Region Haplotypes Research Articles

Association analysis between forkhead box E1 gene and non-syndromic cleft lip with or without cleft palate in Han Chinese population.

This study aims to explore the association between single nucleotide polymorphisms (SNPs) loci near the haplotype region hg19 chr9:100560865-100660865 of the forkhead box E1 (FOXE1) gene and the occurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P) in western Han Chinese population. In the first stage, our study recruited 159 NSCL/P patients and performed targeted region sequencing to screen SNPs loci near the haplotype region of the FOXE1 gene associated with NSCL/P. In the second stage, we selected 21 common SNPs and re-enrolled 1 000 non-syndromic cleft lip only (NSCLO) patients, 1 000 non-syndromic cleft palate only (NSCPO) patients, and 1 000 normal controls to verify the association. PLINK software was used to perform Hardy-Weinberg equilibrium (HWE) test. Association analysis for common variants, gene burden analysis for rare mutations, and function prediction of SNPs with non-synonymous mutations were performed using Mutation Taster and other software programs. In the first stage, 126 variants, including 76 single nucleotide variants and 50 insertion-deletions were identified. All the included SNPs confirmed to HWE, and the results of gene burden analysis and prediction of functional harmfulness for rare variants were not statistically significant. Association analysis showed that rs13292899 of the FOXE1 gene was significantly associated with NSCL/P (P=1.85E-27) and was also correlated with NSCLO (P=6.41E-23) and non-syndromic cleft lip with cleft palate (NSCLP) (P=2.36E-15) subtypes. In the validation phase, rs79268293 (P=0.013, P=0.022), rs10983951 (P=0.009 2, P=0.007 6), rs117227387 (P=0.009 2, P=0.007 6), rs3758250 (P=0.009 2, P=0.007 6), and rs116899397 (P=0.009 2, P=0.007 6) were significantly associated with NSCLO and NSCPO; rs13292899 (P=0.008 5), rs74606599 (P=0.008 3), rs143226042 (P=0.008 3), and rs117236550 (P=0.01) were associated with the occurrence of NSCLO; and rs12343182 (P=0.008 7), rs10119760 (P=0.012), rs10113907 (P=0.012), and rs13299924 (P=0.012) were associated with the occurrence of NSCPO. This study found a new susceptible SNP rs13292899 of the FOXE1 gene that is closely associated with NSCL/P and NSCLO subtype and 13 other SNPs associated with NSCLO or NSCPO.

Development of single nucleotide polymorphisms in key genes of taurine and betaine metabolism in Crassostrea hongkongensis and their association with content-related traits.

Taurine and betaine are important nutrients in Crassostrea hongkongensis and have many important biological properties. To investigate the characteristics of taurine and betaine contents and identify SNPs associated with traits in the C.hongkongensis, we cloned the full-length cDNA of key genes in taurine and betaine (unpublished data) metabolism, determined taurine and betaine content and gene expression in different tissues and months of specimen collection, and developed SNPs in the gene coding region. We cloned the full-length cDNA of cysteine dioxygenase (ChCDO) and cysteine sulfite decarboxylase (ChCSAD), which are key genes involved in taurine metabolism in C. hongkongensis, and found that betaine and taurine contents and the expression of key genes were regulated by seawater salinity. A total of 47 SNP markers were developed in the coding regions of ChCSAD, ChCDO, ChCDH, ChBADH, and ChBHMT using gene fragment resequencing and FLDAS-PCR. Through association analysis in a population of C. hongkongensis in the Maowei Sea, Guangxi, nine SNPs were found to be associated with taurine content, and one SNP was associated with betaine content. Haploid and linkage disequilibrium analyses showed that SNPs in ChCDO formed one linkage group with three haplotypes: ACACA, GTTTG, and GTACA. The average taurine content of the corresponding individuals was 873.88, 838.99, and 930.72 ng/g, respectively, indicating the GTACA haplotype has a significant advantage in terms of taurine content. We identified SNPs associated with taurine and betaine contents in C.hongkongensis for the first time, and found the GTACA haplotype in the ChCDO coding region has a significant advantage in taurine content. These loci and haplotypes can serve as potential molecular markers for the molecular breeding of C. hongkongensis.

