Combined Linkage Research Articles

A novel approach to detecting microduplication in split hand/foot malformation type 3 at the single-cell level: SHFM as a case study

BackgroundSplit hand/foot malformation (SHFM) is a congenital limb deficiency characterized by missing or shortened central digits. Several gene loci have been associated with SHFM. Identifying microduplications at the single-cell level is challenging in clinical practice, and traditional detection methods may lead to misdiagnoses in embryos and pregnant women.ResultsIn this research, we utilized a low cell count and whole-genome amplification products to employ single nucleotide polymorphism arrays, next-generation sequencing, and third-generation sequencing methods to detect copy number variants of microduplications in a SHFM3 case with limited DNA. Additionally, Karyomapping and combined linkage analysis were conducted to validate the results.ConclusionsThis study establishes a new strategy for identifying microduplications or microdeletions at the single-cell level in clinical preimplantation genetic testing, enhancing the efficiency and accuracy of diagnosing microduplication or microdeletion diseases during IVF-PGT and prenatal diagnosis.

Decoding the genetic basis of ear‐related traits in maize (Zea mays L.) using linkage mapping, association mapping and genomic prediction

AbstractAs important yield components, the genetic analysis of ear‐related traits could provide a theoretical basis for maize breeding. Here, we reported the comprehensive genetic architecture of five ear‐related traits using 150 recombinant inbred lines (RIL) populations derived from the cross between Xu178 and K12. Besides, two sets of association populations were used to dissect genetic loci of five traits by genome‐wide association study (GWAS). A total of 32 QTLs of ear‐related traits were detected in the linkage mapping. Based on the mixed linear model (MLM), a total of 117 significant SNP markers of ear‐related traits were detected. Furthermore, a combined GWAS and linkage mapping analysis revealed 51 significant SNP markers fell within the confidence interval of QTLs. A total of seven co‐located significant SNP markers among different traits were found. Finally, six important candidate genes related to grain development were screened out. In addition, through haplotype analysis, two favourable haplotypes were found on chromosome 4, which could increase row number per ear (RNE), kernel number per row (KNR) and grain yield per plant (GYP) to a certain extent. Compared with the random model, the prediction accuracy of genomic prediction (GP) was improved in different degrees by considering the significant SNP markers as fixed effects. The stable genetic QTLs, candidate genes and favourable haplotypes found in this study are valuable resources, which will provide theoretical reference for high‐yield breeding of maize. Taken together, the research results also highlight the benefits of integrating GWAS with GP to further improve the accuracy of GP.

Gender-specific abdominal fat distribution and insulin resistance associated with organophosphate esters and phthalate metabolites exposure

The worldwide prevalence of obesity highlights the potential contribution of endocrine-disrupting chemicals (EDCs). However, common epidemiological measures such as body mass index and waist circumference may misrepresent the intricate obesity risks these chemicals pose across genders. This study delves deeper into abdominal fat by differentiating between subcutaneous and visceral regions by analyzing data from National Health and Nutrition Examination Surveys (NHANES). We particularly investigated the gender-specific associations between organophosphorus flame-retardant metabolites (mOPFRs), phthalates (mPAEs) and accumulated fat indexes from 2536 people. Aiding by Bayesian Kernel Machine Regression (BKMR), we found while co-exposure to mOPFRs and mPAEs was linked to general and abdominal obesity across the entire and gender-specific populations, a gender-specific fat distribution emerged. For women, urinary BDCPP and MBzP were linked to an increased subcutaneous fat index (SFI) [BDCPP OR: 1.12 (95% CI: 1.03–1.21), MBzP OR: 1.09 (95% CI: 1.01–1.18)], but not to visceral fat index (VFI). These metabolites had a combined linkage with SFI, with BDCPP (weighting 22.0%) and DPHP (weighting 31.0%) being the most influential in Quantile g-computation model (qgcomp) model. In men, BCEP exposure exclusively associated with the elevated VFI [OR: 1.14 (95% CI: 1.03–1.26)], a trend further highlighted in mixture models with BCEP as the predominant association. Intriguingly, only males displayed a marked correlation between these metabolites and insulin resistance in subpopulation. An attempted mediation analysis revealed that elevated C-reactive protein mediated 12.1% of the association between urinary BCEP and insulin resistance, suggesting a potential role of inflammation. In conclusion, the gender-specific fat distribution and insulin resistance that associated with mOPFRs represented the potential risk of these chemicals to man.

