina dorsalis (Diptera: Calliphoridae) from the Northern Territory, Australia

by Shilpa Kapoor, Ying Ting Yang, Robyn N. Hall, Robin B. Gasser, Vernon M. Bowles, Trent Perry and Clare A. Anstead

Genes 2024, 15(4), 506; https://doi.org/10.3390/genes15040506 - 18 Apr 2024

Viewed by 1626

Abstract

The Australian sheep blowfly, Lucilia cuprina dorsalis, is a major sheep ectoparasite causing subcutaneous myiasis (flystrike), which can lead to reduced livestock productivity and, in severe instances, death of the affected animals. It is also a primary colonizer of carrion, an efficient [...] Read more.

The Australian sheep blowfly, Lucilia cuprina dorsalis, is a major sheep ectoparasite causing subcutaneous myiasis (flystrike), which can lead to reduced livestock productivity and, in severe instances, death of the affected animals. It is also a primary colonizer of carrion, an efficient pollinator, and used in maggot debridement therapy and forensic investigations. In this study, we report the complete mitochondrial (mt) genome of L. c. dorsalis from the Northern Territory (NT), Australia, where sheep are prohibited animals, unlike the rest of Australia. The mt genome is 15,943 bp in length, comprising 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a non-coding control region. The gene order of the current mt genome is consistent with the previously published L. cuprina mt genomes. Nucleotide composition revealed an AT bias, accounting for 77.5% of total mt genome nucleotides. Phylogenetic analyses of 56 species/taxa of dipterans indicated that L. c. dorsalis and L. sericata are the closest among all sibling species of the genus Lucilia, which helps to explain species evolution within the family Luciliinae. This study provides the first complete mt genome sequence for L. c. dorsalis derived from the NT, Australia to facilitate species identification and the examination of the evolutionary history of these blowflies. Full article

(This article belongs to the Special Issue Mitochondrial DNA Replication and Transcription)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Circular representation of the mitochondrial (mt) genome of Lucilia cuprina dorsalis collected from the Northern Territory, Australia. Large yellow and red arrows with annotated labels situated in the mt genome map indicate the position of protein-coding genes (PCGs) and ribosomal RNA (rRNA) genes. Blue arrows with annotated labels demarcate the positions of transfer RNA (tRNA) genes. The cox genes refer to the cytochrome c oxidase subunits, nad genes refer to NADH dehydrogenase components, the cob gene refers to the cytochrome b gene, and rrnL and rrnS refer to ribosomal RNA genes, respectively (cf. <a href="#app1-genes-15-00506" class="html-app">Table S2</a>). Full article ">Figure 2
AT skew and GC skew of protein-coding genes (PCGs) in the mitochondrial genome of Lucilia cuprina dorsalis collected from the Northern Territory, Australia. The x-axis represents the protein-coding genes (PCGs), and the y-axis represents the AT (blue) and GC skew (orange) values associated with these PCGs. Full article ">Figure 3
Relative synonymous codon usage (RSCU) in the protein-coding genes (PCGs) in the mitochondrial genome of Lucilia cuprina dorsalis collected from the Northern Territory, Australia. The different colors in the column chart represent the codon families corresponding to the amino acids listed under the columns. Full article ">Figure 4
Phylogenetic relationship of Lucilia cuprina dorsalis (Northern Territory, Australia) with 55 members/representatives of the order Diptera. The phylogenetic tree was constructed using the Bayesian inference (BI) and maximum likelihood (ML) methods. The numbers displayed on the branches indicate bootstrap values and posterior probabilities from different analyses in the order: ML/BI. Each member is labeled with the species name, location, and GenBank accession number. Haematobia irritans irritans (Muscidae) was used as the outgroup. Lucilia cuprina dorsalis (Northern Territory, Australia) sequenced in this study is color-coded in red. The family names are labeled as A to E preceding the species names in the following order: A: Muscidae, B: Calliphoridae, C: Oestridae, D: Tachinidae, and E: Sarcophagidae. The tree branches corresponding to the subfamily Luciliinae within the Calliphoridae family are highlighted in blue. The phylogenetic tree presented here is drawn to scale, with a scale bar representing 0.05 estimated substitutions per site. Full article ">

24 pages, 1974 KiB

Open AccessArticle

Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing

by Benjamin M. Helm and Stephanie M. Ware

Genes 2024, 15(4), 505; https://doi.org/10.3390/genes15040505 - 18 Apr 2024

Cited by 4 | Viewed by 1963

Abstract

Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in [...] Read more.

Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach. Over 24% of infants had genetic diagnoses identified (n = 244/1013), and ECA-positive status indicated a 4-fold increased risk of having a genetic disorder. However, ECA status had low–moderate screening performance based on predictive summary index, a compositive measure of positive and negative predictive values. For those with genetic diagnoses, nearly one-third (32%, 78/244) were ECA-negative but had cytogenetic and/or monogenic disorders identified by genetic testing. Thus, if the presence of multiple congenital anomalies is the phenotypic driver to initiate genetic testing, 13.4% (78/580) of infants with isolated CHD with identifiable genetic causes will be missed. Given the prevalence of genetic disorders and limited screening performance of ECA status, this analysis supports genetic testing in all CHD infants in intensive care settings rather than screening based on ECA. Full article

(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)

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Figure 1
Correlations between organ- or system-specific extracardiac anomalies and classes of congenital heart disease. Note: The top panel depicts the correlations across the entire cohort, and the bottom panel summarizes the correlations in patients with a genetic diagnosis identified. The strength of correlation is indicated by the color intensity. Acronyms: Endo = Endocrine, GI = Gastrointestinal/Abdominal Wall, Hematol = Hematology, NTD = Neural Tube Defect. Full article ">Figure 1 Cont.
Correlations between organ- or system-specific extracardiac anomalies and classes of congenital heart disease. Note: The top panel depicts the correlations across the entire cohort, and the bottom panel summarizes the correlations in patients with a genetic diagnosis identified. The strength of correlation is indicated by the color intensity. Acronyms: Endo = Endocrine, GI = Gastrointestinal/Abdominal Wall, Hematol = Hematology, NTD = Neural Tube Defect. Full article ">Figure 2
Results of the decision curve analysis summarizing use of extracardiac anomaly status to screen for genetic disorders. vs. the Test-All and Test-None alternatives. The highest net benefit for using ECA status to screen for high risk of genetic disorders in patients occurs at a risk threshold of ≥14%; however, the Test-All net benefit is higher when the risk threshold is <14%. Full article ">Figure 3
Differences in genetic diagnosis identified across the three time periods of our program and stratified by extracardiac anomaly status. The top panel shows the prevalence of genetic diagnoses overall in each team period, and the lower panel is restricted to comparing prevalence of cytogenetic and monogenic disorders across each time period (using the Cochran–Armitage trend test). Full article ">Figure 3 Cont.
Differences in genetic diagnosis identified across the three time periods of our program and stratified by extracardiac anomaly status. The top panel shows the prevalence of genetic diagnoses overall in each team period, and the lower panel is restricted to comparing prevalence of cytogenetic and monogenic disorders across each time period (using the Cochran–Armitage trend test). Full article ">

12 pages, 2447 KiB

Open AccessArticle

Insights into the Geographical Origins of the Cabo Verde Green Monkey

by Lara Almeida, Ivo Colmonero-Costeira, Maria J. Ferreira da Silva, Cecilia Veracini and Raquel Vasconcelos

Genes 2024, 15(4), 504; https://doi.org/10.3390/genes15040504 - 17 Apr 2024

Viewed by 2623

Abstract

The green monkey Chlorocebus sabaeus, L. 1766, native to West Africa, was introduced to the Cabo Verde Archipelago in the 16th century. Historical sources suggest that, due to the importance of Cabo Verde as a commercial entrepôt in the Atlantic slave trade, [...] Read more.

The green monkey Chlorocebus sabaeus, L. 1766, native to West Africa, was introduced to the Cabo Verde Archipelago in the 16th century. Historical sources suggest that, due to the importance of Cabo Verde as a commercial entrepôt in the Atlantic slave trade, establishing the precise place of origin of this introduced species is challenging. Non-invasive fecal samples were collected from feral and captive green monkey individuals in Cabo Verde. Two mitochondrial fragments, HVRI and cyt b, were used to confirm the taxonomic identification of the species and to tentatively determine the geographic origin of introduction to the archipelago from the African continent. By comparing the new sequences of this study to previously published ones, it was shown that Cabo Verde individuals have unique haplotypes in the HVRI, while also showing affinities to several populations from north-western coastal Africa in the cyt b, suggesting probable multiple sources of introduction and an undetermined most probable origin. The latter is consistent with historical information, but may also have resulted from solely using mtDNA as a genetic marker and the dispersal characteristics of the species. The limitations of the methodology are discussed and future directions of research are suggested. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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Figure 1
Maps representing the geographical location of the samples used in this study for HVRI and cyt b mitochondrial DNA markers. The left corner represents samples from mainland Africa (the dashed line represents the distribution range of Chlorocebus. sabaeus, adapted from the International Union for Conservation of Nature (IUCN) Red List data [<a href="#B25-genes-15-00504" class="html-bibr">25</a>]), the upper right corner samples from Cabo Verde (enlarged in the red box; their locations marked with red dots), and samples from the Americas on the bottom right. Samples retrieved from the GenBank are represented by accession numbers and samples from this study are represented by tissue codes and their locations are marked with red dots. Country colours correspond to the haplotype colours in <a href="#genes-15-00504-f003" class="html-fig">Figure 3</a>. Check <a href="#app1-genes-15-00504" class="html-app">Table S1</a> for further details. Full article ">Figure 2
Pictures of some of the captive green monkeys sampled for this study. The upper left corner represents the privately owned adult female from Cidade Velha, Santiago (ST.06.23.002; photo by Cecilia Veracini). The upper right corner and bottom pictures represent, respectively, the adult male and female from Santa Maria, Sal (S04.23.133 and S04.23.002; photos by Raquel Vasconcelos). Full article ">Figure 3
Haplotype network for the mitochondrial marker HVRI (329 bp; top) and cyt b (402 bp; bottom). The lines represent mutational steps, the circles represent haplotypes, and the dots represent missing haplotypes. The haplotypes are geographically coded by colours that correspond to the colours of the countries shown in <a href="#genes-15-00504-f001" class="html-fig">Figure 1</a>. The size of the circles represents the frequency of the haplotype. Check <a href="#app1-genes-15-00504" class="html-app">Table S1</a> for further details. Full article ">