The relationship between mitochondrial DNA haplotype and its copy number on body weight and morphological traits of Wuliangshan black-bone chickens.

Mitochondria play a pivotal role as carriers of genetic information through their circular DNA molecules. The rapid evolution of the D-loop region in mitochondria makes it an ideal molecular marker for exploring genetic differentiation among individuals within species and populations with close kinship. However, the influence of mtDNA D-loop region haplotypes and mtDNA copy numbers on phenotypic traits, particularly production traits in chickens, remains poorly understood. In this comprehensive study, we conducted D-loop region amplification and sequencing in the blood mitochondria of 232 female Wuliangshan black-bone chickens. Our investigation identified a total of 38 haplotypes, with a focus on 10 haplotypes that included more than five individuals. We meticulously analyzed the correlations between these haplotypes and a range of traits, encompassing body weight, tibial length, tibial circumference, body oblique length, chest width, and chest depth. The results unveiled significant disparities in specific tested traits across different haplotypes, indicating a tangible association between mtDNA haplotypes and traits in chickens. These findings underscore the potential impact of mitochondrial DNA variations on energy metabolism, ultimately leading to divergent chicken phenotypes. Furthermore, our examination revealed positive correlations between mtDNA copy numbers and tested traits for select haplotypes, while other haplotypes exhibited non-uniform relationships between traits and mtDNA copy numbers. In addition, phylogenetic analysis disclosed the involvement of two subspecies of red jungle chicken in the origin of Wuliangshan black-bone chickens. Consequently, our research contributes novel insights into mitochondrial genomic selection, augments comprehension of the roles played by haplotypes and mtDNA copy numbers in chicken population genetics and phylogenetic analysis, and furnishes fundamental data crucial for the preservation and provenance determination of black-bone chickens.

Influence of HLA-G 3' Untranslated Region Haplotypes and SNP +3422 Gene Variants as Host Genetic Factors on the Outcomes of SARS-CoV-2 Infection During Acute and Post-Acute Phases in a German Cohort.

HLA-G, an important immune-checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Since specific single-nucleotide polymorphisms (SNP) in the HLA-G 3'untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA-G expression, we analysed the contribution of these genetic variants as host factors in SARS-CoV-2 infection during acute and post-acute phases. HLA-G gene polymorphisms in the 3'UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID-19) cohort during acute SARS-CoV-2 infection (N = 505) and in the post-acute phase (N = 253). The HLA-G 3'UTR haplotype known as UTR-3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID-19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS-CoV-2 antibodies. In addition, the HLA-G 3'UTR haplotype UTR-7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long-COVID symptoms after SARS-CoV-2 infection. Our study highlights that due to the variability of the 3'UTR genetic background, HLA-G has the potential to contribute to the progression of SARS-CoV-2 infection, extending to the development of Long-COVID symptoms, despite the likely alterations in the microenvironment and associated HLA-G-specific regulatory elements over the course of the disease. By spotlighting HLA-G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID-19 are emphasised.

A genome-wide association study in Swedish colorectal cancer patients with gastric- and prostate cancer in relatives

BackgroundA complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who’s relatives had prostate-, and/or gastric cancer.MethodsThe GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case–control study.ResultsCandidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71–3.62 and p-values < 5 × 10–8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case–control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested.ConclusionsThis study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer.Graphical

Candidate Genetic Loci Modifying the Colorectal Cancer Risk Caused by Lifestyle Risk Factors.

