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Patti Smith : camera solo
This captivating selection of 70 intimate black-and-white photographs conveys Patti Smith's singular experience as a photographer as it relates to many facets of her fascinating life and career.
Book
Gene–Environment Interaction in Yeast Gene Expression
The effects of genetic variants on phenotypic traits often depend on environmental and physiological conditions, but such gene-environment interactions are poorly understood. Recently developed approaches that treat transcript abundances of thousands of genes as quantitative traits offer the opportunity to broadly characterize the architecture of gene-environment interactions. We examined the genetic and molecular basis of variation in gene expression between two yeast strains (BY and RM) grown in two different conditions (glucose and ethanol as carbon sources). We observed that most transcripts vary by strain and condition, with 2,996, 3,448, and 2,037 transcripts showing significant strain, condition, and strain-condition interaction effects, respectively. We expression profiled over 100 segregants derived from a cross between BY and RM in both growth conditions, and identified 1,555 linkages for 1,382 transcripts that show significant gene-environment interaction. At the locus level, local linkages, which usually correspond to polymorphisms in cis-regulatory elements, tend to be more stable across conditions, such that they are more likely to show the same effect or the same direction of effect across conditions. Distant linkages, which usually correspond to polymorphisms influencing trans-acting factors, are more condition-dependent, and often show effects in different directions in the two conditions. We characterized a locus that influences expression of many growth-related transcripts, and showed that the majority of the variation is explained by polymorphism in the gene IRA2. The RM allele of IRA2 appears to inhibit Ras/PKA signaling more strongly than the BY allele, and has undergone a change in selective pressure. Our results provide a broad overview of the genetic architecture of gene-environment interactions, as well as a detailed molecular example, and lead to key insights into how the effects of different classes of regulatory variants are modulated by the environment. These observations will guide the design of studies aimed at understanding the genetic basis of complex traits.
Journal Article
Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression
While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression.
It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.
Journal Article
Saving Old Bones: a non-destructive method for bone collagen prescreening
Bone collagen is an important material for radiocarbon, paleodietary, and paleoproteomic analyses, but it degrades over time, making such analyses more difficult with older material. Collagen preservation between and within archaeological sites is also variable, so that much time, effort, and money can go into the preparation and initial analysis of samples that will not yield meaningful results. To avoid this, various methods are employed to prescreen bone for collagen preservation (e.g., %N, microporosity, and FTIR spectroscopic analyses), but these are often destructive and/or require exportation for analysis. Here, we explore near-infrared spectroscopy as a tool for gauging the collagen content of ground and whole bone from about 500 to 45,000 years ago. We show that a portable spectrometer’s ability to quantify collagen content and classify specimens by preservation status is comparable to that of other popular prescreening methods. Moreover, near-infrared spectroscopy is non-destructive and spectra can be acquired in a few seconds.
Journal Article
Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress
Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.
Journal Article
Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study
Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.
Journal Article
Life-history trade-offs and senescence in plants
An increasing number of studies have shown that senescence, the functional decline in traits and increased risk of mortality with increasing age, occurs in organisms in wild populations, but there is a wide range of diversity in the patterns of senescence across species. The antagonistic pleiotropy and the disposable soma theories of senescence predict that there will be life‐history trade‐offs between performance at early‐ and late‐life stages. Plants show variation in senescence patterns and thus provide an opportunity to evaluate life‐history trade‐offs and senescence. Many plant species can be easily followed demographically and their environments, resources and allocation to reproduction can be manipulated, which makes them particularly good models to address these questions. We compared the results from 22 studies of plant senescence in the wild and compiled 20 examples of life‐history trade‐offs in plants. Some of the unique features of plants that may influence senescence patterns and trade‐offs in the wild are highlighted through the results. We found all three age‐specific patterns: age decline, age improvement and no change with age for plants in the wild. Most species showed an age‐dependent decline in at least one trait but, even within a species, the age‐specific patterns of traits varied. Results also showed that trade‐offs vary across environments and that plants can manipulate their resource pool through increases in photosynthesis, which will influence the manifestation of trade‐offs. We conclude that aspects of plant biology including dynamic resource pools, the impact of size, dormancy and below‐ground storage may influence both the patterns of senescence and life‐history trade‐offs. The diversity of plant life forms and life cycles provide a wealth of opportunities to experimentally study senescence in the context of life‐history trade‐offs. A free Plain Language Summary can be found within the Supporting Information of this article. A free Plain Language Summary can be found within the Supporting Information of this article.
Journal Article
Properties of structural variants and short tandem repeats associated with gene expression and complex traits
Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits.
Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.
Journal Article
Epigenetic Mechanisms in Obesity: Broadening Our Understanding of the Disease
Now recognized as more than just the result of overeating or the consumption of poor-quality foods, obesity is understood to be a multifactorial disease, strongly correlated with a variety of environment-gene interactions. In addressing the complex public health issue of obesity, medical practitioners, along with their allied healthcare counterparts, face the challenge of reducing its prevalence by utilizing and sharing with patients the current, yet incomplete, scientific knowledge concerning the disease. While continued research is required to strengthen direct cause-effect relationships, substantial evidence links post-translational modifications such as DNA methylation and histone modifications of several candidate \"obesity\" genes to the predilection for obesity. Additional evidence supports the influence of maternal diet during the gestational period, individual diet, and other lifestyle and genetic factors in obesity. The purpose of this review is to synthesize the current information concerning epigenetic modifications that appear to support, or result from, the development of obesity. Such mechanisms may serve as therapeutic targets for developing novel prevention and/or treatment strategies for obesity or as epigenetic biomarkers for monitoring recovery.
Journal Article
The Social Determinants of Loneliness During COVID-19: Personal, Community, and Societal Predictors and Implications for Treatment
ObjectiveThe COVID-19 pandemic dramatically altered social determinants of health including work, education, social connections, movement, and perceived control; and loneliness was commonly experienced. This longitudinal study examined how social determinants at the personal (micro), community (meso), and societal (macro) levels predicted loneliness during the pandemic.MethodsParticipants were 2056 Australian adults surveyed up to three times over 18 months in 2020 and 2021. Multi-level mixed-effect regressions were conducted predicting loneliness from social determinants at baseline and two follow-ups.ResultsLoneliness was associated with numerous micro determinants: male gender, lifetime diagnosis of a mental health disorder, experience of recent stressful event(s), low income, living alone or couples with children, living in housing with low natural light, noise, and major building defects. Lower resilience and perceived control over health and life were also associated with greater loneliness. At the meso level, reduced engagement with social groups, living in inner regional areas, and living in neighbourhoods with low levels of belongingness and collective resilience was associated with increased loneliness. At the macro level, increased loneliness was associated with State/Territory of residence.ConclusionsTherapeutic initiatives must go beyond psychological intervention, and must recognise the social determinants of loneliness at the meso and macro levels.
Journal Article