20 pages, 2426 KiB

Open AccessReview

Genetic and Epigenetic Associations with Post-Transplant Diabetes Mellitus

by Zeinab Abdelrahman, Alexander Peter Maxwell and Amy Jayne McKnight

Genes 2024, 15(4), 503; https://doi.org/10.3390/genes15040503 - 17 Apr 2024

Viewed by 2102

Abstract

Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance [...] Read more.

Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance test (OGTT). The task of diagnosing PTDM continues to pose challenges, given the potential for diabetes to manifest at different time points after transplantation, thus demanding constant clinical vigilance and repeated testing. Interpreting HbA1c levels can be challenging after renal transplantation. Pre-transplant risk factors for PTDM include obesity, sedentary lifestyle, family history of diabetes, ethnicity (e.g., African-Caribbean or South Asian ancestry), and genetic risk factors. Risk factors for PTDM include immunosuppressive drugs, weight gain, hepatitis C, and cytomegalovirus infection. There is also emerging evidence that genetic and epigenetic variation in the organ transplant recipient may influence the risk of developing PTDM. This review outlines many known risk factors for PTDM and details some of the pathways, genetic variants, and epigenetic features associated with PTDM. Improved understanding of established and emerging risk factors may help identify people at risk of developing PTDM and may reduce the risk of developing PTDM or improve the management of this complication of organ transplantation. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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12 pages, 1912 KiB

Open AccessArticle

The Impact of Blood Sample Processing on Ribonucleic Acid (RNA) Sequencing

by Zhiyu Liu, Tinglan Ouyang, Yuwei Yang, Yuqi Sheng, Huajuan Shi, Quanjun Liu, Yunfei Bai and Qinyu Ge

Genes 2024, 15(4), 502; https://doi.org/10.3390/genes15040502 - 17 Apr 2024

Viewed by 1555

Abstract

In gene quantification and expression analysis, issues with sample selection and processing can be serious, as they can easily introduce irrelevant variables and lead to ambiguous results. This study aims to investigate the extent and mechanism of the impact of sample selection and [...] Read more.

In gene quantification and expression analysis, issues with sample selection and processing can be serious, as they can easily introduce irrelevant variables and lead to ambiguous results. This study aims to investigate the extent and mechanism of the impact of sample selection and processing on ribonucleic acid (RNA) sequencing. RNA from PBMCs and blood samples was investigated in this study. The integrity of this RNA was measured under different storage times. All the samples underwent high-throughput sequencing for comprehensive evaluation. The differentially expressed genes and their potential functions were analyzed after the samples were placed at room temperature for 0h, 4h and 8h, and different feature changes in these samples were also revealed. The sequencing results showed that the differences in gene expression were higher with an increased storage time, while the total number of genes detected did not change significantly. There were five genes showing gradient patterns over different storage times, all of which were protein-coding genes that had not been mentioned in previous studies. The effect of different storage times on seemingly the same samples was analyzed in this present study. This research, therefore, provides a theoretical basis for the long-term consideration of whether sample processing should be adequately addressed. Full article

(This article belongs to the Section RNA)