65%-70% of colorectal cancer (CRC) cases are considered sporadic; they arise under the influence of environmental factors in individuals lacking a family history of CRC. Low-risk genetic variants are believed to contribute to CRC risk, in tandem with lifestyle factors. Six hundred sixteen nonfamilial Swedish CRC cases with at least 1 of the following 5 risk factors: smoking, excessive alcohol consumption, physical inactivity, adherence to an unhealthy diet, and excess body weight were included in this study. A control group consisting of 1,642 healthy individuals was used. Cases and controls were genotyped from blood samples at the Centre for Inherited Disease Research at Johns Hopkins University within the Colorectal Transdisciplinary Study research collaboration, using the Illumina Infinium OncoArray-500 K BeadChip. Five separate genome-wide haplotype association analyses were performed, one for each risk factor. Logistic regression models were used to estimate associations between haplotypes (exposure) and CRC (outcome) in cases with lifestyle risk factors vs controls. Haplotypes with an odds ratio >1 were considered candidate risk markers, denoting an area of interest in the genome. A significance threshold of P < 5 × 10-8 was used. We found 17 haplotype regions significantly associated with CRC in cases vs controls. Several regions included genes linked to inflammation and tumor promotion. We concluded that having certain genetic variants was associated with an increased risk of CRC compared with healthy controls among cases with known lifestyle risk factors. The interplay of lifestyle and genetic risk factors calls for further elucidation.

Association Study of 3-untranslated region Haplotype of Human leukocyte antigen-G Gene with Lupus.

Background: Human leukocyte antigen-G (HLA-G) is a pivotal protein involved in immune regulation and tolerance, while systemic lupus erythematosus (SLE) is a multifaceted autoimmune condition influenced by genetic and environmental factors. Research indicates that variations and mutations in HLA-G may impact SLE development. Objective: This study aimed to explore the relationship between polymorphisms in the 3'-untranslated region (UTR) of the HLA-G gene and SLE. Methods: DNA from 100 SLE patients and 100 controls was analyzed using polymerase chain reaction to amplify the target sequence. Allele and genotype frequencies were determined, and haplotypes were assessed using Haploview v.4.2 software, with linkage disequilibrium calculated. Results: Findings revealed that the +2960 Ins allele was significantly linked to SLE as a risk factor, with the Del allele showing a protective effect. In addition, the +3010C allele and +3187A allele were significantly associated with SLE at both allele and genotype levels. The +3142 GG homozygote was notably linked to SLE at the genotype level. Haplotype analysis identified UTR-2 haplotypes as risk factors for SLE, whereas the UTR-1 haplotype was protective, shedding light on genetic factors influencing SLE risk. Conclusion: This study underscores the importance of HLA-G gene 3'-UTR polymorphisms in SLE susceptibility, suggesting their potential as diagnostic or therapeutic targets.

Abstract 74: The rs1173771 Haplotype Associated with Blood Pressure Influences Chromatin Interactions Involving the Natriuretic Peptide Receptor 3 Gene Promoter

Determining the mechanisms of action for human blood pressure (BP) variants in the noncoding regions of genome, particularly large haplotypes containing multiple variants, is both critical and challenging. Human BP-associated rs1173771 locus includes a haplotype containing 11 single nucleotide polymorphisms (SNPs) spanning 17.4 kbp. The Linkage Disequilibrium (LD) region is approximately 126 kbp from the transcription start site of the closest protein-coding gene NPR3 (natriuretic peptide receptor 3). We used genome editing and region-capture Micro-C to examine the effect of the rs1173771 haplotype on the expression of neighboring genes and the chromatin mechanisms involved. The BP-elevating and -lowering haplotypes of rs1173771 locus were precisely reconstituted in human induced pluripotent stem cells (iPSCs) using an efficient, two-step genome editing technique. We then differentiated the edited iPSCs to endothelial (iEC) and vascular smooth muscle cells (iVSMC). The BP-elevating haplotype significantly (p ≤ 0.05) decreased NPR3 expression in iEC and iVSMC. Using region capture Micro-C targeting the rs1173771 haplotype region and the promoter regions of neighboring genes, we found in both iECs and iVSMCs, the BP-elevating rs1173771 haplotype increased chromatin contacts between the rs1173771 haplotype region and NPR3 promoter region, compared to the BP-lowering haplotype. Statistical comparison of chromatin interaction using HiCCompare showed the interactions of a genomic segment overlapping the 5’ end of the rs1173771 haplotype region with the NPR3 promoter region and a region just upstream of the promoter were 10 and 6 fold stronger (p.adj ≤ 0.001) in iECs with homozygous BP-elevating haplotype compared to BP-lowering haplotype. Similarly, in iVSMCs, the interaction of a genomic segment overlapping the rs1173771 haplotype region with a region just upstream of the NPR3 promoter was 4 fold stronger (p.adj = 0.02) for homozygous BP-elevating haplotype compared to BP-lowering haplotype. These results suggest that the BP-elevating rs1173771 haplotype interacts with the NPR3 promoter more strongly to suppress NPR3 expression, possibly through the recruitment of inhibitory protein complexes.

