Genome-wide Single Nucleotide Polymorphism Research Articles

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury

Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20's enzyme function and increase NF- κB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20's anti-inflammatory function in an NF- κB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- κB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- κB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3+ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.

Genome-wide SNP analyses reveal a substantial gene flow and isolated-genetic structure of sea cucumber Holothuria leucospilota populations in Western Central Pacific

The black sea cucumber Holothuria leucospilota is a commercially exploited species in the Western and Central Pacific region including Australia and Vietnam, where it has been overfished. There is interest to develop captive breeding, sea ranching and restocking programs for H. leucospilota. However, the wide distribution of this species could lead to genetic structure among site, which needs to be considered for responsible genetic management for example, restocking. This is the first study to investigate population genetics in H. leucospilota, between Australia and Vietnam, using single nucleotide polymorphisms (SNPs). The results indicated that there was high gene flow (Nm > 4) and genetic similarities among three Vietnamese populations, which inferred a high panmictic stock structure in Vietnam. Less gene flow (Nm > 1) was indicated between Vietnam and Mooloolaba (Eastern Australia) populations, and there was a significant genetic differentiation among any Vietnamese populations and Mooloolaba population (FST from 0.034 to 0.043; P < 0.05). Surprisingly, there was a major genetic difference (FST > 0.2) and a restricted gene flow (Nm <1) between Darwin (Northern Australia) population and other sea cucumber populations studied (Vietnam and Eastern Australia), which revealed a genetic break/divergence in Darwin. Based on these findings, we can propose that the Vietnamese sea cucumber stocks be considered as a single genetic stock with concordant implications for genetic management. We consider whether the genetic differences in the Darwin stock arise from bottlenecking and are not reflective of adaptive differences. In summary, the results from this study provide basic genetic information on H. leucospilota populations, that would help to design restocking management plans, genetic conservation initiatives and sea ranching programs for H. leucospilota.

Genomic insights of evolutionary divergence and life history innovations in Antarctic brittle stars.

Understanding the drivers of evolutionary innovation provides a crucial perspective of how evolutionary processes unfold across taxa and ecological systems. It has been hypothesised that the Southern Ocean provided ecological opportunities for novelty in the past. However, the drivers of innovation are challenging to pinpoint as the evolutionary genetics of Southern Ocean fauna are influenced by Quaternary glacial-interglacial cycles, oceanic currents and species ecology. Here we examined the genome-wide single nucleotide polymorphisms of the Southern Ocean brittle stars Ophionotus victoriae (five arms, broadcaster) and O. hexactis (six arms, brooder). We found that O. victoriae and O. hexactis are closely-related species with interspecific gene flow. During the late Pleistocene, O. victoriae likely persisted in a connected deep water refugium and in situ refugia on the Antarctic continental shelf and around Antarctic islands; O. hexactis persisted exclusively within in situ island refugia. Within O. victoriae, contemporary gene flow linking to the Antarctic Circumpolar Current, regional gyres and other local oceanographic regimes was observed. Gene flow connecting West and East Antarctic islands near the Polar Front was also detected in O. hexactis. A strong association was detected between outlier loci and salinity in O. hexactis. Both O. victoriae and O. hexactis are associated with genome-wide increase in alleles at intermediate-frequencies; the alleles associated with this peak appear to be species specific, and these intermediate-frequency variants are far more excessive in O. hexactis. We hypothesise that the peak in alleles at intermediate frequencies could be related to adaptation in the recent past, linked to evolutionary innovations of increase in arm number and a switch to brooding from broadcasting, in O. hexactis.

Blood cell traits and risk of glaucoma: A two-sample mendelian randomization study.