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Figure 1
RNA integrity and correlation of differential treated samples. (A) The RNA integrity number extracted from PBMCs samples. The gray line represented donor 01. The blue and orange lines represented donor 02 and donor 03. (B) Correlation coefficient diagram of PBMCs samples from donor 01. The intensity of the color represented the similarity. (C) Gene clustering of RNA-Seq data from whole blood samples (F means female, M means male, 1–3 represent the numbers of different donors). Full article ">Figure 2
Five selected genes’ expression levels and their changes with different storage times. (A) The five genes showed significantly different FPKM within 8 h of PBMCs from donor 01; (B,C) The five genes showed significantly different FPKM within 24 h from donor 02 and donor 03. Full article ">Figure 3
Comparison of the difference between whole blood and PBMCs sample extraction. (A) the number of significantly different genes between whole blood and PBMCs. (B) the number of up-regulated and down-regulated genes between whole blood and PBMCs. Full article ">Figure 4
Differential expressed gene of Go and KEGG diagrams between whole blood and PBMCs samples. (A–C) denoted differential gene GO analysis of biological processes, cell components and molecular functions of the top 10 genes, respectively, p < 0.05; (D) key genes in KEGG pathway. Full article ">

27 pages, 3462 KiB

Open AccessReview

Principles in the Management of Glioblastoma

by Domingos Roda, Pedro Veiga, Joana Barbosa Melo, Isabel Marques Carreira and Ilda Patrícia Ribeiro

Genes 2024, 15(4), 501; https://doi.org/10.3390/genes15040501 - 17 Apr 2024

Cited by 12 | Viewed by 4857

Abstract

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in [...] Read more.

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (IDH), methylation of O⁶-methylguanine-DNA methyltransferase (MGMT), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene MGMT predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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Simplified schematic representation of the PI3K/AKT/mTOR, RAS/RAF/MAPK, RB and p53 pathways and how they interact. The activation of the PI3K/AKT/mTOR and RAS/RAF/MAPK pathways by the binding of growth factors to the RTKs plays an important role in cell proliferation. MDM2 and MDM4 are negative regulators of p53. p14 inhibits MDM2, contributing to p53 expression. These pathways interact in different ways, highlighting potential targets of therapeutic intervention. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License. Full article ">Figure 2
Non-coding RNAs (ncRNAs) classification and some lncRNAs and miRNAS with oncogenic (blue) and tumor suppressor (green) potential in glioblastoma. Housekeeping ncRNAs include transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA). Regulatory RNAs include long non-coding RNAs and small non-coding RNAs. MicroRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and tRNA-derived small RNAs (tsRNAs) are small non-coding RNAs. Full article ">Figure 3
Glioblastoma management overview. Glioblastoma diagnosis is based on MRI and biopsy samples. Current standard treatment consists of maximal surgical resection followed by radiation and adjuvant TMZ. Liquid biopsy emerges as a promising tool in the management of this disease, ultimately contributing to the development of targeted therapies. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License. Full article ">Figure 4
Contrast-enhanced MRI of a glioblastoma. (a) Contrast-enhanced T1 image.; (b) T2 image showing oedema. Full article ">Figure 5
(a) Isodose distribution first course to 40 Gy intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) radiation technique; (b) isodose distribution boost dose to 60 Gy (IMRT)/(VMAT) radiation technique. Full article ">

10 pages, 1544 KiB

Open AccessArticle

Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome

by Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide and Eirik Frengen

Genes 2024, 15(4), 500; https://doi.org/10.3390/genes15040500 - 17 Apr 2024

Cited by 3 | Viewed by 2272

Abstract

Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause [...] Read more.

Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient’s fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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Figure 1
Cerebral MRI examination of the patient at the age of 2 years and 9 months. (A) T2 weighted axial image at the level of the centrum semiovale shows multiple lesions with varying degrees of high signal intensity typical of cavitary leukoencephalopathy. (B,C) Axial diffusion-weighted magnetic resonance imaging (DWI) (b1000 (B) and apparent diffusion coefficient (ADC) maps) (C) at the level of the centrum semiovale shows diffusion restriction along the margins (yellow parenthesis) of the cavitary leukoencephalopathy. (D) T2 weighted axial image at the level of corona radiata shows high signal of cavitary leukoencephalopathy in both frontal lobes (green arrows) and corpus callosum cysts (yellow arrows). (E) T1 weighted sagittal image shows thinning of the corpus callosum with low intensity foci compatible with cystic formations (green arrows). In the dorsal aspect of medulla oblongata, there is a 7 mm elongated low-signal lesion (yellow arrows). A magnification of this area is displayed in the rectangle below. (F) T2 weighted axial image at the level of the upper part of the medulla oblongata shows symmetric minute high signal changes (yellow arrows). An enlarged image of the area is shown in the rectangle below. The lesions correspond to the dorsal lesion displayed in the rectangle in E and are localized in close proximity to the dorsal motor nuclei of the vagus nerve. (G) T2 weighted axial image at the level of the mesencephalon shows high signal of periaqueductal gray matter (yellow arrows) and subtle increased signal in the substantia nigra on both sides (green arrows). (H) T2 weighted coronal image shows subtle high signal in the medial parts of both thalami (yellow arrows) and substantia nigra (green arrows) on both sides. There are also signal changes in the cerebral white matter at the level of centrum semiovale on both sides (blue arrows). Full article ">Figure 2
(A) WGS data of the patient (P), her father (F), and mother (M) showing the homozygous 12.9 Kb deletion (red box) on chromosome 7 overlapping the entire NDUFA4 gene seq[GRCh37]del(7)(p21.3) NC_000007.13:g.10969473_10982428. The parents were heterozygous for the deletion (note the decreased read depth). Genomic positions are in Kb. (B) Modified screenshot from UCSC genome browser showing the deletion (black bar) chr7:10,969,448–10,982,429 and the presence of Alu elements at its borders. Genomic positions are in Kb. (C) Sanger sequencing of the PCR product amplifying the proximal breakpoint of the chr7 deletion. Bases highlighted in yellow identify sequence from chr7, bases in grey identify sequences from chr19, which start at chr19:14427161. (D) Sanger sequencing of the PCR product amplified at the distal breakpoint of the chr7 deletion, juxtaposed to chr19:14,427,497. In (C,D), bases highlighted in yellow and grey identify sequences from chr7 and chr19, respectively. (E) WGS data from the patient showing increased read depth in the region from chr19:14,427,161–14,427,497 indicating a duplication (red box). This sequence was found inserted at chr7:10,969,448. Note that the reads with a paired end mapping at chr7 are indicated in light blue. (F) Modified screenshot from UCSC genome browser showing the duplicated region (black bar) at chr19:14,427,161–14,427,497 and its overlaps with Alu elements. Full article ">Figure 3
The ETC complex activities in fibroblasts from the patient presented relative to those in control fibroblasts. The activities were measured in whole cell lysates as described in the Materials and Method. Cells from 3 independent cultivations were used. COX/CS activity is significantly lower than control values (p = 0.005). For NQR/CS and SDH/CS: n = 2. Full article ">

16 pages, 2601 KiB

Open AccessArticle

Proteomic Analysis of Lysine Acetylation and Succinylation to Investigate the Pathogenicity of Virulent Pseudomonas syringae pv. tomato DC3000 and Avirulent Line Pseudomonas syringae pv. tomato DC3000 avrRpm1 on Arabidopsis thaliana

by Yongqiang Ding, Yangxuan Liu, Kexin Yang, Yiran Zhao, Chun Wen, Yi Yang and Wei Zhang

Genes 2024, 15(4), 499; https://doi.org/10.3390/genes15040499 - 16 Apr 2024

Viewed by 1752

Abstract

Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) is able to infect many economically important crops and thus causes substantial losses in the global agricultural economy. Pst DC3000 can be divided into virulent lines and avirulent lines. For instance, the pathogen effector avrRPM1 [...] Read more.

Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) is able to infect many economically important crops and thus causes substantial losses in the global agricultural economy. Pst DC3000 can be divided into virulent lines and avirulent lines. For instance, the pathogen effector avrRPM1 of avirulent line Pst-avrRpm1 (Pst DC3000 avrRpm1) can be recognized and detoxified by the plant. To further compare the pathogenicity mechanisms of virulent and avirulent Pst DC3000, a comprehensive analysis of the acetylome and succinylome in Arabidopsis thaliana was conducted following infection with virulent line Pst DC3000 and avirulent line Pst-avrRpm1. In this study, a total of 1625 acetylated proteins encompassing 3423 distinct acetylation sites were successfully identified. Additionally, 229 succinylated proteins with 527 unique succinylation sites were detected. A comparison of these modification profiles between plants infected with Pst DC3000 and Pst-avrRpm1 revealed significant differences. Specifically, modification sites demonstrated inconsistencies, with a variance of up to 10% compared to the control group. Moreover, lysine acetylation (Kac) and lysine succinylation (Ksu) displayed distinct preferences in their modification patterns. Lysine acetylation is observed to exhibit a tendency towards up-regulation in Arabidopsis infected with Pst-avrRpm1. Conversely, the disparity in the number of Ksu up-regulated and down-regulated sites was not as pronounced. Motif enrichment analysis disclosed that acetylation modification sequences are relatively conserved, and regions rich in polar acidic/basic and non-polar hydrophobic amino acids are hotspots for acetylation modifications. Functional enrichment analysis indicated that the differentially modified proteins are primarily enriched in the photosynthesis pathway, particularly in relation to light-capturing proteins. In conclusion, this study provides an insightful profile of the lysine acetylome and succinylome in A. thaliana infected with virulent and avirulent lines of Pst DC3000. Our findings revealed the potential impact of these post-translational modifications (PTMs) on the physiological functions of the host plant during pathogen infection. This study offers valuable insights into the complex interactions between plant pathogens and their hosts, laying the groundwork for future research on disease resistance and pathogenesis mechanisms. Full article

