Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in Scn5a-1798insD mice.

AIMS: Patients with mutations in SCN5A encoding NaV1.5 often display variable severity of electrical and structural alterations, but the underlying mechanisms are not fully elucidated. We here investigate the combined modulatory effect of genetic background and age on disease severity in the Scn5a1798insD/+ mouse model. METHODS AND RESULTS: In vivo electrocardiogram and echocardiograms, ex vivo electrical and optical mapping, and histological analyses were performed in adult (2-7 months) and aged (8-28 months) wild-type (WT) and Scn5a1798insD/+ (mutant, MUT) mice from the FVB/N and 129P2 inbred strains. Atrio-ventricular (AV) conduction, ventricular conduction, and ventricular repolarization are modulated by strain, genotype, and age. An aging effect was present in MUT mice, with aged MUT mice of both strains showing prolonged QRS interval and right ventricular (RV) conduction slowing. 129P2-MUT mice were severely affected, with adult and aged 129P2-MUT mice displaying AV and ventricular conduction slowing, prolonged repolarization, and spontaneous arrhythmias. In addition, the 129P2 strain appeared particularly susceptible to age-dependent electrical, functional, and structural alterations including RV conduction slowing, reduced left ventricular (LV) ejection fraction, RV dilatation, and myocardial fibrosis as compared to FVB/N mice. Overall, aged 129P2-MUT mice displayed the most severe conduction defects, RV dilatation, and myocardial fibrosis, in addition to the highest frequency of spontaneous arrhythmia and inducible arrhythmias. CONCLUSION: Genetic background and age both modulate disease severity in Scn5a1798insD/+ mice and hence may explain, at least in part, the variable disease expressivity observed in patients with SCN5A mutations. Age- and genetic background-dependent development of cardiac structural alterations furthermore impacts arrhythmia risk. Our findings therefore emphasize the importance of continued assessment of cardiac structure and function in patients carrying SCN5A mutations.

Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

Identification of genomic regions controlling spikelet degeneration under FRIZZLE PANICLE (FZP) defect genetic background in rice.

The FZP gene plays a critical role in the formation of lateral branches and spikelets in rice panicle architecture. This study investigates the qSBN7 allele, a hypomorphic variant of FZP, and its influence on panicle architectures in different genetic backgrounds. We evaluated two backcross inbred lines (BILs), BC5_TCS10sbn and BC3_TCS10sbn, each possessing the homozygous qSBN7 allele but demonstrating differing degrees of spikelet degeneration. Our analysis revealed that BC5_TCS10sbn had markedly low FZP expression, which corresponded with an increase in axillary branches and severe spikelet degeneration. Conversely, BC3_TCS10sbn exhibited significantly elevated FZP expression, leading to fewer secondary and tertiary branches, and consequently decreased spikelet degeneration. Compared to BC5_TCS10sbn, BC3_TCS10sbn carries three additional chromosomal substitution segments from its donor parent, IR65598-112-2. All three segments significantly enhance the expression of FZP and reduce the occurrence of tertiary branch and spikelet degeneration. These findings enhance our understanding of the mechanisms regulating FZP and aid rice breeding efforts.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

Characterization of chromosomal segment substitution lines developed in the genetic background of rice variety K 343.

In this study, BC3F2 convergent population [(K343*3/RML22 × K343*3/DHMAS) × K343] was constructed by marker-assisted backcross breeding using K343 as the recurrent parent. DHMAS and RML22 were used as donor parents for the rice blast resistance genes Pi54 and Pi9, respectively. The population was first characterized using GGT 2.0 software, which showed 96.7% of the recurrent genome recovery covering 13953.6 cM, while DHMAS and RML22 showed 1.6% (235.5 cM) and 1.2% (177.1 cM) introgression respectively. The chromosomal segment substitution lines (CSSLs) were then identified using CSSL Finder software. A total of 36 CSSLs were identified, including 22 for DHMAS/K343 and 14 for RML22/K343. Introgression rates for donor substituted segments in DHMAS/K343 CSSLs ranged from 0.54% to 5.99%, with donor coverage of 44.5%, while in RML22/K343 CSSLs, introgression rates ranged from 0.54% to 4.75%, with donor coverage of 24.5%. The identified CSSLs would be a valuable genetic pool and could be used as genomic resources for the discovery and mapping of important genes and QTLs in rice genetic improvement.