Importance: Glaucoma is the second leading cause of blindness in the world. The causal direction and magnitude of the association between blood cell traits and glaucoma is uncertain because of the susceptibility of observational studies to confounding and reverse causation. Objective: To explore whether there is a causal relationship of blood cell traits including white blood cell (WBC) count (WBCC) and its subtypes [basophil cell count (BASO), monocyte cell count (MONO), lymphocyte cell count (LYMPH), eosinophil cell count (EOS), neutrophil cell count (NEUT)], red blood cell (RBC) count (RBCC), red blood distribution width (RDW), platelet count (PLT), and plateletcrit (PCT) on glaucoma risk. Methods: A two-sample Mendelian randomization (MR) analysis was conducted. Genome-wide significant single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) on human blood cell traits were utilized as exposure instruments and the dataset for outcome was from the GWAS summary data of glaucoma. In the univariable MR analysis, we examined the association between genetic evidence of blood cell traits and glaucoma. To further investigate the potential causal mechanisms underlying the observed association, we performed multivariable MR analysis with three models, taking into account the mediator effect of inflammation and oxidative stress. According to Bonferroni-corrected for the 10 exposures in 3 methods, the MR study yielded a statistically significant p-value of 0.0017. Results: Genetically BASO, PCT, LYMPH, and PLT were potentially positively associated with glaucoma in the European ancestry [BASO: Odds ratio (OR) = 1.00122, 95% confidence interval (CI), 1.00003-1.00242, p = 0.045; PCT: OR = 1.00078, 95% CI, 1.00012-1.00143, p = 0.019; LYMPH: OR = 1.00076, 95% CI, 1.00002-1.00151, p = 0.045; PLT: OR = 1.00065, 95% CI, 1.00006-1.00123, p = 0.030], There was insufficient evidence to support a causal association of MONO, NEUT, EOS, WBCC, RBCC and RDW (MONO: OR = 1.00050, p = 0.098; NEUT: OR = 1.00028, p = 0.524; EOS: OR = 1.00020, p = 0.562; WBCC: OR = 1.00008, p = 0.830; RBCC: OR = 0.99996, p = 0.920; RDW: OR = 0.99987, p = 0.734) with glaucoma. The multivariable MR with model 1, 2, and 3 demonstrated that BASO, PCT, LYMPH, and PLT were still potentially genetically associated with the risk of glaucoma. Conclusion: Our study reveals a genetic predisposition to higher LYMPH, BASO, PLT, and PCT are associated with a higher risk of glaucoma, whereas WBCC, MONO, EOS, NEUT, RBCC, and RDW are not associated with the occurrence of glaucoma. This finding also supports previous observational studies associating immune components with glaucoma, thus provide guidance on the predication and prevention for glaucoma.

Population genetic structure of the maize weevil, Sitophilus zeamais, in southern Mexico.

The maize weevil, Sitophilus zeamais, is a ubiquitous pest of maize and other cereal crops worldwide and remains a threat to food security in subsistence communities. Few population genetic studies have been conducted on the maize weevil, but those that exist have shown that there is very little genetic differentiation between geographically dispersed populations and that it is likely the species has experienced a recent range expansion within the last few hundred years. While the previous studies found little genetic structure, they relied primarily on mitochondrial and nuclear microsatellite markers for their analyses. It is possible that more fine-scaled population genetic structure exists due to local adaptation, the biological limits of natural species dispersal, and the isolated nature of subsistence farming communities. In contrast to previous studies, here, we utilized genome-wide single nucleotide polymorphism data to evaluate the genetic population structure of the maize weevil from the southern and coastal Mexican states of Oaxaca and Chiapas. We employed strict SNP filtering to manage large next generation sequencing lane effects and this study is the first to find fine-scale genetic population structure in the maize weevil. Here, we show that although there continues to be gene flow between populations of maize weevil, that fine-scale genetic structure exists. It is possible that this structure is shaped by local adaptation of the insects, the movement and trade of maize by humans in the region, geographic barriers to gene flow, or a combination of these factors.

Genome-wide SNPs reveal recurrent waves of speciation in niche-pockets, in Europe's most venomous snake.