The application of haplotypes instead of species-level ranks modifies the interpretation of ecological preferences in lichen symbiont interactions in Parmelia

The analysis of the interaction between main bionts (mycobiont and photobiont) in the lichen symbiosis delivers substantial information about their preferences in the selection of symbiotic partners, and their ecological preferences. The selectivity in the Parmelia genus has been defined as strong so far. However, data on this lichen genus, which includes several widely distributed species, are biogeographically limited. Therefore, using specialization indicators and extended sampling, in this study, we estimated the interactions between the main bionts of selected Parmelia spp., using two levels of estimation (species/OTU and haplotype). A comparison of mycobiont-photobiont interactions at different levels showed that considering only mycobiont species and Trebouxia OTUs, greater specialization is found, while Parmelia species studied in this work present a more generalistic strategy in photobiont choice when haplotypes are considered. Despite the uneven sampling of Parmelia species, the interpretation of specialization within species and individuals of the genus leads to a more precise and accurate interpretation of their adaptation strategies. Furthermore, the data from P. sulcata indicate the existence of a different pool of compatible haplotypes in some geographical regions compared to neighboring areas. This observation suggests the potential influence of climatic factors.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

A common Alu insertion in the 3'UTR of TMEM106B is associated with risk of dementia.

Sequence variants in TMEM106B have been associated with an increased risk of developing dementia. As part of our efforts to generate a set of mouse lines in which we replaced the mouse Tmem106b gene with a human TMEM106B gene comprised of either a risk or protective haplotype, we conducted an in-depth sequence analysis of these alleles. We also analyzed transcribed TMEM106B sequences using RNA-seq data (AD Knowledge portal) and full genome sequences (1000 Genomes). We identified an AluYb8 insertion in the 3' untranslated region (3'UTR) of the TMEM106B risk haplotype. We found this AluYb8 insertion in every risk haplotype analyzed, but not in either protective haplotypes or in non-human primates. We conclude that this risk haplotype arose early in human development with a single Alu-insertion event within a unique haplotype context. This AluYb8 element may act as a functional variant in conferring an increased risk of developing dementia. We conducted an in-depth sequence analysis of (1) a risk and (2) a protective haplotype of the human TMEM106B gene. We also analyzed transcribed TMEM106B sequences using RNA-seq data (AD Knowledge Portal) and full genome sequences (1000 Genomes). We identified an AluYb8 insertion in the 3' untranslated region (3'UTR) of the TMEM106B risk haplotype. We found this AluYb8 insertion in every risk haplotype analyzed, but not in either protective haplotypes or in non-human primates. This AluYb8 element may act as a functional variant in conferring an increased risk of developing dementia.

Natural genetic diversity of the DBL domain of a novel member of the Plasmodium vivax erythrocyte binding-like proteins (EBP2) in the Amazon rainforest

In malaria parasites, the erythrocyte binding-like proteins (EBL) are a family of invasion proteins that are attractive vaccine targets. In the case of Plasmodium vivax, the widespread malaria parasite, blood-stage vaccines have been largely focused on a single EBL candidate, the Duffy binding-like domain (DBL) of the Duffy binding protein (DBPII), due to its well-characterized role in the reticulocyte invasion. A novel P. vivax EBL family member, the Erythrocyte binding protein (EBP2, also named EBP or DBP2), binds preferentially to reticulocytes and may mediate an alternative P. vivax invasion pathway. To gain insight into the natural genetic diversity of the DBL domain of EBP2 (region II; EBP2-II), we analyzed ebp2-II gene sequences of 71 P. vivax isolates collected in different endemic settings of the Brazilian Amazon rainforest, where P. vivax is the predominant malaria-associated species. Although most of the substitutions in the ebp2-II gene were non-synonymous and suggested positive selection, the results showed that the DBL domain of the EBP2 was much less polymorphic than that of DBPII. The predominant EBP2 haplotype in the Amazon region corresponded to the C127 reference sequence first described in Cambodia (25% C127-like haplotype). An overview of ebp2-II gene sequences available at GenBank (n = 352) from seven countries (Cambodia, Madagascar, Myanmar, PNG, South Korea, Thailand, Vietnam) confirmed the C127-like haplotype as highly prevalent worldwide. Two out of 43 haplotypes (5 to 20 inferred per country) showed a global frequency of 60%. The results presented here open new avenues of research pursuit while suggesting that a vaccine based on the DBL domain of EBP2 should target a few haplotypes for broad coverage.