(This article belongs to the Special Issue Genetics of Abiotic Stress Tolerance in Plants Volume II)

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Venn diagrams of the identified acetylated (A) and succinylated (B) sites. The blue color represents the control, while the red and green color represent Arabidopsis leaf samples infected with Pst DC3000 and Pst-AvrRpm1, respectively. The numerical values correspond to the quantity of lysine modification sites in each category. Full article ">Figure 2
Column diagram depicting the distribution of Kac (A) and Ksu (B) sites across distinct comparison groups. Con represents the control, while DC3000 and rpm1 represent Arabidopsis leaf samples infected with Pst DC3000 and Pst-AvrRpm1, respectively. Kac: lysine acetylation; Ksu: lysine succinylation. Blue indicates the up while red indicates down. Full article ">Figure 3
Motif analysis of the detected lysine acetylation (Kac) and lysine succinylation (Ksu) sites. Heat map analysis of the amino acid compositions around the acetylated (A) and succinylated (B) sites. Red indicates an amino acid that is significantly enriched, while green indicates an amino acid that is significantly reduced. Full article ">Figure 4
GO-based enrichment analysis of identified proteins. Enrichment analyses of the identified lysine-acetylated (A) and lysine-succinylated (B) proteins in the GO annotation and pathway categories. GO: Gene Ontology; BP: Biological Process; MF: Molecular Function; CC: Cellular Component. Full article ">Figure 5
Enrichment analysis of KEGG pathways associated with down-regulated differentially modified Kac (A) and Ksu (B) proteins in A. thaliana. The significance of enrichment was evaluated using a two-tailed Fisher’s exact test. Terms with a corrected p-value < 0.05 were considered statistically significant. Full article ">Figure 6
Protein domain enrichment analysis of acetylated (A) and succinylated (B) proteins. The significance of enrichment was evaluated using a two-tailed Fisher’s exact test. Terms with a corrected p-value < 0.05 were considered statistically significant. Full article ">Figure 7
Detailed information on the photosynthesis-antenna protein pathway involving differentially modified Kac and Ksu proteins. The detected subunits of the light-harvesting chlorophyll protein complex are labeled with fold. White indicates non-significant change, red indicates down-regulation, while the yellow indicates both up-regulation and down-regulation. Full article ">

11 pages, 1494 KiB

Open AccessArticle

Comparison of Fecal MicroRNA Isolation Using Various Total RNA Isolation Kits

by Theresa Lederer, Noam M. Hipler, Cosima Thon, Juozas Kupcinskas and Alexander Link

Genes 2024, 15(4), 498; https://doi.org/10.3390/genes15040498 - 16 Apr 2024

Cited by 2 | Viewed by 2090

Abstract

Fecal specimens have long been regarded as promising sources for gastrointestinal cancer screening and have, thus, been extensively investigated in biomarker research. MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating various biological processes. They are commonly dysregulated during tumor development and [...] Read more.

Fecal specimens have long been regarded as promising sources for gastrointestinal cancer screening and have, thus, been extensively investigated in biomarker research. MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating various biological processes. They are commonly dysregulated during tumor development and exhibit differential expression in feces. To assess the preanalytical feasibility of fecal miRNA analysis, we systematically compared the performance of commonly used total RNA extraction methods. Fecal samples from healthy subjects were utilized for this evaluation. Various methods, including miRNeasy, Universal, Trizol, RNeasy, and mirVana kits, were employed to isolate total RNA. MiRNA expression analyses were conducted using TaqMan or SYBR Green qRT-PCR for a subset of miRNAs, with externally spiked-in cel-miR-39 used for normalization. Most methods demonstrated similar performance in terms of the total RNA concentration and purity. Externally spiked cel-miR-39 and endogenous miRNAs (RNU6b, miR-16, and miR-21) exhibited comparable concentrations across the different RNA isolation methods, whereas the RNeasy mini kit consistently yielded lower values. Our findings suggest that various isolation methods produce reproducible and comparable miRNA expression results, supporting the potential comparability and translational applicability of miRNA-based biomarker research in the future. Full article

(This article belongs to the Special Issue Non-coding RNAs in Human Health and Disease)