Within the Balkan Peninsula, topographic and climatic agents have promoted biodiversity and shaped the speciation history of many ectotherms. Here, we targeted an iconic European reptile, the nose-horned viper species-complex (Vipera ammodytes), and explored its spatial and temporal evolution. We (1) utilized genome-wide SNPs to infer genetic structure and build a time-calibrated species-tree, and (2) applied species distribution modeling (SDM) with niche-divergence tests among major phylogenomic clades. Geographically structured genetic diversity was found. Cycles of recurrent isolation and expansion during glacial-interglacial periods led to allopatric speciation and to secondary contacts and formation of multiple hybrid zones throughout the Balkan Peninsula. Deep divergence is still detected among populations separated by old and imminent biogeographical barriers (e.g. Pindos Mountain Range, the Cyclades islands etc.), but in most cases speciation is incomplete. At the other end of the speciation continuum, we recognize two well-differentiated lineages, currently lacking any evidence of gene-flow; one is distributed in the Northwestern Balkans and the other in the Southeastern Balkans, further expanding into Asia. Despite their split 5 Mya, there is no evidence of ecological divergence, as speciation probably occurred in niche-pockets of analogous environments. These two lineages probably represent different species, while V. transcaucasiana does not merit species-status. By comparing the genomic phylogenies to an updated mitochondrial one, we propose an evolutionary scenario that resolves all mito-nuclear conflicts, according to which the history of the V. ammodytes species-complex was shaped by complex processes, including a major event of introgressive hybridization with asymmetric mitochondrial capture.

Abstract 5234: Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea

Abstract Background: One of the major topics about colorectal cancer (CRC) is the core role of various immune cells against cancer cells. To comprehensively understand genetic basis of immune system underlying CRC progression, association of single-nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of immune-related genes were investigated with colorectal cancer survival. Methods: CRC patients enrolled in the Seoul National University Hospital with prospective follow-up were included in the study. From blood-derived DNA from CRC patients, genome-wide SNPs were genotyped by using the Korea Biobank Array (KoreanChip). 2,729 immune-related genes were selected from Ensembl, Gene Ontology (GO), and KEGG database and 37,398 mapped SNPs were extracted. SNP or PRS-based Cox proportional hazard models were fit for events of overall survival (OS) and progression-free survival (PFS) estimating effect sizes with hazard ratios (HRs). PRS was calculated as effect size weighted sum of risk alleles of individual patients and categorized into tertiles. To investigate enriched pathways, protein-protein interaction networks analysis was conducted. Bonferroni-corrected p-value (1.3 × 10−6) was used as statistically significance threshold. Results: Among 960 CRC patients, 154 (16.0%) occurred events of death and 245 (25.5%) of progression during the follow-up (median=1,698 days, range=7-2,563 days). For OS, a statistically significant associations were mapped to ACTR3B, ST6GAL1, COTL1, PRKCZ, and CAMK1D genes with the strongest SNP rs14808985 (HR=3.07, P=1.87 × 10−7). For PFS, marginal association was mapped to MECOM gene with the strongest SNP rs16854234 (HR=1.48, P=6.13 × 10−6). In PRS analysis, the highest tertile group showed the prominently increased risk for OS (HR=25.0, P&amp;lt;2.0 × 10−16 ) and PFS (HR=5.88, P&amp;lt;2.0 × 10−16 ) compared with the lowest group for a reference. In protein-protein interaction networks analysis, the strongest enrichments were shown in Th17 cell differentiation pathway for OS and in adherences junction for PFS. Conclusions: We identified novel predictive biomarker genetic variants in ACTR3B and MECOM genes associated with OS and PFS, respectively, among CRC patients. Additionally, we presented PRS as a useful biomarker for survival outcomes and suggested enriched biological pathways involved in CRC progression. These knowledges can promote the understanding of CRC survival and the development of immune-related therapeutic interventions for CRC patients in the future. Citation Format: Dabin Yun, Nan Song, Jin-Ah Sim, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5234.