GWAS and Transcriptomic Analysis Identify OsRING315 as a New Candidate Gene Controlling Amylose Content and Gel Consistency in Rice

Cooking quality is the main factor determining the market value of rice. Although several major genes and a certain number of QTLs controlling cooking quality have been identified, the genetic complexity and environmental susceptibility limit the further improvement for cooking quality by molecular breeding. This research conducted a genome-wide association study to elucidate the QTLs related to cooking quality including amylose content (AC), gel consistency (GC) and alkali spreading value (ASV) by using 450 rice accessions consisting of 300 indica and 150 japonica accessions in two distinct environments. A total of 54 QTLs were identified, including 25 QTLs for AC, 12 QTLs for GC and 17 QTLs for ASV. Among them, 10 QTLs were consistently observed by the same population in both environments. Six QTLs were co-localized with the reported QTLs or cloned genes. The Wx gene for AC and GC, and the ALK gene for ASV were identified in every population across the two environments. The qAC9-2 for AC and the qGC9-2 for GC were defined to the same interval. The OsRING315 gene, encoding an E3 ubiquitin ligase, was considered as the candidate gene for both qAC9-2 and qGC9-2. The higher expression of OsRING315 corresponded to the lower AC and higher GC. Three haplotypes of OsRING315 were identified. The Hap 1 mainly existed in the japonica accessions and had lower AC. The Hap 2 and Hap 3 were predominantly present in the indica accessions, associated with higher AC. Meanwhile, the GC of accessions harboring Hap 1 was higher than that of accessions harboring Hap 3. In addition, the distribution of the three haplotypes in several rice-growing regions was unbalanced. The three traits of cooking quality are controlled by both major and minor genes and susceptible to environmental factors. The expression level of OsRING315 is related to both AC and GC, and this gene can be a promising target in quality improvement by using the gene editing method. Moreover, the haplotypes of OsRING315 differentiate between indica and japonica, and reveal the differences in GC and AC between indica and japonica rice.

Effect of an endothelial regulatory module on plasma proteomics in exercising horses

Elite performing exercise requires an intricate modulation of the blood pressure to support the working muscles with oxygen. We have previously identified a genomic regulatory module that associates with differences in blood pressures of importance for elite performance in racehorses. This study aimed to determine the effect of the regulatory module on the protein repertoire. We sampled plasma from 12 Coldblooded trotters divided into two endothelial regulatory module haplotype groups, a sub-elite performing haplotype (SPH) and an elite performing haplotype (EPH), each at rest and exercise. The haplotype groups and their interaction were interrogated in two analyses, i) individual paired ratio analysis for identifying differentially abundant proteins of exercise (DAPE) and interaction (DAPI) between haplotype and exercise, and ii) unpaired ratio analysis for identifying differentially abundant protein of haplotype (DAPH). The proteomics analyses revealed a widespread change in plasma protein content during exercise, with a decreased tendency in protein abundance that is mainly related to lung function, tissue fluids, metabolism, calcium ion pathway and cellular energy metabolism. Furthermore, we provide the first investigation of the proteome variation due to the interaction between exercise and related blood pressure haplotypes, which this difference was related to a faster switch to the lipoprotein and lipid metabolism during exercise for EPH. The molecular signatures identified in the present study contribute to an improved understanding of exercise-related blood pressure regulation.

