With the emphasis on analysing genotype-by-environment interactions within the framework of genomic selection and genome-wide association analysis, there is an increasing demand for reliable tools ...that can be used to simulate large-scale genomic data in order to assess related approaches. We proposed a theory to simulate large-scale genomic data on genotype-by-environment interactions and added this new function to our developed tool GPOPSIM. Additionally, a simulated threshold trait with large-scale genomic data was also added. The validation of the simulated data indicated that GPOSPIM2.0 is an efficient tool for mimicking the phenotypic data of quantitative traits, threshold traits, and genetically correlated traits with large-scale genomic data while taking genotype-by-environment interactions into account. This tool is useful for assessing genotype-by-environment interactions and threshold traits methods.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to ...neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
Before the anthrax letter attacks of 2001, the developing field of microbial forensics relied on microbial genotyping schemes based on a small portion of a genome sequence. Amerithrax, the ...investigation into the anthrax letter attacks, applied high-resolution whole-genome sequencing and comparative genomics to identify key genetic features of the letters' Bacillus anthracis Ames strain. During systematic microbiological analysis of the spore material from the letters, we identified a number of morphological variants based on phenotypic characteristics and the ability to sporulate. The genomes of these morphological variants were sequenced and compared with that of the B. anthracis Ames ancestor, the progenitor of all B. anthracis Ames strains. Through comparative genomics, we identified four distinct loci with verifiable genetic mutations. Three of the four mutations could be directly linked to sporulation pathways in B. anthracis and more specifically to the regulation of the phosphorylation state of Spo0F, a key regulatory protein in the initiation of the sporulation cascade, thus linking phenotype to genotype. None of these variant genotypes were identified in single-colony environmental B. anthracis Ames isolates associated with the investigation. These genotypes were identified only in B. anthracis morphotypes isolated from the letters, indicating that the variants were not prevalent in the environment, not even the environments associated with the investigation. This study demonstrates the forensic value of systematic microbiological analysis combined with whole-genome sequencing and comparative genomics.
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD ...LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
Flowering is one of the most critical processes in the reproductive phenology in fruit trees including olive. Under Mediterranean climate, olive flowering period normally occurs from early to late ...spring. Therefore, flowering time could be affected by environmental conditions such as water availability and temperature, thus influencing flower quality as well. Previous works have demonstrated the effect of genotype and environment on olive flowering, but those factors have never been compared in a single study nor their interaction evaluated. In the present work, we used a multi-environment trial established in four different agro-climatic conditions of Andalucía, Southern Spain, to test the genetic and environmental influences on flowering timing (flowering period, full bloom period, and full bloom date) and flower quality (flower number, perfect flower number and perfect flower percentage). Most of the variability found for flowering phenology parameters was due to environmental influence. On the contrary, for flowering quality parameters, most of the variability was of a genetic nature. In all cases, the genotype-environment interaction was significant. In this sense, the genotype by environment effects biplot model used to analyse the interaction showed that most of the genotypes evaluated have low stability for most of the parameters evaluated, except ‘Picual’ for flowering phenology parameters and ‘Koroneiki’ for quality. This emphasize the benefits of multi-environment trials on olive in order to select the best genotypes adapted to different environments and as a tool to face the future variability of environmental conditions caused by the climate-warming scenario. In conclusion, multi-environment trials allowed to efficiently quantify the effects of genetic and environmental factors and of their interaction on flowering phenology and on flower quality in olive.
Objectives: Extended high-risk human papillomavirus (hrHPV) genotype testing has recently been introduced in routine cervical cancer screening. Changes in national and regional hrHPV genotype ...prevalence offer an objective baseline indicator of the future impact of mass HPV vaccination and HPV-based cervical screening. Methods: This retrospective study reports nationwide hrHPV genotyping results from July 2018 to June 2019 in 29 KingMed Diagnostics laboratories throughout China. Results: In total, 2,458,227 hrHPV genotyping results were documented from KingMed's nationwide laboratory database during the study period. The overall prevalence of hrHPV-positive results was 19.1%, with twin peaks for highest hrHPV infection rates in women younger than 30 years of age (22.0%) and 50 years of age and older (21.8%). The most frequently detected hrHPV genotypes were HPV-52 (4.7%), HPV-16 (3.4%), HPV-53 (2.5%), HPV-58 (2.4%), HPV-51 (2.0%), and HPV-68 (1.6%). Overall, hrHPV-positive results varied regionally from 15.3% to 24.4%. Conclusions: Nationwide hrHPV genotyping results from KingMed laboratories offer a baseline for measuring the future impact of large-scale HPV vaccination. High hrHPV infection rates in older (greater than or equal to 50 years) Chinese women likely reflect the limited extent of cervical screening in China. High rates of hrHPV infection and variable regional hrHPV genotype distribution may represent limiting factors for cost-effective implementation of hrHPV-based cervical screening in China. KEY WORDS HPV genotype; Cervical cancer; China; Prevalence
In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent ...offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes.