PCYT2 deficiency in Saarlooswolfdogs with progressive retinal, central, and peripheral neurodegeneration

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2:c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2:c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency.

Combined linkage analysis and association mapping identifies genomic regions associated with yield-related and drought-tolerance traits in wheat (Triticum aestivum L.).

Combined linkage analysis and association mapping identified genomic regions associated with yield and drought tolerance, providing information to assist breeding for high yield and drought tolerance in wheat. Wheat (Triticum aestivum L.) is one of the most widely grown food crops and provides adequate amounts of protein to support human health. Drought stress is the most important abiotic stress constraining yield during the flowering and grain development periods. Precise targeting of genomic regions underlying yield- and drought tolerance-responsive traits would assist in breeding programs. In this study, two water treatments (well-watered, WW, and rain-fed water stress, WS) were applied, and five yield-related agronomic traits (plant height, PH; spike length, SL; spikelet number per spike, SNPS; kernel number per spike, KNPS; thousand kernel weight, TKW) and drought response values (DRVs) were used to characterize the drought sensitivity of each accession. Association mapping was performed on an association panel of 304 accessions, and linkage analysis was applied to a doubled haploid (DH) population of 152 lines. Eleven co-localized genomic regions associated with yield traits and DRV were identified in both populations. Many previously cloned key genes were located in these regions. In particular, a TKW-associated region on chromosome 2D was identified using both association mapping and linkage analysis and a key candidate gene, TraesCS2D02G142500, was detected based on gene annotation and differences in expression levels. Exonic SNPs were analyzed by sequencing the full length of TraesCS2D02G142500 in the association panel, and a rare haplotype, Hap-2, which reduced TKW to a lesser extent than Hap-1 under drought stress, and the Hap-2 varieties presented drought-insensitive. Altogether, this study provides fundamental insights into molecular targets for high yield and drought tolerance in wheat.

Acute pancreatitis and metabolic syndrome: genetic correlations and causal associations.

Although there is a definite correlation between the Metabolic Syndrome (MetS) and Acute Pancreatitis (AP), cause is yet unknown. The current work combined linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) approaches to fill this important information gap. In this study, we harnessed the power of publicly available gene-wide association databases (GWAS) to explore the intricate relationship between MetS and its components with AP. The cornerstone of our analysis was the Inverse-Variance Weighted (IVW) method, serving as our primary analytical tool. In addition to IVW, we complemented our investigation with several other robust MR methods, including MR-Egger, Weighted Median, Maximum Likelihood, and MR-PRESSO. By employing this diverse set of analytical approaches, we sought to ensure the comprehensiveness and robustness of our findings. LDSC regression indicated a genetic correlation between MetS and AP. Univariate MR results indicated a genetic association between MetS (OR = 1.084; 95% CI, 1.005-1.170; P = 0.037), BMI (OR = 1.459; 95% CI, 1.325-1.606; P = 1.46E-14), WHR (OR = 1.189; 95% CI, 1.068-1.323; P = 1.56 E-03), TG (OR = 1.110; 95% CI, 1.001-1.231; P = 0.047), and FI (OR = 1.798; 95% CI, 1.245-2.595; P = 1.74E-03) were able to significantly increase the risk of AP. The results of multivariate MR analysis revealed that these causality associations still existed. Our investigation has yielded compelling evidence that substantiates the presence of both a genetic correlation and a causal relationship between MetS and AP.

RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia.

Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype-phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.

Identification of solvent retention capacity quantitative trait loci by combined linkage and association mapping in wheat (Triticum aestivum L.)

AbstractSolvent retention capacity (SRC) is an important tool for assessing wheat quality by estimating the biochemical characteristics of flour components. Although it has been widely used in wheat breeding programs, its genetic architecture is still poorly understood. Hence, the objective of this study was to find quantitative trait loci (QTLs) associated with four SRC traits, namely sucrose SRC, sodium carbonate SRC, water SRC and lactic acid SRC, in a recombinant inbred line population consisting of 173 lines descended from Shannong 01–35/Gaocheng 9411 and an association panel of 205 wheat varieties. The 90K single nucleotide polymorphism array was used to genotype both populations. SRC was primarily influenced by genotype, with broad‐sense heritability (H2) ranging from 59.72% to 80.76%. Linkage mapping revealed seven major QTLs on chromosomes 1B, 4B, 5B, and 6B. Among them, QSc1B.6‐27 was repeatedly identified in two different environments, with a 14.7% phenotypic variance explained value. Additionally, 24 significant QTLs, consisting of 57 marker‐trait associations, were identified using association mapping across four environments. Nineteen of them explained more than 10.0% of the phenotypic variance, with QSU6A.141 explaining the most (20.1%). Two common chromosomal regions were discovered when combining the two mapping populations. These regions were located between IACX5803 and BS00067000_51 on chromosome 1B and between IACX557 and CAP11_c3631_75 on chromosome 4B, respectively. In addition, four candidate genes associated with wheat SRC were identified. These findings shed light on the complex genetic mechanisms underlying wheat SRC and may help to genetically enhance wheat quality.