A GWAS in Swedish colorectal cancer families with gastric and prostate cancer.

e15644 Background: We have previously suggested a syndrome with increased risk for colorectal- and other cancers, primarily gastric- and prostate cancer. The data favoured this syndrome inherited as a complex disease. Therefore, we conducted a Genome Wide Association Study (GWAS) on colorectal cancer patients, who’s relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model.Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios (ORs) between 1.71-3.62 and p-values &lt; 5x10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of 122 colorectal cancer patients with gastric- and prostate cancer in their families identified 10 candidate variants from six of the loci in the haplotype regions to finally be tested in a nested case-control study of similar colorectal cancer cases and controls. Conclusions: There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. [Table: see text]

Physiological role and mechanisms of action for a long noncoding haplotype region.

Most common sequence variants associated with human traits are in noncoding regions of the genome, form haplotypes with other noncoding variants, and exhibit small effect sizes in the general population. Determining the physiological roles and mechanisms of action for these noncoding variants, particularly large haplotypes containing multiple variants, is both critical and challenging. To address this challenge, we developed an approach that integrates physiological studies in genetically engineered and phenotypically permissive animal models, precise editing of large haplotypes in human induced pluripotent stem cells (hiPSCs), and targeted chromatin conformation analysis. We applied this approach to examine the blood pressure associated rs1173771 locus, which includes a haplotype containing 11 single nucleotide polymorphisms (SNPs) spanning 17.4 kbp. Deleting the orthologous noncoding region in the genome of the Dahl salt-sensitive rat attenuated the salt-induced increase in systolic blood pressure by nearly 10 mmHg. This attenuation of hypertension appeared to be mediated by upregulation of the adjacent gene Npr3 (natriuretic peptide receptor 3) in arteries, enhancing vasodilation. The blood pressure-elevating and -lowering haplotypes were precisely reconstituted in hiPSCs using an efficient, two-step genome editing technique. The blood pressure-elevating haplotype decreased NPR3 expression in endothelial cells and vascular smooth muscle cells derived from the edited, isogenic hiPSCs. The influence of the haplotype was partially recapitulated by the sentinel SNP rs1173771. Additionally, the blood pressure-elevating haplotype showed significantly greater chromatin interactions with the NPR3 promoter region. This study illustrates the feasibility of ascertaining the physiological roles and mechanisms of action for large noncoding haplotypes. Our efficient, integrated, and targeted approach can be applied to investigate other noncoding variants.

Genetic composition of green sea turtles (Chelonia mydas) at coastal feeding areas of Uruguay

The highly migratory and marine nature of species such as green sea turtles (Chelonia mydas) may hinder understanding of basic life history and impact ensuing management and conservation applications across their full range. To elucidate the linkages between juvenile green turtles foraging in coastal waters of Uruguay in the Southwestern Atlantic Ocean to their future nesting or feeding grounds, this study investigated their genetic composition . A total of 201 tissue samples were collected from turtles that had stranded or were intentionally captured for scientific research along the Uruguayan coast (ca. 33°–35°S) during two sampling periods (2003–2005 and 2009–2014). Samples were pooled for analysis. Twelve mitochondrial control region haplotypes and ten subhaplotypes were identified, all of which had been previously detected at Atlantic or Caribbean nesting beaches. Mixed Stock Analysis revealed that most turtles traced to the Ascension Island rookery, representing a substantial connection to the remote mid-Atlantic island thousands of kilometers distant. Other nesting areas, such as Guinea Bissau in Africa and Trindade Island in Brazil, represented less significant sources. There was no significant temporal or spatial genetic structure within Uruguayan waters, suggesting dispersion along this coast. Despite the geographic distance from the nesting beach, the significant connection to the Ascension Island rookery underscores the importance of considering rookery population size and ocean current influences in understanding source contributions. These findings emphasize the need for conservation efforts, including the maintenance of existing protected areas and the creation of new ones, to ensure the long-term conservation of green turtles connected to various nesting colonies and feeding grounds.