Genetic Background of Blood ß-Hydroxybutyrate Acid Concentrations in Early-Lactating Holstein Dairy Cows Based on Genome-Wide Association Analyses.

Ketosis is a common metabolic disorder in the early lactation of dairy cows. It is typically diagnosed by measuring the concentration of ß-hydroxybutyrate (BHB) in the blood. This study aimed to estimate the genetic parameters of blood BHB and conducted a genome-wide association study (GWAS) based on the estimated breeding value. Phenotypic data were collected from December 2019 to August 2023, comprising blood BHB concentrations in 45,617 Holstein cows during the three weeks post-calving across seven dairy farms. Genotypic data were obtained using the Neogen Geneseek Genomic Profiler (GGP) Bovine 100 K SNP Chip and GGP Bovine SNP50 v3 (Illumina Inc., San Diego, CA, USA) for genotyping. The estimated heritability and repeatability values for blood BHB levels were 0.167 and 0.175, respectively. The GWAS result detected a total of ten genome-wide significant associations with blood BHB. Significant SNPs were distributed in Bos taurus autosomes (BTA) 2, 6, 9, 11, 13, and 23, with 48 annotated candidate genes. These potential genes included those associated with insulin regulation, such as INSIG2, and those linked to fatty acid metabolism, such as HADHB, HADHA, and PANK2. Enrichment analysis of the candidate genes for blood BHB revealed the molecular functions and biological processes involved in fatty acid and lipid metabolism in dairy cattle. The identification of novel genomic regions in this study contributes to the characterization of key genes and pathways that elucidate susceptibility to ketosis in dairy cattle.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Reproductive system, temperature, and genetic background effects in experimentally evolving populations of Caenorhabditis elegans.

Experimental evolution (EE) is a powerful research framework for gaining insights into many biological questions, including the evolution of reproductive systems. We designed a long-term and highly replicated EE project using the nematode C. elegans, with the main aim of investigating the impact of reproductive system on adaptation and diversification under environmental challenge. From the laboratory-adapted strain N2, we derived isogenic lines and introgressed the fog-2(q71) mutation, which changes the reproductive system from nearly exclusive selfing to obligatory outcrossing, independently into 3 of them. This way, we obtained 3 pairs of isogenic ancestral populations differing in reproductive system; from these, we derived replicate EE populations and let them evolve in either novel (increased temperature) or control conditions for over 100 generations. Subsequently, fitness of both EE and ancestral populations was assayed under the increased temperature conditions. Importantly, each population was assayed in 2-4 independent blocks, allowing us to gain insight into the reproducibility of fitness scores. We expected to find upward fitness divergence, compared to ancestors, in populations which had evolved in this treatment, particularly in the outcrossing ones due to the benefits of genetic shuffling. However, our data did not support these predictions. The first major finding was very strong effect of replicate block on populations' fitness scores. This indicates that despite standardization procedures, some important environmental effects were varying among blocks, and possibly compounded by epigenetic inheritance. Our second key finding was that patterns of EE populations' divergence from ancestors differed among the ancestral isolines, suggesting that research conclusions derived for any particular genetic background should never be generalized without sampling a wider set of backgrounds. Overall, our results support the calls to pay more attention to biological variability when designing studies and interpreting their results, and to avoid over-generalizations of outcomes obtained for specific genetic and/or environmental conditions.

A small proportion of Zebu genetic background in crossbred calves may not be enough to improve resistance against natural bovine Babesia spp. infections.