Modeling the impact of different PrEP targeting strategies combined with a clinic-based HIV-1 nucleic acid testing intervention in Kenya

BackgroundUp to 69% of adults who acquire HIV in Kenya seek care for acute retroviral symptoms, providing an important opportunity for early diagnosis and HIV care engagement. The Tambua Mapema Plus (TMP) trial tested a combined HIV-1 nucleic acid testing, linkage, treatment, and partner notification intervention for adults with symptoms of acute HIV infection presenting to health facilities in coastal Kenya. We estimated the potential impact on the Kenyan HIV epidemic of providing PrEP to individuals testing negative in TMP, if scaled up. MethodsWe developed an agent-based simulation of HIV-1 transmission using TMP data and current Kenyan statistics. PrEP interventions were layered onto a model of TMP as standard of care, to estimate additional potential population-level impact of enrolling HIV-negative individuals identified through TMP on PrEP over 10 years. Four scenarios were modeled: PrEP for uninfected individuals in disclosed serodiscordant couples; PrEP for individuals with concurrent partnerships; PrEP for all uninfected individuals identified through TMP; and PrEP integrated into the enhanced partner services component of TMP. FindingsProviding PrEP to both individuals with concurrent partnerships and uninfected partners identified through enhanced partner services reduced new HIV infections and was efficient based on numbers needed to treat (NNT). The mean percent of infections averted was 2.79 (95%SI:−10.83, 15.24) and 4.62 (95%SI:−9.5, 16.82) when PrEP uptake was 50% and 100%, respectively, and median NNT was 22.54 (95%SI:not defined, 6.45) and 27.55 (95%SI:not defined, 11.0), respectively. Providing PrEP for all uninfected individuals identified through TMP averted up to 12.68% (95%SI:0.17, 25.19) of new infections but was not efficient based on the NNT: 200.24 (95%SI:523.81, 123.23). ConclusionsProviding PrEP to individuals testing negative for HIV-1 nucleic acid after presenting to a health facility with symptoms compatible with acute HIV adds value to the TMP intervention, provided PrEP is targeted effectively and efficiently. FundingNational Institutes of Health, Sub-Saharan African Network for TB/HIV Research Excellence.

Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome has been known to be caused by dominant gain-of-function mutations in GLUD1, encoding the mitochondrial enzyme glutamate dehydrogenase. Pathogenic GLUD1 mutations enhance enzymatic activity by reducing its sensitivity to allosteric inhibition by GTP. Two recent independent studies showed that a similar HI/HA phenotype can be caused by biallelic mutations in SLC25A36, encoding pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane: one study reported a single case caused by a homozygous truncating mutation in SLC25A36 resulting in lack of expression of SLC25A36 in patients' fibroblasts. A second study described two siblings with a splice site mutation in SLC25A36, causing reduction of mitochondrial GTP content, putatively leading to hyperactivation of glutamate dehydrogenase. In an independent study, through combined linkage analysis and exome sequencing, we demonstrate in four individuals of two Bedouin Israeli related families the same disease-causing SLC25A36 (NM_018155.3) c.284 + 3A > T homozygous splice-site mutation found in the two siblings. We demonstrate that the mutation, while causing skipping of exon 3, does not abrogate expression of mRNA and protein of the mutant SLC25A36 in patients' blood and fibroblasts. Affected individuals had hyperinsulinism, hyperammonemia, borderline low birth weight, tonic-clonic seizures commencing around 6months of age, yet normal intellect and no significant other morbidities. Chronic constipation, hypothyroidism, and developmental delay previously described in a single patient were not found. We thus verify that biallelic SLC25A36 mutations indeed cause HI/HA syndrome and clearly delineate the disease phenotype.

