Single nucleotide polymorphism-based genome-wide chromosome copy change, loss of heterozygosity, and aneuploidy in Barrett's esophagus neoplastic progression.

Chromosome copy gain, loss, and loss of heterozygosity (LOH) involving most chromosomes have been reported in many cancers; however, less is known about chromosome instability in premalignant conditions. 17p LOH and DNA content abnormalities have been previously reported to predict progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Here, we evaluated genome-wide chromosomal instability in multiple stages of BE and EA in whole biopsies. Forty-two patients were selected to represent different stages of progression from BE to EA. Whole BE or EA biopsies were minced, and aliquots were processed for flow cytometry and genotyped with a paired constitutive control for each patient using 33,423 single nucleotide polymorphisms (SNP). Copy gains, losses, and LOH increased in frequency and size between early- and late-stage BE (P 30% in early and late stages, respectively. A set of statistically significant events was unique to either early or late, or both, stages, including previously reported and novel abnormalities. The total number of SNP alterations was highly correlated with DNA content aneuploidy and was sensitive and specific to identify patients with concurrent EA (empirical receiver operating characteristic area under the curve = 0.91). With the exception of 9p LOH, most copy gains, losses, and LOH detected in early stages of BE were smaller than those detected in later stages, and few chromosomal events were common in all stages of progression. Measures of chromosomal instability can be quantified in whole biopsies using SNP-based genotyping and have potential to be an integrated platform for cancer risk stratification in BE

Power to Detect Risk Alleles Using Genome-Wide Tag SNP Panels

Advances in high-throughput genotyping and the International HapMap Project have enabled association studies at the whole-genome level. We have constructed whole-genome genotyping panels of over 550,000 (HumanHap550) and 650,000 (HumanHap650Y) SNP loci by choosing tag SNPs from all populations genotyped by the International HapMap Project. These panels also contain additional SNP content in regions that have historically been overrepresented in diseases, such as nonsynonymous sites, the MHC region, copy number variant regions and mitochondrial DNA. We estimate that the tag SNP loci in these panels cover the majority of all common variation in the genome as measured by coverage of both all common HapMap SNPs and an independent set of SNPs derived from complete resequencing of genes obtained from SeattleSNPs. We also estimate that, given a sample size of 1,000 cases and 1,000 controls, these panels have the power to detect single disease loci of moderate risk (λ ∼ 1.8–2.0). Relative risks as low as λ ∼ 1.1–1.3 can be detected using 10,000 cases and 10,000 controls depending on the sample population and disease model. If multiple loci are involved, the power increases significantly to detect at least one locus such that relative risks 20%–35% lower can be detected with 80% power if between two and four independent loci are involved. Although our SNP selection was based on HapMap data, which is a subset of all common SNPs, these panels effectively capture the majority of all common variation and provide high power to detect risk alleles that are not represented in the HapMap data

Highly parallel oligonucleotide purification and functionalization using reversible chemistry

We have developed a cost-effective, highly parallel method for purification and functionalization of 5′-labeled oligonucleotides. The approach is based on 5′-hexa-His phase tag purification, followed by exchange of the hexa-His tag for a functional group using reversible reaction chemistry. These methods are suitable for large-scale (micromole to millimole) production of oligonucleotides and are amenable to highly parallel processing of many oligonucleotides individually or in high complexity pools. Examples of the preparation of 5′-biotin, 95-mer, oligonucleotide pools of >40K complexity at micromole scale are shown. These pools are prepared in up to ~16% yield and 90–99% purity. Approaches for using this method in other applications are also discussed

The photosynthesis - leaf nitrogen relationship at ambient and elevated atmospheric carbon dioxide: a meta-analysis