The phenotype of an individual can be affected not only by the individual's own genotypes, known as direct genetic effects (DGE), but also by genotypes of interacting partners, indirect genetic ...effects (IGE). IGE have been detected using polygenic models in multiple species, including laboratory mice and humans. However, the underlying mechanisms remain largely unknown. Genome-wide association studies of IGE (igeGWAS) can point to IGE genes, but have not yet been applied to non-familial IGE arising from "peers" and affecting biomedical phenotypes. In addition, the extent to which igeGWAS will identify loci not identified by dgeGWAS remains an open question. Finally, findings from igeGWAS have not been confirmed by experimental manipulation.
We leverage a dataset of 170 behavioral, physiological, and morphological phenotypes measured in 1812 genetically heterogeneous laboratory mice to study IGE arising between same-sex, adult, unrelated mice housed in the same cage. We develop and apply methods for igeGWAS in this context and identify 24 significant IGE loci for 17 phenotypes (FDR < 10%). We observe no overlap between IGE loci and DGE loci for the same phenotype, which is consistent with the moderate genetic correlations between DGE and IGE for the same phenotype estimated using polygenic models. Finally, we fine-map seven significant IGE loci to individual genes and find supportive evidence in an experiment with a knockout model that Epha4 gives rise to IGE on stress-coping strategy and wound healing.
Our results demonstrate the potential for igeGWAS to identify IGE genes and shed light into the mechanisms of peer influence.
Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate ...immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.
Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.
The median progression-free survival (PFS) for PHBR score < 0.5 vs. ≥ 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.
Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.
In the early 2000s, the global emergence of rotavirus (RVA) G12P8 genotype was noted, while G12P6 and G12P9 combinations remained rare in humans. This study aimed to characterize and phylogenetically ...analyze three Brazilian G12P9 and four G12P6 RVA strains from 2011 to 2020, through RT-PCR and sequencing, in order to enhance our understanding of the genetic relationship between human and animal-origin RVA strains. G12P6 strains displayed a DS-1-like backbone, showing a distinct genetic clustering. G12P6 IAL-R52/2020, IAL-R95/2020 and IAL-R465/2019 strains clustered with 2019 Northeastern G12P6 Brazilian strains and a 2018 Benin strain, whereas IAL-R86/2011 strain grouped with 2010 Northern G12P6 Brazilian strains and G2P4 strains from the United States and Belgium. These findings suggest an African genetic ancestry and reassortments with co-circulating American strains sharing the same DS-1-like constellation. No recent zoonotic reassortment was observed, and the DS-1-like constellation detected in Brazilian G12P6 strains does not seem to be genetically linked to globally reported intergenogroup G1/G3/G9/G8P8 DS-1-like human strains. G12P9 strains exhibited an AU-1-like backbone with two different genotype-lineage constellations: IAL-R566/2011 and IAL-R1151/2012 belonged to a VP3/M3.V Lineage, and IAL-R870/2013 to a VP3/M3.II Lineage, suggesting two co-circulating strains in Brazil. This genetic diversity is not observed elsewhere, and the VP3/M3.II Lineage in G12P9 strains seems to be exclusive to Brazil, indicating its evolution within the country. All three G12P9 AU-1-like strains were closely relate to G12P9 strains from Paraguay (2006–2007) and Brazil (2010). Phylogenetic analysis also highlighted that all South American G12P9 AU-1-like strains had a common origin and supports the hypothesis of their importation from Asia, with no recent introduction from globally circulating G12P9 strains or reassortments with local G12 strains P8 or P6. Notably, certain genes in the Brazilian G12P9 AU-1-like strains share ancestry with feline/canine RVAs (VP3/M3.II, NSP4/E3.IV and NSP2/N3.II), whereas NSP1/A3.VI likely originated from artiodactyls, suggesting a history of zoonotic transmission with human strains. This genomic data adds understanding to the molecular epidemiology of G12P6 and G12P9 RVA strains in Brazil, offering insights into their genetic diversity and evolution.
PDF