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Graphical study design. Workflow of the study. Full article ">Figure 2
Total RNA and purity. (A) General comparison on total RNA level. (B) Comparison of purity of miRNAs. ** p ≤ 0.01; *** p ≤ 0.001. Full article ">Figure 3
Correlation between the kits. Pearson correlation between the different kits based on Ct values and the amount of total RNA and RNA purity. ** p = 0.01; **** p = <0.0001. Full article ">Figure 4
Performance of miRNA analysis and reproducibility analyses. (A) Data are presented as raw Ct for RNU6b and cel-miR-39, miR-16, and miR-21. (B) Data forming direct comparisons between miRNeasy and mirVana kits are presented as raw Ct for cel-miR-39, miR-16, and miR-21. (C) Extraction analyses for the independent qPCR run to confirm the validity of the data. ** p ≤ 0.01; *** p ≤ 0.001. Full article ">Figure 5
Comparison of normalized miR-21 levels. (A) miR-21 expression normalized to cel-miR-39 ΔCt method. (B) miR-21 expression normalized to combined cel-miR-39 and miR-16. Full article ">

13 pages, 535 KiB

Open AccessArticle

Association of CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T Polymorphisms with Tacrolimus Dose, Serum Concentration, and Biochemical Parameters in Mexican Patients with Kidney Transplant

by Edith Viridiana Alatorre-Moreno, Ana Miriam Saldaña-Cruz, Edsaúl Emilio Pérez-Guerrero, María Cristina Morán-Moguel, Betsabé Contreras-Haro, David Alejandro López-de La Mora, Ingrid Patricia Dávalos-Rodríguez, Alejandro Marín-Medina, Alicia Rivera-Cameras, Luz-Ma Adriana Balderas-Peña, José Juan Gómez-Ramos, Laura Cortés-Sanabria and Mario Salazar-Páramo

Genes 2024, 15(4), 497; https://doi.org/10.3390/genes15040497 - 16 Apr 2024

Cited by 1 | Viewed by 1834

Abstract

Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified [...] Read more.

Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified in the genes encoding CYP3A4, CYP3A5, and ABCB1, including CYP3A4-392A/G (rs2740574), CYP3A5 6986A/G (rs776746), and ABCB1 3435C/T (rs1045642). This study aims to evaluate the association among CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T polymorphisms and TAC, serum concentration, and biochemical parameters that may affect TAC pharmacokinetics in Mexican kidney transplant (KT) patients. Methods: Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and ABCB1 gene polymorphisms were genotyped using qPCR TaqMan. Serum TAC concentration (as measured) and intervening variables were assessed. Logistic regression analyses were performed at baseline and after one month to assess the extent of the association between the polymorphisms, intervening variables, and TAC concentration. Results: The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13–21.9; p = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54–93.08; p = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79–88.23; p = 0.018) were strongly associated with TAC pharmacokinetic variability. Conclusion: The findings of this study of the Mexican population showed that CYP3A5-6986 A/G GG genotype is associated with a four-fold increase in the likelihood of encountering a TAC concentration of more than 15 ng/dL. The co-occurrence of the CYP3A5-6986GG genotype and the use of drugs that increase TAC concentration correlates with a nine-fold increased risk of experiencing a TAC at a level above 15 ng/mL. Therefore, these patients have an increased susceptibility to TAC-associated toxicity. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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15 pages, 3832 KiB

Open AccessReview

Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

by Pashtun Shahim, Gina Norato, Ninet Sinaii, Henrik Zetterberg, Kaj Blennow, Leighton Chan and Christopher Grunseich

Genes 2024, 15(4), 496; https://doi.org/10.3390/genes15040496 - 16 Apr 2024

Cited by 4 | Viewed by 2960

Abstract

Background: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS. Methods: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, [...] Read more.

Background: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS. Methods: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939. Results: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival. Discussion: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls. Full article

(This article belongs to the Special Issue Advances in Genetics of Motor Neuron Diseases)

