Single nucleotide polymorphisms (SNPs) are useful markers for phylogenetic studies owing in part to their ubiquity throughout the genome and ease of collection. Restriction site associated DNA ...sequencing (RADseq) methods are becoming increasingly popular for SNP data collection, but an assessment of the best practises for using these data in phylogenetics is lacking. We use computer simulations, and new double digest RADseq (ddRADseq) data for the lizard family Phrynosomatidae, to investigate the accuracy of RAD loci for phylogenetic inference. We compare the two primary ways RAD loci are used during phylogenetic analysis, including the analysis of full sequences (i.e., SNPs together with invariant sites), or the analysis of SNPs on their own after excluding invariant sites. We find that using full sequences rather than just SNPs is preferable from the perspectives of branch length and topological accuracy, but not of computational time. We introduce two new acquisition bias corrections for dealing with alignments composed exclusively of SNPs, a conditional likelihood method and a reconstituted DNA approach. The conditional likelihood method conditions on the presence of variable characters only (the number of invariant sites that are unsampled but known to exist is not considered), while the reconstituted DNA approach requires the user to specify the exact number of unsampled invariant sites prior to the analysis. Under simulation, branch length biases increase with the amount of missing data for both acquisition bias correction methods, but branch length accuracy is much improved in the reconstituted DNA approach compared to the conditional likelihood approach. Phylogenetic analyses of the empirical data using concatenation or a coalescent-based species tree approach provide strong support for many of the accepted relationships among phrynosomatid lizards, suggesting that RAD loci contain useful phylogenetic signal across a range of divergence times despite the presence of missing data. Phylogenetic analysis of RAD loci requires careful attention to model assumptions, especially if downstream analyses depend on branch lengths.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Resolving the short phylogenetic branches that result from rapid evolutionary diversification often requires large numbers of loci. We collected targeted sequence capture data from 585 nuclear loci ...(541 ultraconserved elements and 44 protein-coding genes) to estimate the phylogenetic relationships among iguanian lizards in the North American genus Sceloporus. We tested for diversification rate shifts to determine if rapid radiation in the genus is correlated with chromosomal evolution.
The phylogenomic trees that we obtained for Sceloporus using concatenation and coalescent-based species tree inference provide strong support for the monophyly and interrelationships among nearly all major groups. The diversification analysis supported one rate shift on the Sceloporus phylogeny approximately 20-25 million years ago that is associated with the doubling of the speciation rate from 0.06 species/million years (Ma) to 0.15 species/Ma. The posterior probability for this rate shift occurring on the branch leading to the Sceloporus species groups exhibiting increased chromosomal diversity is high (posterior probability = 0.997).
Despite high levels of gene tree discordance, we were able to estimate a phylogenomic tree for Sceloporus that solves some of the taxonomic problems caused by previous analyses of fewer loci. The taxonomic changes that we propose using this new phylogenomic tree help clarify the number and composition of the major species groups in the genus. Our study provides new evidence for a putative link between chromosomal evolution and the rapid divergence and radiation of Sceloporus across North America.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Major modifications to the pharyngeal jaw apparatus are widely regarded as a recurring evolutionary key innovation that has enabled adaptive radiation in many species-rich clades of percomorph ...fishes. However one of the central predictions of this hypothesis, that the acquisition of a modified pharyngeal jaw apparatus will be positively correlated with explosive lineage diversification, has never been tested. We applied comparative methods to a new time-calibrated phylogeny of labrid fishes to test whether diversification rates shifted at two scales where major pharyngeal jaw innovations have evolved: across all of Labridae and within the subclade of parrotfishes.
Diversification patterns within early labrids did not reflect rapid initial radiation. Much of modern labrid diversity stems from two recent rapid diversification events; one within julidine fishes and the other with the origin of the most species-rich clade of reef-associated parrotfishes. A secondary pharyngeal jaw innovation was correlated with rapid diversification within the parrotfishes. However diversification rate shifts within parrotfishes are more strongly correlated with the evolution of extreme dichromatism than with pharyngeal jaw modifications.
