More than 5 million single-nucleotide polymorphisms (SNPs) with minor-allele frequency greater than 10% are expected to exist in the human genome. Some of these SNPs may be associated with risk of ...developing common diseases. To assess the power of currently available SNPs to detect such associations, we resequenced 50 genes in two ethnic samples and measured patterns of linkage disequilibrium between the subset of SNPs reported in dbSNP and the complete set of common SNPs. Our results suggest that using all 2.7 million SNPs currently in the database would detect nearly 80% of all common SNPs in European populations but only 50% of those common in the African American population and that efficient selection of a minimal subset of SNPs for use in association studies requires measurement of allele frequency and linkage disequilibrium relationships for all SNPs in dbSNP.
Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies ...contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.
Significant progress has been made in elucidating single nucleotide polymorphism diversity in the human population. However, the majority of the variation space in the genome is structural and ...remains partially elusive. One form of structural variation is tandem repeats (TRs). Expansion of TRs are responsible for over 40 diseases, but we hypothesize these represent only a fraction of the pathogenic repeat expansions that exist. Here we characterize long or expanded TR variation in 1,115 human genomes as well as a replication cohort of 2,504 genomes, identified using ExpansionHunter Denovo. We found that individual genomes typically harbor several rare, large TRs, generally in non-coding regions of the genome. We noticed that these large TRs are enriched in their proximity to Alu elements. The vast majority of these large TRs seem to be expansions of smaller TRs that are already present in the reference genome. We are providing this TR profile as a resource for comparison to undiagnosed rare disease genomes in order to detect novel disease-causing repeat expansions.
Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with >40 monogenic disorders
1
. Their involvement in complex disorders is largely ...unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2-20 bp motifs in 17,231 genomes of families with autism
2
,
3
and population controls
4
. We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in
DMPK
and
FXN
, known for neuromuscular conditions, and in novel loci such as
FGF14
and
CACNB1
. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.
Recent studies have suggested that a significant fraction of the human genome is contained in blocks of strong linkage disequilibrium, ranging from ∼5 to >100 kb in length, and that within these ...blocks a few common haplotypes may account for >90% of the observed haplotypes. Furthermore, previous studies have suggested that common haplotypes in candidate genes are generally shared across populations and represent the majority of chromosomes in each population. The conclusions drawn from these preliminary studies, however, are based on an incomplete knowledge of the variation in the regions examined. To bridge this gap in knowledge, we have completely resequenced 100 candidate genes in a population of African descent and one of European descent. Although these genes have been well studied because of their medical importance, we demonstrate that a large amount of sequence variation has not yet been described. We also report that the average number of inferred haplotypes per gene, when complete data is used, is higher than in previous reports and that the number and proportion of all haplotypes represented by common haplotypes per gene is variable. Furthermore, we demonstrate that haplotypes shared between the two populations constitute only a fraction of the total number of haplotypes observed and that these shared haplotypes represent fewer of the African-descent chromosomes than was expected from previous studies. Finally, we show that restricting variation discovery to coding regions does not adequately describe all common haplotypes or the true haplotype block structure observed when all common variation is used to infer haplotypes. These data, derived from complete knowledge of genetic variation in these genes, suggest that the haplotype architecture of candidate genes across the human genome is more complex than previously suggested, with important implications for candidate gene and genomewide association studies.
In the version of this article initially published online, two pairs of headings were switched with each other in Table 4: "Recall (PCR free)" was switched with "Recall (with PCR)," and "Precision ...(PCR free)" was switched with "Precision (with PCR)." The error has been corrected in the print, PDF and HTML versions of this article.
We have formulated a numerical model with strongly temperature-dependent viscosity to calculate thermal structure and flow-field in subduction zones. One important particularity of the model is that ...the overriding plate is not fixed over its whole thickness in order to allow material exchange between the wedge and the upper lithosphere. Numerical problems due to very high-viscosity contrasts are avoided by coupling a finite difference method and a finite element method for solving the energy conservation equation and the Stockes equation, respectively. In this model, a temperature decrease from 1400 to 1300
°C increases the viscosity by an order of magnitude. We study the temperature structure and the velocity field of the subducting slab and mantle wedge. Surface heat flow, velocity anomalies, and geometry of the partial melting zone are also calculated. To study the effect that boundary conditions play on the interaction between the mantle wedge, overriding plate and subducting plate, we examine models with both fixed and free-slip conditions applied to the overriding plate. When the overriding plate is allowed to move laterally (free-slip), the subducting slab is thick, and both the temperature field and the convective motions in the mantle wedge are similar to those observed when using constant viscosity numerical models or analytical corner flow models. If the surface of the overriding plate is fixed, the subducting slab is thin and the mantle wedge impinges upon the overriding plate forming a high-temperature nose between the overriding plate and subducting lithosphere. Furthermore, viscous decoupling occurs implicitly at shallow depth between the slab and the wedge because hot material from the wedge is entrained close to the trench. In that case, the subducting slab tectonically erodes the lower lithosphere of the overriding plate leading to high-temperatures, low seismic velocities, high attenuation and high heat flow beneath volcanic arc, in agreement with geophysical observations.
When using Hap660 data for imputation, we observed detection rates of 92.9% when imputing with the DCEG Reference Set and 84.7% with the 1000 Genomes and HapMap reference sets relative to the ...detection rate attained with directly genotyped SNPs; for OmniExpress data, we observed detection rates of 93.9% and 86.2% for these reference sets, respectively. Because imputation accuracy depends on the similarity of haplotypes between reference and study populations, we examined an extreme scenario in which we used a reference population from Finland (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, ATBC) to impute genotypes using OmniExpress data from a US population of European ancestry (PLCO) (Supplementary Fig. 1).
Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of ...pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in ∼10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer.
Laser-based tissue microdissection is an important tool for the molecular evaluation of histological sections. The technology has continued to advance since its initial commercialization in the ...1990s, with improvements in many aspects of the process. More recent developments are tailored toward an automated, operator-independent mode that relies on antibodies as targeting probes, such as immuno–laser capture microdissection or expression microdissection (xMD). Central to the utility of expression-based dissection techniques is the effect of the staining process on the biomolecules in histological sections. To investigate this issue, the authors analyzed DNA, RNA, and protein in immunostained, microdissected samples. DNA was the most robust molecule, exhibiting no significant change in quality after immunostaining but a variable 50% to 75% decrease in the total yield. In contrast, RNA in frozen and ethanol-fixed, paraffin-embedded samples was susceptible to hydrolysis and digestion by endogenous RNases during the initial steps of staining. Proteins from immunostained tissues were successfully analyzed by one-dimensional electrophoresis and mass spectrometry but were less amenable to solution phase assays. Overall, the results suggest investigators can use immunoguided microdissection methods for important analytic techniques; however, continued improvements in staining protocols and molecular extraction methods are key to further advancing the capability of these methods.
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