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Figure 1
Neurofilament structures and preferred reporting items for systematic reviews and meta-analyses: flow diagram. (A) Structure and assembly of neurofilaments with a length of ~60 nm and a diameter of ~10 nm. Neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), and α internexin are the subunits of neurofilaments. All neurofilament subunits have a conserved α-helical rod domain comprising several coiled coils, and variable amino-terminal globular head regions and carboxy-terminal globular head regions and carboxy-terminal tail domains. NfM and NfH subunits have long carboxy-terminal domains with multiple Lys-Ser-Pro repeats that are heavily phosphorylated. The tail domains of NfM and NfH radiate outward from the filament core because of the negative charges from large numbers of glutamic acid and phosphorylated serine and threonine residues. E segment, glutamic-rich segment; E1, glutamic acid-rich segment 1; E2, glutamic acid-rich segment 2; KSP, lysine–serine–proline; SP, serine–proline; KE, lysine–glutamic acid; KEP, lysine–glutamic acid–proline. (B) Search strategy and records identified, as well as article exclusion following screening for eligibility. Full article ">Figure 2
Forest plots and receiver operating characteristic curves for the diagnostic accuracy of CSF neurofilament light chain and phosphorylated neurofilament heavy chain in ALS and controls and disease mimics. Forest plots of sensitivity, specificity, and summary receiver operating characteristics (SROCs) and their confidence intervals for (A) NfL and (B) pNfH distinguishing ALS from controls. Forest plots of sensitivity and SROCs and their confidence intervals for (C) NfL and (D) pNfH distinguishing ALS from mimics are presented. Each individual dot in the SROC represents a unique study. The orange diamond represents the summary estimate of sensitivity and false-positive rate (1-specificity), and the dotted circle represents the 95% confidence region. On top of each SROC, “n” represents the total number of participants in the analyses. Feneberg et al. [<a href="#B17-genes-15-00496" class="html-bibr">17</a>]: early symptomatic ALS vs. controls. Feneberg et al. [<a href="#B17-genes-15-00496" class="html-bibr">17</a>]: late symptomatic ALS vs. controls. Saracino et al. [<a href="#B35-genes-15-00496" class="html-bibr">35</a>]: GRN patients vs. controls. Saracino et al. [<a href="#B35-genes-15-00496" class="html-bibr">35</a>]: C9orf72 patients vs. controls. Full article ">Figure 3
Meta-analysis of correlations between CSF and blood neurofilaments. (A) Correlations between cerebrospinal fluid (CSF) and blood neurofilament light (NfL). (B) Correlations between CSF and serum phosphorylated neurofilament heavy chain (pNfH). All correlations were calculated using the Spearman’s rank method. Markers indicate estimates, with the size of the marker indicating weight; horizontal lines represent 95% CIs; diamonds represent summary estimates, with the outer points indicating 95% CIs. Full article ">Figure 4
Meta-analysis of CSF and blood neurofilaments and their associations with clinical markers of ALS functional score and disease progression. Correlation of NfL (A) and pNfH (B) measured in blood with ALS Functional Rating Scale (ALSFRS-R). Correlation of NfL (C) and pNfH (D) measured in blood with disease progression. All correlations were calculated using the Spearman’s rank method. Markers indicate estimates, with the size of the marker indicating weight; horizontal lines represent 95% CIs; diamonds represent summary estimates, with the outer points indicating 95% CIs. Full article ">Figure 5
Neurofilament and Survival. (A) Higher CSF or blood NfL (B) is associated with shorter survival in patients with ALS. (C) pNfH measured in CSF and survival time. (D) pNfH measured in serum and survival time. Full article ">Figure 6
Clinical trial sample size requirements based on neurofilaments. (A,B) Sample size requirements for a placebo-controlled clinical trial of a treatment aimed at reducing neurofilament levels in cases relative to controls. Sample sizes are plotted against potential treatment effectiveness (A) or effect size (Cohen’s d) estimates (B). The gray dashed vertical line indicates the 25% effectiveness level used in trials of drug intervention in other neurodegenerative diseases [<a href="#B34-genes-15-00496" class="html-bibr">34</a>]. Full article ">

13 pages, 870 KiB

Open AccessArticle

Heritability of Gene Expression Measured from Peripheral Blood in Older Adults

by Sri C. Kanchibhotla, Karen A. Mather, Nicola J. Armstrong, Liliana G. Ciobanu, Bernhard T. Baune, Vibeke S. Catts, Peter R. Schofield, Julian N. Trollor, David Ames, Perminder S. Sachdev and Anbupalam Thalamuthu

Genes 2024, 15(4), 495; https://doi.org/10.3390/genes15040495 - 16 Apr 2024

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Abstract

The contributions of genetic variation and the environment to gene expression may change across the lifespan. However, few studies have investigated the heritability of blood gene expression in older adults. The current study therefore aimed to investigate this question in a community sample [...] Read more.

The contributions of genetic variation and the environment to gene expression may change across the lifespan. However, few studies have investigated the heritability of blood gene expression in older adults. The current study therefore aimed to investigate this question in a community sample of older adults. A total of 246 adults (71 MZ and 52 DZ twins, 69.91% females; mean age—75.79 ± 5.44) were studied. Peripheral blood gene expression was assessed using Illumina microarrays. A heritability analysis was performed using structural equation modelling. There were 5269 probes (19.9%) from 4603 unique genes (23.9%) (total 26,537 probes from 19,256 genes) that were significantly heritable (mean h² = 0.40). A pathway analysis of the top 10% of significant genes showed enrichment for the immune response and ageing-associated genes. In a comparison with two other gene expression twin heritability studies using adults from across the lifespan, there were 38 out of 9479 overlapping genes that were significantly heritable. In conclusion, our study found ~24% of the available genes for analysis were heritable in older adults, with only a small number common across studies that used samples from across adulthood, indicating the importance of examining gene expression in older age groups. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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