Quantitative trait locus for calving traits on Bos taurus autosome 18 in Holstein cattle is embedded in a complex genomic region

Although the quantitative trait locus (QTL) on chromosome 18 (BTA18) associated with paternal calving ease and stillbirth in Holstein Friesian cattle and its cross has been known for over 20 years, to our knowledge, the exact causal genetic sequence has yet escaped identification. The aim of this study was to re-examine the region of the published QTL on BTA18 and to investigate the possible reasons behind this elusiveness. For this purpose, we carried out a combined linkage disequilibrium and linkage analysis using genotyping data of 2,697 German Holstein Friesian (HF) animals and subsequent whole-genome sequencing (WGS) data analyses and genome assembly of HF samples. We confirmed the known QTL in the 95% confidence interval of 1.089 Mbp between 58.34 and 59.43 Mbp on BTA18. Additionally, these 4 SNPs in the near-perfect linkage disequilibrium with the QTL haplotype were identified: rs381577268 (on 57,816,137 bp, C/T), rs381878735 (on 59,574,329 bp, A/T), rs464221818 (on 59,329,176 bp, C/T), and rs472502785 (on 59,345,689 bp, T/C). Search for the causal mutation using short and long-read sequences, and methylation data of the BTA18 QTL region did not reveal any candidates though. The assembly showed problems in the region, as well as an abundance of segmental duplications within and around the region. Taking the QTL of BTA18 in Holstein cattle as an example, the data presented in this study comprehensively characterize the genomic features that could also be relevant for other such elusive QTL in various other cattle breeds and livestock species as well.

Combined linkage mapping and association analysis uncovers candidate genes for 25 leaf-related traits across three environments in maize.

Combined linkage and association analysis revealed five co-localized genetic loci across multiple environments. The key gene Zm00001d026491 was further verified to influence leaf length by candidate gene association analysis. Leaf morphology and number determine the canopy structure and thus affect crop yield. Herein, the genetic basis and key genes for 25 leaf-related traits, including leaf lengths (LL), leaf widths (LW), and leaf areas (LA) of eight continuous leaves under the tassel, and the number of leaves above the primary ear (LAE), were dissected by using an association panel and a biparental population. Using an intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, 290 quantitative trait loci (QTL) controlling these traits were detected across different locations, among which 115 QTL were individually repeatedly identified in at least two environments. Using the association panel, 165 unique significant single-nucleotide polymorphisms (SNPs) were associated with target traits (P < 2.15E-06), of which 35 were separately detected across multiple environments. In total, 42 pleiotropic QTL/SNPs (pQTL/SNPs) were responsible for at least two of the LL, LW, LA, and LAE traits across multiple environments. Combining the QTL mapping and association study, five unique SNPs were located within the confidence intervals of seven QTL, and 77 genes were identified based on the linkage disequilibrium regions of co-localized SNP loci. Gene-based association studies verified that the intragenic variants in the candidate gene Zm00001d026491 influenced LL of the third leaf counted from the top node. These findings will provide vital information to understanding the genetic basis of leaf-related traits and help to cultivate maize varieties with ideal plant architecture.

PCYT1A Missense Variant in Vizslas with Disproportionate Dwarfism

Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 (SD3). The most striking skeletal changes comprised a marked shortening and deformation of the humerus and femur. An extended pedigree with six affected dogs suggested autosomal recessive inheritance. Combined linkage and homozygosity mapping localized a potential genetic defect to a ~4 Mb interval on chromosome 33. We sequenced the genome of an affected dog, and comparison with 926 control genomes revealed a single, private protein-changing variant in the critical interval, PCYT1A:XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid, XP_038439059.1:p.(Y225H). We observed perfect co-segregation of the genotypes with the phenotype in the studied family. When genotyping additional Vizslas, we encountered a single dog with disproportionate dwarfism that did not carry the mutant PCYT1A allele, which we hypothesize was due to heterogeneity. In the remaining 130 dogs, we observed perfect genotype-phenotype association, and none of the unaffected dogs were homozygous for the mutant PCYT1A allele. PCYT1A loss-of-function variants cause spondylometaphyseal dysplasia with cone-rod dystrophy (SMD-CRD) in humans. The skeletal changes in Vizslas were comparable to human patients. So far, no ocular phenotype has been recognized in dwarf Vizslas. We propose the PCYT1A missense variant as a candidate causative variant for SD3. Our data facilitate genetic testing of Vizslas to prevent the unintentional breeding of further affected puppies.