Estimation of leaf photosynthetic rate (A) from leaf nitrogen content (N) is both conceptually and numerically important in models of plant, ecosystem and biosphere responses to global change. The relationship between A and N has been studied extensively at ambient CO{sub 2} but much less at elevated CO{sub 2}. This study was designed to (1) assess whether the A-N relationship was more similar for species within than between community and vegetation types, and (2) examine how growth at elevated CO{sub 2} affects the A-N relationship. Data were obtained for 39 C{sub 3} species grown at ambient CO{sub 2} and 10 C{sub 3} species grown at ambient and elevated CO{sub 2}. A regression model was applied to each species as well as to species pooled within different community and vegetation types. Cluster analysis of the regression coefficients indicated that species measured at ambient CO{sub 2} did not separate into distinct groups matching community or vegetation type. Instead, most community and vegetation types shared the same general parameter space for regression coefficients. Growth at elevated CO{sub 2} increased photosynthetic nitrogen use efficiency for pines and deciduous trees. When species were pooled by vegetation type, the A-N relationship for deciduous trees expressed on a leaf-mass bask was not altered by elevated CO{sub 2}, while the intercept increased for pines. When regression coefficients were averaged to give mean responses for different vegetation types, elevated CO{sub 2} increased the intercept and the slope for deciduous trees but increased only the intercept for pines. There were no statistical differences between the pines and deciduous trees for the effect of CO{sub 2}. Generalizations about the effect of elevated CO{sub 2} on the A-N relationship, and differences between pines and deciduous trees will be enhanced as more data become available

Computational Analysis of Whole-Genome Differential Allelic Expression Data in Human

Allelic imbalance (AI) is a phenomenon where the two alleles of a given gene are expressed at different levels in a given cell, either because of epigenetic inactivation of one of the two alleles, or because of genetic variation in regulatory regions. Recently, Bing et al. have described the use of genotyping arrays to assay AI at a high resolution (∼750,000 SNPs across the autosomes). In this paper, we investigate computational approaches to analyze this data and identify genomic regions with AI in an unbiased and robust statistical manner. We propose two families of approaches: (i) a statistical approach based on z-score computations, and (ii) a family of machine learning approaches based on Hidden Markov Models. Each method is evaluated using previously published experimental data sets as well as with permutation testing. When applied to whole genome data from 53 HapMap samples, our approaches reveal that allelic imbalance is widespread (most expressed genes show evidence of AI in at least one of our 53 samples) and that most AI regions in a given individual are also found in at least a few other individuals. While many AI regions identified in the genome correspond to known protein-coding transcripts, others overlap with recently discovered long non-coding RNAs. We also observe that genomic regions with AI not only include complete transcripts with consistent differential expression levels, but also more complex patterns of allelic expression such as alternative promoters and alternative 3′ end. The approaches developed not only shed light on the incidence and mechanisms of allelic expression, but will also help towards mapping the genetic causes of allelic expression and identify cases where this variation may be linked to diseases

Effect of Restricted Preen-Gland Access on Maternal Self Maintenance and Reproductive Investment in Mallards

As egg production and offspring care are costly, females should invest resources adaptively into their eggs to optimize current offspring quality and their own lifetime reproductive success. Parasite infections can influence maternal investment decisions due to their multiple negative physiological effects. The act of preening--applying oils with anti-microbial properties to feathers--is thought to be a means by which birds combat pathogens and parasites, but little is known of how preening during the reproductive period (and its expected disease-protecting effects) influences maternal investment decisions at the level of the egg.Here, we experimentally prevented female mallards (Anas platyrhynchos) from accessing their preen gland during breeding and monitored female immunoresponsiveness (e.g., plasma lysozyme concentration) as well as some egg traits linked to offspring quality (e.g., egg mass, yolk carotenoid content, and albumen lysozyme levels). Females with no access to their preen gland showed an increase in plasma lysozyme level compared to control, normally preening females. In addition, preen-gland-restricted females laid significantly lighter eggs and deposited higher carotenoid concentrations in the yolk compared to control females. Albumen lysozyme activity did not differ significantly between eggs laid by females with or without preen gland access.Our results establish a new link between an important avian self-maintenance behaviour and aspects of maternal health and reproduction. We suggest that higher yolk carotenoid levels in eggs laid by preen-gland-restricted females may serve to boost health of offspring that would hatch in a comparatively microbe-rich environment

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

BioRXiv version. Please see https://rubenarslan.github.io/generation_scotland_pedigree_gcta/ to access this website in a browsable form