The main objective of cattle breeders in tropical and subtropical regions is to acquire animals with taurine-productive traits adapted to the broad weather range of these regions. However, one of the main challenges on using taurine genetics in these areas is the high susceptibility of these animals to tick-borne diseases. Consequently, the present study evaluated from 10 November 2021-19 April 2022, the over 13 assessments, the Babesia bovis and Babesia bigemina DNA loads and the IgG anti-B. bovis and anti-B. bigemina levels in Angus (n = 17, 100% Taurine) and Ultrablack (n = 14, ∼82% taurine and 18% Zebu) calves. Data were analyzed using a multivariate mixed model with repeated measures of the same animal including the fixed effects of evaluation, genetic group, sex, Babesia spp., and their interactions. The repeatability values were estimated from the (co)variances matrix and expressed for each species. The correlations between the DNA loads (CNlog) and IgG titers (S/P) values for the two species were also estimated using the same model. Regarding the specific IgG antibody titers for both Babesia spp., no significant differences were observed between the two genetic groups. However, for B. bovis and B. bigemina DNA loads, Ultrablack calves presented significantly higher values than Angus calves. Under the conditions evaluated in this study, our findings suggest that the low percentage of Zebu genetic in the Ultrablack breed was insufficient to improve resistance against babesiosis. Further studies must demonstrate if the low percentages of Zebu genetics in Taurine breeds can modify the susceptibility to babesiosis infections.

Spatio-temporal distribution and genetic background of elastic proteins inside the chitin/chitosan matrix of insects including their functional significance for locomotion.

In insects, cuticle proteins interact with chitin and chitosan of the exoskeleton forming crystalline, amorphic or composite material structures. The biochemical and mechanical composition of the structure defines the cuticle's physical properties and thus how the insect cuticle behaves under mechanical stress. The tissue-specific ratio between chitin and chitosan and its pattern of deacetylation are recognized and interpreted by cuticle proteins depending on their local position in the body. Despite previous research, the assembly of the cuticle composites in time and space including its functional impact is widely unexplored. This review is devoted to the genetics underlying the temporal and spatial distribution of elastic proteins and the potential function of elastic proteins in insects with a focus on Resilin in the fruit fly Drosophila. The potential impact and function of localized patches of elastic proteins is discussed for movements in leg joints, locomotion and damage resistance of the cuticle. We conclude that an interdisciplinary research approach serves as an integral example for the molecular mechanisms of generation and interpretation of the chitin/chitosan matrix, not only in Drosophila but also in other arthropod species, and might help to synthesize artificial material composites.

Impact of genetic background as a risk factor for atherosclerotic cardiovascular disease: A protocol for a nationwide genetic case-control (CV-GENES) study in Brazil.

Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).

Genetic Background of Acute Heart Rate Response to Exercise.

The acute heart rate response (AHRR) to physical activity, which refers to the change in heart rate during and after exercise, has been associated with cardiovascular and all-cause mortality. Previous studies have shown that AHRR is significantly determined by genetics in addition to environmental and lifestyle factors. The aim of this study was to investigate the genetic background of AHRR by analysing ten single nucleotide polymorphisms (SNPs) associated with leisure-time physical activity (LTPA) in 620 samples from the Hungarian population. The AHRR can be characterised as the difference between post-exercise and resting heart rate, i.e., the delta heart rate (ΔHR) defined by the YMCA 3 min step test, with a lower value indicating better cardiovascular fitness. The association of SNPs with ΔHR was analysed both separately and in combination using an optimised polygenic score (oPGS). The results showed that five SNPs (rs10252228, rs459465, rs6022999, rs8097348, and rs12405556) had at least nominally significant (p < 0.05) individual associations with ΔHR. After optimizing the PGS, a cumulative effect was observed for eight SNPs (rs6022999, rs12405556, rs459465, rs10252228, rs8097348, rs10887741, rs12612420, and rs7023003) that had a strong and statistically significant association with ΔHR (B = -2.51, 95% CI: -3.46--1.76; p = 2.99 × 10-9). Of the four main domains of physical activity, the oPGS showed a significant positive association only with LTPA (B = 84.60; 95%CI: 25.23-143.98; p = 0.005). In conclusion, our results suggest that the SNPs we investigated influence individual leisure-time physical activity, mediated by their effects on the acute heart rate response.

Genetic background modulates the effect of glucocorticoids on proliferation, differentiation and myelin formation of oligodendrocyte lineage cells.