Viral nervous necrosis resistance in gilthead sea bream (Sparus aurata) at the larval stage: heritability and accuracy of genomic prediction with different training and testing settings

BackgroundThe gilthead sea bream (Sparus aurata) has long been considered resistant to viral nervous necrosis (VNN), until recently, when significant mortalities caused by a reassortant nervous necrosis virus (NNV) strain were reported. Selective breeding to enhance resistance against NNV might be a preventive action. In this study, 972 sea bream larvae were subjected to a NNV challenge test and the symptomatology was recorded. All the experimental fish and their parents were genotyped using a genome-wide single nucleotide polymorphism (SNP) array consisting of over 26,000 markers.ResultsEstimates of pedigree-based and genomic heritabilities of VNN symptomatology were consistent with each other (0.21, highest posterior density interval at 95% (HPD95%): 0.1–0.4; 0.19, HPD95%: 0.1–0.3, respectively). The genome-wide association study suggested one genomic region, i.e., in linkage group (LG) 23 that might be involved in sea bream VNN resistance, although it was far from the genome-wide significance threshold. The accuracies (r) of the predicted estimated breeding values (EBV) provided by three Bayesian genomic regression models (Bayes B, Bayes C, and Ridge Regression) were consistent and on average were equal to 0.90 when assessed in a set of cross-validation (CV) procedures. When genomic relationships between training and testing sets were minimized, accuracy decreased greatly (r = 0.53 for a validation based on genomic clustering, r = 0.12 for a validation based on a leave-one-family-out approach focused on the parents of the challenged fish). Classification of the phenotype using the genomic predictions of the phenotype or using the genomic predictions of the pedigree-based, all data included, EBV as classifiers was moderately accurate (area under the ROC curve 0.60 and 0.66, respectively).ConclusionsThe estimate of the heritability for VNN symptomatology indicates that it is feasible to implement selective breeding programs for increased resistance to VNN of sea bream larvae/juveniles. Exploiting genomic information offers the opportunity of developing prediction tools for VNN resistance, and genomic models can be trained on EBV using all data or phenotypes, with minimal differences in classification performance of the trait phenotype. In a long-term view, the weakening of the genomic ties between animals in the training and test sets leads to decreased genomic prediction accuracies, thus periodical update of the reference population with new data is mandatory.

Genetic assessment improves conservation efforts for the critically endangered oceanic island endemic Hibiscus liliiflorus.

Hibiscus liliiflorus, endemic to the Indian Ocean island of Rodrigues, is one of the rarest plant species in the world; only 2 wild individuals remain. Previously, when 4 wild individuals remained, the Mauritian Wildlife Foundation (MWF) in Rodrigues propagated cuttings of them in their nursery, then planted seedlings produced in the nursery into 3 outplanted populations on the island. Our goals were to: 1) assess whether all 4 original wild genotypes are represented in the MWF nursery; 2) determine whether ex situ living collections at international botanical gardens maintain unique genotypes of H. liliiflorus; 3) assess whether nursery individuals have crossed or self-fertilized to produce seed and quantify their relative contributions to outplanted populations; and 4) provide recommendations for future conservation actions. We used a 2b-RADseq approach to produce 2,711 genome-wide single nucleotide polymorphisms (SNPs) from 98 samples. Genotype identity analysis, principal component analysis, and model-based clustering in STRUCTURE found 4 genotypes extant in Rodrigues but no unique genotypes in ex situ botanic garden collections. Only 3 genotypes are represented in the MWF nursery; the one remaining genotype is represented by an extant wild individual. Parentage analysis showed that seeds produced in the MWF nursery resulted from both self-fertilization and crossing between genotypes, a result supported by internal relatedness and hybrid index calculations. Each outplanted population is dominated by a subset of parental genotypes, and we propose actions to balance the parental contributions to outplanted populations. Our study highlights how genetic assessments of ex situ conservation projects help conserve critically endangered species.

RASA3 is a candidate gene in sickle cell disease-associated pulmonary hypertension and pulmonary arterial hypertension.

Pulmonary hypertension (PH)is associated with significant morbidity and mortality. RASA3 is a GTPase activatingprotein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associatedPH and pulmonary arterial hypertension (PAH).Cis-expression quantitative trait loci (eQTL)were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC)of three SCD cohorts. Genome-wide single nucleotide polymorphisms (SNPs)near or in the RASA3 gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA,AA).We found that PBMC RASA3 expression was lower in patients with SCD-associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD-associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

The evolutionary history of rice azaleas (Rhododendron tschonoskii alliance) involved niche evolution to a montane environment.