A common regulatory haplotype doubles lactoferrin concentration in milk

BackgroundBovine lactoferrin (Lf) is an iron absorbing whey protein with antibacterial, antiviral, and antifungal activity. Lactoferrin is economically valuable and has an extremely variable concentration in milk, partly driven by environmental influences such as milking frequency, involution, or mastitis. A significant genetic influence has also been previously observed to regulate lactoferrin content in milk. Here, we conducted genetic mapping of lactoferrin protein concentration in conjunction with RNA-seq, ChIP-seq, and ATAC-seq data to pinpoint candidate causative variants that regulate lactoferrin concentrations in milk.ResultsWe identified a highly-significant lactoferrin protein quantitative trait locus (pQTL), as well as a cislactotransferrin (LTF) expression QTL (cis-eQTL) mapping to the LTF locus. Using ChIP-seq and ATAC-seq datasets representing lactating mammary tissue samples, we also report a number of regions where the openness of chromatin is under genetic influence. Several of these also show highly significant QTL with genetic signatures similar to those highlighted through pQTL and eQTL analysis. By performing correlation analysis between these QTL, we revealed an ATAC-seq peak in the putative promotor region of LTF, that highlights a set of 115 high-frequency variants that are potentially responsible for these effects. One of the 115 variants (rs110000337), which maps within the ATAC-seq peak, was predicted to alter binding sites of transcription factors known to be involved in lactation-related pathways.ConclusionsHere, we report a regulatory haplotype of 115 variants with conspicuously large impacts on milk lactoferrin concentration. These findings could enable the selection of animals for high-producing specialist herds.

Evolutionary Diversity of Coxsackievirus A6 Causing Severe Hand, Foot, and Mouth Disease - China, 2012-2023.

Coxsackievirus A6 (CVA6) has emerged as a significant pathogen responsible for severe cases of hand, foot, and mouth disease (HFMD). This study aims to delineate the demographic characteristics and analyze the viral evolution of severe HFMD associated with CVA6, thereby assisting in its surveillance and management. In this investigation, 74 strains of CVA6 were isolated from samples collected from severe HFMD cases between 2012 and 2023. The VP1 gene sequences of CVA6 were amplified and analyzed to assess population historical dynamics and evolutionary characteristics using BEAST, DnaSP6, and PopART. A significant portion (94.4%) of severe CVA6-associated HFMD cases (51 out of 54, with 20 lacking age information) were children under 5 years old. Among the 74 CVA6 strains analyzed, 72 belonged to the D3a sub-genotype, while only two strains were D2 sub-genotype. The average genetic distance between VP1 sequences prior to 2015 was 0.027, which increased to 0.051 when compared to sequences post-2015. Historical population dynamics analysis indicated three significant population expansions of severe CVA6-associated HFMD during 2012-2013, 2013-2014, and 2019-2020, resulting in the formation of 65 distinct haplotypes. Consistent with the MCC tree findings, transitioning between regional haplotypes required multiple base substitutions, showcasing an increase in population diversity during the evolutionary process (from 14 haplotypes in 2013 to 55 haplotypes over the subsequent decade). CVA6, associated with severe HFMD, is evolving and presents a risk of outbreak occurrence. Thus, enhanced surveillance of severe HFMD is imperative.

Genetic investigation of Cuvier's beaked whale, Ziphius cavirostris, along the coast of Türkiye and Northern Cyprus, based on mtDNA sequences

Abstract The Cuvier's beaked whale, Ziphius cavirostris, is a cosmopolitan species and the only beaked whale species commonly found in the Mediterranean Sea. Five strandings of Cuvier's beaked whale were reported along the Aegean/Mediterranean Seas coasts of Türkiye and northern coast of Cyprus in 2016–2017. Mitochondrial DNA (mtDNA) control region (430–444 bp) and cytochrome b (cytb) (382–424 bp) sequences each revealed two different haplotypes (four out of five individuals had the same haplotype for each locus) on these stranded animals. The control region haplotypes were identical to two previously identified haplotypes from the Ionian (Greece) and Adriatic (Croatia) Seas. Only one of the cytb haplotypes had previously been described from the Adriatic Sea (Italy) and the other one was detected for the first time. In a comparison of these haplotypes with Cuvier's beaked whale haplotypes previously reported from outside the Mediterranean Sea, the Mediterranean subpopulation shows genetic differentiation based upon the presence of two unique haplotypes. Additional mtDNA sequences from the Mediterranean Sea are needed for a better understanding of the genetic population structure of this species and to elaborate more concrete conservation measures.