EEG-based spatial elements optimisation design method

In the field of digital design, a recent hot topic is the study of the interaction between spatial environment design and human factors. Electroencephalogram (EEG) and eye tracking can be used as quantitative analysis methods for architectural space evaluation; however, conclusions from existing studies on improving the quality of spatial environments based on human factors tend to remain qualitative. In order to realise the quantitative optimisation design of spatial elements from human physiological data, this research used the digital space optimisation method and perceptual evaluation research. In this way, it established an optimisation method for built space elements in real-time using human psychological indicators. Firstly, this method used the specific indicators of the Meditation value and Attention value in the human EEG signal, taking the ThinkGear AM (TGAM) module as the optimisation objective, the architectural space colour and the window size as the optimisation object, and the multi-objective genetic algorithm as the optimisation tool. Secondly, this research combined virtual reality scenarios and parametric linkage models to realise this optimisation method to establish a tool platform and workflow. Thirdly, this study took the optimisation of a typical living space as an example and recruited 50 volunteers to participate in an optimisation experiment. The results indicated that with the iterative optimisation of the multi-objective genetic algorithm, the specific EEG index decreases significantly and the standard deviation of the in-dex fluctuates and decreases during the iterative process, which further indicates that the optimisation method established in this study with the specific EEG index as the optimisation objective is effective and feasible. In addition, this study laid the foundation for more EEG indicators and more complex spatial element opti-misation research in the future.

Identification and genomic characterization of major effect bacterial blight resistance locus (BB-13) in Upland cotton (Gossypium hirsutum L.).

Identification and genomic characterization of major resistance locus against cotton bacterial blight (CBB) using GWAS and linkage mapping to enable genomics-based development of durable CBB resistance and gene discovery in cotton. Cotton bacterial leaf blight (CBB), caused by Xanthomonas citri subsp. malvacearum (Xcm), has periodically been a damaging disease in the USA. Identification and deployment of genetic resistance in cotton cultivars is the most economical and efficient means of reducing crop losses due to CBB. In the current study, genome-wide association study (GWAS) of CBB resistance using an elite diversity panel of 380 accessions, genotyped with the cotton single nucleotide polymorphism (SNP) 63K array, and phenotyped with race-18 of CBB, localized the CBB resistance to a 2.01-Mb region in the long arm of chromosome D02. Molecular genetic mapping using an F6 recombinant inbred line (RIL) population showed the CBB resistance in cultivar Arkot 8102 was controlled by a single locus (BB-13). The BB-13 locus was mapped within the 0.95-cM interval near the telomeric region in the long arm of chromosome D02. Flanking SNP markers, i04890Gh and i04907Gh of the BB-13 locus, identified from the combined linkage analysis and GWAS, targeted it to a 371-Kb genomic region. Candidate gene analysis identified thirty putative gene sequences in the targeted genomic region. Nine of these putative genes and two NBS-LRR genes adjacent to the targeted region were putatively involved in plant disease resistance and are possible candidate genes for BB-13 locus. Genetic mapping and genomic targeting of the BB13 locus in the current study will help in cloning the CBB-resistant gene and establishing the molecular genetic architecture of the BB-13 locus towards developing durable resistance to CBB in cotton.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD=6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

Linkage mapping combined with GWAS revealed the genetic structural relationship and candidate genes of maize flowering time-related traits

BackgroundFlowering time is an important agronomic trait of crops and significantly affects plant adaptation and seed production. Flowering time varies greatly among maize (Zea mays) inbred lines, but the genetic basis of this variation is not well understood. Here, we report the comprehensive genetic architecture of six flowering time-related traits using a recombinant inbred line (RIL) population obtained from a cross between two maize genotypes, B73 and Abe2, and combined with genome-wide association studies to identify candidate genes that affect flowering time.ResultsOur results indicate that these six traits showed extensive phenotypic variation and high heritability in the RIL population. The flowering time of this RIL population showed little correlation with the leaf number under different environmental conditions. A genetic linkage map was constructed by 10,114 polymorphic markers covering the whole maize genome, which was applied to QTL mapping for these traits, and identified a total of 82 QTLs that contain 13 flowering genes. Furthermore, a combined genome-wide association study and linkage mapping analysis revealed 17 new candidate genes associated with flowering time.ConclusionsIn the present study, by using genetic mapping and GWAS approaches with the RIL population, we revealed a list of genomic regions and candidate genes that were significantly associated with flowering time. This work provides an important resource for the breeding of flowering time traits in maize.