The formation of isolated montane geography on islands promotes evolution, speciation, and then radiation if there are ecological changes. Thus, investigating evolutionary histories of montane species and associated ecological changes may help efforts to understand how endemism formed in islands' montane floras. To explore this process, we investigated the evolutionary history of the Rhododendron tschonoskii alliance, which grows in montane environments of the Japanese archipelago and the Korean Peninsula. We studied the five species in the R. tschonoskii alliance and 30 outgroup species, using genome-wide single-nucleotide polymorphisms and cpDNA sequences, in association with environmental analyses. The monophyletic R. tschonoskii alliance diverged since the late Miocene. Species in the alliance currently inhabit a cold climatic niche that is largely different from that of the outgroup species. We observed clear genetic and niche differentiations between the taxa of the alliance. The association of the alliance's evolution with the formation of cooler climates on mountains indicates that it was driven by global cooling since the mid-Miocene and by rapid uplift of mountains since the Pliocene. The combination of geographic and climatic isolation promoted high genetic differentiation between taxa, which has been maintained by climatic oscillations since the Quaternary.

MP40-16 MICROULTRASOUND IN THE DETECTION OF THE INDEX LESION IN PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP40-16 MICROULTRASOUND IN THE DETECTION OF THE INDEX LESION IN PROSTATE CANCER Adriana Marcela Pedraza Bermeo, Raghav Gupta, Michael A. Gorin, Mani Menon, and Ashutosh Tewari Adriana Marcela Pedraza BermeoAdriana Marcela Pedraza Bermeo More articles by this author , Raghav GuptaRaghav Gupta More articles by this author , Michael A. GorinMichael A. Gorin More articles by this author , Mani MenonMani Menon More articles by this author , and Ashutosh TewariAshutosh Tewari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003278.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The natural history of PCa is driven by an index lesion (IL), which is often either the largest in size and/or highest in grade. By analyzing genome-wide single nucleotide polymorphisms and copy number variations, researchers have been able to show that the vast majority of metastatic prostate cancers have monoclonal origins. Therefore, the identification of IL plays a key role in treatment decision-making.Microultrasound (MUS) provides a resolution of up to 70 microns. Evidence seems to suggest comparable performance to mpMRI in the identification of clinically significant prostate cancer. The goal of our study is to evaluate the accuracy of a transrectal MUS for the detection of the IL in prostate cancer compared to mpMRI. METHODS: Two hundred and eighty-one patients who underwent robot-assisted radical prostatectomy (RARP) from June 2021 to May 2022 were included. All received mpMRI and MUS within three months prior to RARP. MUS was performed by experienced urologists blinded to mpMRI and biopsy results. The IL in the radical prostatectomy specimen was defined as the lesion with extraprostatic extension, the highest Gleason Score (GS), or the largest tumor volume if the GS was the same. A correlation between imaging and final pathology findings was performed. A descriptive statistical analysis is presented. RESULTS: The patients’ prostates were analyzed in 12 regions (anterior/posterior, right/left, apex/mid/base). A total of 3,372 regions were identified. Of these, 731 were involved by the IL. Compared to final pathology, MUS demonstrated a sensitivity, specificity, PPV, and NPV of 66%, 96%, 81%, and 92%, respectively, while mpMRI showed a sensitivity, specificity, PPV, and NPV of 66%, 97%, 87%, and 91%, respectively, for the detection of the IL. Most of the lesions missed by MUS were located in the anterior zone (62%). CONCLUSIONS: MUS has comparable diagnostic performance to mpMRI in identifying prostate cancer index lesion. MUS is less expensive, provides a real-time anatomic evaluation, and has no lag in the acquisition process. Prospective randomized trials are needed to verify our results. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e551 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adriana Marcela Pedraza Bermeo More articles by this author Raghav Gupta More articles by this author Michael A. Gorin More articles by this author Mani Menon More articles by this author Ashutosh Tewari More articles by this author Expand All Advertisement PDF downloadLoading ...