The temporal lag between pharyngeal jaw modifications and changes in diversification rates casts doubt on the key innovation hypothesis as a simple explanation for much of the richness seen in labrids and scarines. Although the possession of a secondarily modified PJA was correlated with increased diversification rates, this pattern is better explained by the evolution of extreme dichromatism (and other social and behavioral characters relating to sexual selection) within Scarus and Chlorurus. The PJA-innovation hypothesis also fails to explain the most dominant aspect of labrid lineage diversification, the radiation of the julidines. We suggest that pharyngeal jaws might have played a more important role in enabling morphological evolution of the feeding apparatus in labrids and scarines rather than in accelerating lineage diversification.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
(
) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.
We characterized
and its subspecies in colorectal tumors and examined associations with tumor ...characteristics and colorectal cancer-specific survival. We conducted deep sequencing of
,
, and bacterial
genes in tumors from 1,994 patients with colorectal cancer and assessed associations between
presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations.
, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies
. Presence of
was associated with higher colorectal cancer-specific mortality (HR, 1.97;
= 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13;
= 0.0002) and those who received chemotherapy HR, 1.92; confidence interval (CI), 1.07-3.45;
= 0.029). Only
subspecies
, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16;
= 0.0016), subspecies
and
were not (HR, 1.07;
= 0.86). Additional adjustment for tumor stage suggests that the effect of
on mortality is partly driven by a stage shift. Presence of
was associated with microsatellite instable tumors, tumors with
exonuclease domain mutations, and
mutations, and suggestively associated with
mutations.
, and particularly subspecies
, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes.
Our findings identify the
subspecies
as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.
Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In ...addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated.
We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex.
values were adjusted using Bonferroni correction.
The association between minor allele of rs7200950 (
) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected
= 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (
), rs75676021 (
), and rs74429678 (
) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men.
Our study reported a gene-wide statistically significant interaction with sex (
). Although significant interaction by smoking pack-years (
) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted.
Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.
Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival ...times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time.
We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis.
A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10
). The most significant variant at this locus, rs76766811 (P = 1.6x10
), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10
and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10
).
In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).
Low serum 25-hydroxyvitamin D 25(OH)D concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low ...25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival.
Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer.
The 25(OH)D decreasing allele of SNP rs2282679 (
gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall HR = 1.54; confidence interval (CI), 0.86-2.78 and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33;
= 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43,
= 0.02).
Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue.
Further studies are warranted to investigate the association in specific subgroups.
(1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to ...2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity.
Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses.
The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity.
Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.
A family history of colorectal cancer (CRC) in first‐degree relatives (FDRs) increases the risk of CRC. However, the influence of family history on survival among CRC patients remains unclear. We ...conducted a pooled analysis of survival in 5010 incident CRC cases. Cox proportional hazards models were used to estimate the association of family history with overall survival (OS) and CRC‐specific survival (CSS). We also assessed the impact of the number of affected FDRs and age at CRC diagnosis in the affected FDRs on survival. Among CRC cases, 819 (16%) patients reported a family history of CRC. There were 1580 total deaths over a median follow‐up of 4.6 years, of which 1046 (66%) deaths were due to CRC. Having a family history of CRC was not associated with OS hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.89–1.19 or CSS (HR, 1.13; 95% CI, 0.95–1.36). There were no associations between the number of affected relatives or age at CRC diagnosis of the affected relative with survival (all Ptrend > 0.05). However, a family history of CRC did confer worse CSS in patients diagnosed with distal colon cancer (HR, 1.45, 95% CI, 1.03–2.04). A family history of CRC was generally not associated with survival after CRC diagnosis. However, having a family history of CRC was associated with worse CRC prognosis in individuals with distal colon cancer, suggesting a possible genetic predisposition with distinct pathogenic mechanism that may lead to worse survival in this group.
In a pooled analysis of 5010 patients with colorectal cancer (CRC), having a family history of CRC in first‐degree relatives was not associated with overall survival hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.89–1.19 or CRC‐specific survival (CSS) HR, 1.13; 95% CI, 0.95–1.36. However, having a family history of CRC was associated with worse CSS in patients with distal colon cancer (HR, 1.45; 95% CI, 1.03–2.04), suggesting a possible genetic predisposition with distinct pathogenic mechanism that may lead to worse survival in this group.
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