Terrorism Situation and Counter-Terrorism Police Cooperation in South Asia and Southeast Asia

New changes of terrorism situation in South Asia and Southeast Asia could be seen from the increase of numbers of terrorist attacks, the increase retaliatory terrorist attacks and the increase of the combined risks and linkage effects of terrorism and other non-traditional security issues. The terrorist threat in South Asia and Southeast Asia is expected to continue in the near future because the threats severely posed by the ongoing conflict in Afghanistan, the interaction and allying of terrorist organizations and terrorists’ exploitation of advanced technology. However, the practice of counter-terrorism police cooperation in South Asia and Southeast Asia was weak and fragile due to the poor performance of ASEAN counter-terrorism cooperation, the police cooperation within the framework of international organizations and cooperation at the bilateral and small multilateral level has not really meet the current challenges. The solutions offered in this paper are 4 ways to improve counter-terrorism police cooperation in South Asia and Southeast Asia: build a comprehensive and efficient counter-terrorism police cooperation mechanism, a stable and practical coordination mechanism, a joint counter-terrorism intelligence fusion center, a quality and level counter-terrorism police training mechanism of South Asia and Southeast Asia.

Modeling the Impact of HIV-1 Nucleic Acid Testing Among Symptomatic Adult Outpatients in Kenya.

Up to 69% of adults who acquire HIV in Kenya seek care before seroconversion, providing an important opportunity for early diagnosis and treatment. The Tambua Mapema Plus (TMP) trial tested a combined HIV-1 nucleic acid testing, linkage, treatment, and partner notification intervention for adults aged 18-39 years with symptoms of acute HIV infection presenting to health facilities in coastal Kenya. We estimated the potential impact of TMP on the Kenyan HIV epidemic. We developed an agent-based network model of HIV-1 transmission using TMP data and Kenyan statistics to estimate potential population-level impact of targeted facility-based testing over 10 years. Three scenarios were modeled: standard care [current use of provider-initiated testing and counseling (PITC)], standard HIV rapid testing scaled to higher coverage obtained in TMP (scaled-up PITC), and the TMP intervention. Standard care resulted in 90.7% of persons living with HIV (PLWH) knowing their status, with 67.5% of those diagnosed on treatment. Scaled-up PITC resulted in 94.4% of PLWH knowing their status and 70.4% of those diagnosed on treatment. The TMP intervention achieved 97.5% of PLWH knowing their status and 80.6% of those diagnosed on treatment. The percentage of infections averted was 1.0% (95% simulation intervals: -19.2% to 19.9%) for scaled-up PITC and 9.4% (95% simulation intervals: -8.1% to 24.5%) for TMP. Our study suggests that leveraging new technologies to identify acute HIV infection among symptomatic outpatients is superior to scaled-up PITC in this population, resulting in >95% knowledge of HIV status, and would reduce new HIV infections in Kenya.

BSA‑seq and genetic mapping reveals AhRt2 as a candidate gene responsible for red testa of peanut.

The candidate recessive gene AhRt2 responsible for red testa of peanut was identified through combined BSA-seq and linkage mapping approaches. The testa colorof peanuts (Arachis hypogaea L.) is an important trait, and those with red testa are particularly popular owing to the high-anthocyanin content. However, the identification of genes underlying the regulation of the red testa trait in peanut are rarely reported. In order to fine map red testa gene, two F2:4 populations were constructed through the cross of YZ9102 (pink testa) with ZH12 (red testa) and ZH2 (red testa). Genetic analysis indicated that red testa was controlled by a single recessive gene named as AhRt2 (Red testa gene 2). Using BSA-seq approach, AhRt2 was preliminary identified on chromosome 12, which was further mapped to a 530-kb interval using 220 recombinant lines through linkage mapping. Furthermore, functional annotation, expression profiling, and the analyses of sequence variation confirmed that the anthocyanin reductase namely (Arahy.IK60LM) was the most likely candidate gene for AhRt2. It was found that a SNP in the third exon of AhRt2 altered the encoding amino acids, and was associated with red testa in peanut. In addition, a closely linked molecular marker linked with red testa trait in peanut was also developed for future studies. Our results provide valuable insight into the molecular mechanism underlying peanut testa color and present significant diagnostic marker resources for marker-assisted selected breeding in peanut.