Implications of past and present genetic connectivity for management of the saltwater crocodile (Crocodylus porosus).

Effective management of protected species requires information on appropriate evolutionary and geographic population boundaries and knowledge of how the physical environment and life-history traits combine to shape the population structure and connectivity. Saltwater crocodiles (Crocodylus porosus) are the largest and most widely distributed of living crocodilians, extending from Sri Lanka to Southeast Asia and down to northern Australia. Given the long-distance movement capabilities reported for C. porosus, management units are hypothesised to be highly connected by migration. However, the magnitude, scale, and consistency of connection across managed populations are not fully understood. Here we used an efficient genotyping method that combines DArTseq and sequence capture to survey 3000 high-quality genome-wide single nucleotide polymorphisms from 1176 C. porosus sampled across nearly the entire range of the species in Queensland, Australia. We investigated historical and present-day connectivity patterns using fixation and diversity indices coupled with clustering methods and the spatial distribution of kin pairs. We inferred kinship using forward simulation coupled with a kinship estimation method that is robust to unspecified population structure. The results demonstrated that the C. porosus population has substantial genetic structure with six broad populations correlated with geographical location. The rate of gene flow was highly correlated with spatial distance, with greater differentiation along the east coast compared to the west. Kinship analyses revealed evidence of reproductive philopatry and limited dispersal, with approximately 90% of reported first and second-degree relatives showing a pairwise distance of <50 km between sampling locations. Given the limited dispersal, lack of suitable habitat, low densities of crocodiles and the high proportion of immature animals in the population, future management and conservation interventions should be considered at regional and state-wide scales.

Genetic dissection of complex traits in citrus: additive and non-additive genetic variances, inbreeding depression, and single-chromosome heritability

Genetic evaluation in breeding programs generally considers only additive genetic effects; however, non-additive genetic effects may also contribute to phenotypic and genotypic values. Furthermore, the distributions of causal variants in target traits are associated with the efficiency of accumulation of favorable alleles and are therefore important for plant breeding. Despite this, non-additive effects remain to be fully investigated in citrus. Moreover, although quantitative trait loci in citrus have been previously identified, they cannot adequately explain the genetic variance. Therefore, we attempted to estimate non-additive effects, such as dominance and additive-by-additive effects, together with directional dominance as an indicator of inbreeding depression and with chromosome heritability, which reflects the distributions of causal variants for fruit-quality traits in citrus. Phenotypic records of the fruit weight, sugar content, and acid content of 455 cultivars and their progeny were analyzed. Genomic relationship matrices for non-additive effects and single-chromosome genetic effects were constructed using 2319 genome-wide single nucleotide polymorphism loci, which were also used to evaluate directional dominance. These phenotype and genotype records were analyzed using genomic best linear unbiased prediction models. Through this analysis, we showed (1) overestimation of narrow-sense heritability due to substantial contributions of non-additive effects in the tested traits, (2) evidence of inbreeding depression in fruit weight, and (3) highly polygenic architectures in the tested traits. These findings could contribute to precise evaluation of genotypic values and the development of efficient breeding strategies.

Detection of Biallelic Loss of DNA Repair Genes in Formalin-Fixed, Paraffin-Embedded Tumor Samples Using a Novel Tumor-Only Sequencing Panel

Patient selection for synthetic lethal-based cancer therapy may be improved by assessment of gene-specific loss of heterozygosity (LOH) and biallelic loss of function (LOF). This report describes SyNthetic lethal Interactions for Precision Diagnostics (SNiPDx), a targeted next-generation sequencing (NGS) panel for detection of LOH and biallelic LOF alterations in 26 target genes focused on DNA damage response pathways, in tumor-only formalin-fixed, paraffin-embedded (FFPE) samples. NGS was performedacross all exons of these 26 genes and encompassed a total of 7632 genome-wide single-nucleotide polymorphisms on genomic DNA from 80 FFPE solid tumor samples. The Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing algorithm was optimized to assess tumor purity and copy number based on heterozygous single-nucleotide polymorphisms. SNiPDx demonstrated high sensitivity (95%) and specificity (91%) for LOH detection compared with whole genome sequencing. Positive agreement with local NGS-based testing in the detection of genetic alterations was 95%. SNiPDx detected 93% of biallelic ATM LOF mutations, 100% of ATM single-nucleotide variants and small insertions/deletions, and 100% of all ATM LOH status events identified by orthogonal NGS-based testing. SNiPDx is a novel, clinically feasible test for analysis of allelic status in FFPE tumor samples, which demonstrated high accuracy when compared with other NGS-based approaches in clinical use.