Anxiety disorders are prevalent mental disorders. Their predisposition involves a combination of genetic and environmental risk factors, such as psychosocial stress. Myelin plasticity was recently associated with chronic stress in several mouse models. Furthermore, we found that changes in both myelin thickness and node of Ranvier morphology after chronic social defeat stress are influenced by the genetic background of the mouse strain. To understand cellular and molecular effects of stress-associated myelin plasticity, we established an oligodendrocyte (OL) model consisting of OL primary cell cultures isolated from the C57BL/6NCrl (B6; innately non-anxious and mostly stress-resilient strain) and DBA/2NCrl (D2; innately anxious and mostly stress-susceptible strain) mice. Characterization of naïve cells revealed that D2 cultures contained more pre-myelinating and mature OLs compared with B6 cultures. However, B6 cultures contained more proliferating oligodendrocyte progenitor cells (OPCs) than D2 cultures. Acute exposure to corticosterone, the major stress hormone in mice, reduced OPC proliferation and increased OL maturation and myelin production in D2 cultures compared with vehicle treatment, whereas only OL maturation was reduced in B6 cultures. In contrast, prolonged exposure to the synthetic glucocorticoid dexamethasone reduced OPC proliferation in both D2 and B6 cultures, but only D2 cultures displayed a reduction in OPC differentiation and myelin production. Taken together, our results reveal that genetic factors influence OL sensitivity to glucocorticoids, and this effect is dependent on the cellular maturation stage. Our model provides a novel framework for the identification of cellular and molecular mechanisms underlying stress-associated myelin plasticity.

Biotransformation of the azo dye reactive orange 16 by Aspergillus flavus A5P1: Performance, genetic background, pathway, and mechanism.

This study reports the strain Aspergillus flavus A5P1 (A5P1), which is with the capable of degrading the azo dye reactive orange 16 (RO16). The mechanism of RO16 degradation by A5P1 was elucidated through genomic analysis, enzymatic analysis, degradation pathway analysis and oxidative stress analysis. Strain A5P1 exhibited aerobic degradation of RO16, with optimal degradation at an initial pH of 3.0. Genomic analysis indicates that strain A5P1 possesses the potential for acid tolerance and degradation of azo dye. Enzymatic analysis, combined with degradation product analysis, demonstrated that extracellular laccase, intracellular lignin peroxidase, and intracellular quinone reductase were likely key enzymes in the RO16 degradation process. Oxidative stress analysis revealed that cell stress responses may participate in the RO16 biotransformation process. The results indicated that the biotransformation of RO16 may involves biological processes such as transmembrane transport of RO16, cometabolism of the strain with RO16, and cell stress responses. These findings shed light on the biodegradation of RO16 by A5P1, indicating A5P1's potential for environmental remediation.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Translation variation across genetic backgrounds reveals a post-transcriptional buffering signature in yeast.

Gene expression is known to vary among individuals, and this variability can impact the phenotypic diversity observed in natural populations. While the transcriptome and proteome have been extensively studied, little is known about the translation process itself. Here, we therefore performed ribosome and transcriptomic profiling on a genetically and ecologically diverse set of natural isolates of the Saccharomyces cerevisiae yeast. Interestingly, we found that the Euclidean distances between each profile and the expression fold changes in each pairwise isolate comparison were higher at the transcriptomic level. This observation clearly indicates that the transcriptional variation observed in the different isolates is buffered through a phenomenon known as post-transcriptional buffering at the translation level. Furthermore, this phenomenon seemed to have a specific signature by preferentially affecting essential genes as well as genes involved in complex-forming proteins, and low transcribed genes. We also explored the translation of the S. cerevisiae pangenome and found that the accessory genes related to introgression events displayed similar transcription and translation levels as the core genome. By contrast, genes acquired through horizontal gene transfer events tended to be less efficiently translated. Together, our results highlight both the extent and signature of the post-transcriptional buffering.

Association of Genetic Markers with the Risk of Early-Onset Breast Cancer in Kazakh Women.

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10-6) and MGAT5 gene (p = 8.4 × 10-6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10-4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction.

Transplantable Subcutaneous Tumor Models.

Mouse tumor models are essential in cancer research, especially in elucidating malignancy, developing prevention, diagnosis, and new therapeutic approaches. Nowadays, due to standardized ways of maintaining animal colonies and the availability of mouse strains with known genetic backgrounds and approaches to reduce the variability of tumor size between animals, transplantable mouse tumor models can be widely used in translational cancer research. Here, we describe the induction of different subcutaneous tumor models in mice, in particular xenograft and syngeneic that can be used as experimental tumor models.