Genome-wide identification and annotation of SNPs and their mapping in candidate genes related to milk production and fertility traits in Badri cattle

This study was conducted in Badri cattle using a double digest restriction-site associated DNA sequencing approach. The study aimed to identify and annotate high confidence single nucleotide polymorphisms (SNPs) and their mapping in candidate genes related to production and fertility in dairy cattle. A total of 7,168,552 genome-wide SNPs were initially identified in Badri cattle by alignment with theBos indicusreference genome. After filtration of SNPs, 65,483 high confidence SNPs were retained and further used for downstream analysis. Annotation of high confidence SNPs revealed 99.197% SNPs had modifier impact, 0.326% SNPs were low impact, 0.036% were high impact, and 0.441% were moderate impact SNPs. Most SNPs in Badri cattle were found in intergenic, transcript and intronic regions. The candidate genes for milk production PRKCE, ABCG2, GHR, EPS8, CAST and NRXN1 were found to harbour maximum high confidence variants. Among candidate genes for fertility in cattle, ATP2B1, SOX5, WDR27, ARHGAP12, CACNA1D, ANKRD6, GRIA3, ZNF521 and CAST822 have maximum high confidence variants mapped in them. The SNPs found mapped in the candidate genes will be important genetic tools in the search for phenotype-modifying nucleotide changes and will aid in formulating relevant genetic improvement programmes for dairy cattle.

Taxonomic study of Scytosiphon (Phaeophyceae) from temperate coasts of Argentina.

Scytosiphon is a common intertidal genus widely distributed on temperate coasts worldwide. Recently, eight species have been delimited with molecular tools. Although S. lomentaria is the only species that predominates in the macroalgal literature of the Southwestern Atlantic Ocean (SwAO), unpublished molecular data obtained for a population study of S. lomentaria revealed hidden species diversity of Scytosiphon among the individuals collected from four localities at the SwAO. The aim of this study was to revise the identity and phylogenetic relationships of Scytosiphon from temperate coasts of the SwAO using DNA data. Thalli were collected from the Argentinean coast between 39° S and 43° S, from which cox1 and rbcL gene sequences were obtained. Phylogenies and haplotype networks were inferred and morphology of gametophytes was studied. Four species were recognized, S. lomentaria, S. promiscuus, S. shibazakiorum, and one species that belongs to a complex of species known as "Scytosiphon Atlantic complex." This complex was known to occur only in the North Atlantic, however, the results found in this study revealed that it has an extended distribution range that includes the southern hemisphere, where its populations have high genetic diversity and unique haplotypes. The morphological differences among the four species were subtle; denoting that previous Scytosiphon records from the SwAO attributed to the renowned S. lomentaria could represent different species. In addition, sex ratio and genome-wide single nucleotide polymorphisms (SNPs) analyses were done for populations of S. promiscuus presumably introduced to the SwAO, and the results indicated that they included female-dominant parthenogenetic populations, which were probably introduced from Japan.

Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations. In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2. In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p=2.0× 10-5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (pZ-test = 2.1× 10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR]=0.62, 95% confidence intervals [CI]=0.5-0.8, p= 3.4× 10-5 ) but not BRAF mutant (p= 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta=-0.037, standard error [SE]=0.017, p= 3.2× 10-2 ) and reduced RASAL2 expression in cultured fibroblasts (p= 1.6× 10-11 ). Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.

Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses. Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.