Genetic architecture describes the characteristics of genetic variation that are responsible for heritable phenotypic variability. It depends on the number of genetic variants affecting a trait, ...their frequencies in the population, the magnitude of their effects and their interactions with each other and the environment. Defining the genetic architecture of a complex trait or disease is central to the scientific and clinical goals of human genetics, which are to understand disease aetiology and aid in disease screening, diagnosis, prognosis and therapy. Recent technological advances have enabled genome-wide association studies and emerging next-generation sequencing studies to begin to decipher the nature of the heritable contribution to traits and disease. Here, we describe the types of genetic architecture that have been observed, how architecture can be measured and why an improved understanding of genetic architecture is central to future advances in the field.
Farmers throughout the United States report a shortage of workers. At the same time, there are proposals to strengthen the enforcement of existing immigration laws. In this paper, we develop an ...equilibrium approach to examine the impact of removing undocumented workers from the California agricultural labor market, and to infer whether there is evidence of shortages using individual-worker data. We find evidence that is consistent with a persistent shortage in some sub-sectors of the California farm labor market. Further, we conduct counter-factual policy simulations over a range of possible policy alternatives, and find that removing 50% all undocumented farm workers from the state would lead to an increase in wages of over 22%.
The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from ...Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.
► I examine recent reports examining epigenetic variation in wild plant populations. ► DNA methylation polymorphism patterns in populations suggest adaptive variation. ► Disentangling genetic and ...epigenetic variation remains a significant challenge. ► Integration of molecular and population studies is needed to understand epigenetics.
Researchers are beginning to use wild plant populations to survey and assess cytosine methylation polymorphisms in a population and ecological genetic framework. These studies support the plausibility of adaptive epigenetic alleles, but uncertainty remains due to the difficulty in untangling genetic and epigenetic variation in wild populations. The increasing emphasis on stress-induced epigenetic alterations and transgenerational phenomena among researchers focused on epigenetic mechanisms should push practitioners of this subfield to consider the questions and tools of colleagues grappling with epigenetics from ecological and evolutionary perspectives.
We present a practical implementation of a Monte Carlo method to estimate the significance of cross-correlations in unevenly sampled time series of data, whose statistical properties are modelled ...with a simple power-law power spectral density. This implementation builds on published methods; we introduce a number of improvements in the normalization of the cross-correlation function estimate and a bootstrap method for estimating the significance of the cross-correlations. A closely related matter is the estimation of a model for the light curves, which is critical for the significance estimates. We present a graphical and quantitative demonstration that uses simulations to show how common it is to get high cross-correlations for unrelated light curves with steep power spectral densities. This demonstration highlights the dangers of interpreting them as signs of a physical connection. We show that by using interpolation and the Hanning sampling window function we are able to reduce the effects of red-noise leakage and to recover steep simple power-law power spectral densities. We also introduce the use of a Neyman construction for the estimation of the errors in the power-law index of the power spectral density. This method provides a consistent way to estimate the significance of cross-correlations in unevenly sampled time series of data.
Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether ...genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR).
For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations.
Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.
Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host ...immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.
COVID‐19 and Food Supply Chains Chenarides, Lauren; Manfredo, Mark; Richards, Timothy J.
Applied economic perspectives and policy,
March 2021, Letnik:
43, Številka:
1
Journal Article
Recenzirano
The COVID‐19 pandemic exposed critical weaknesses in the US food supply chain. Faced with the near‐complete loss of the food service distribution channel, stories of wasted food, failing suppliers, ...and food shortages were common. We argue that the pandemic revealed a fundamental lack of resilience in the food supply chain that, while causing short‐term welfare losses, need not have happened, and resulted from a failure of vision rather than a market failure in the traditional sense. We present a model of supply chain flexibility, grounded in real options theory, that demonstrates how firms can increase shareholder value by maintaining flexibility across supply chains. We present an example from the US fresh produce industry (onions) to demonstrate our hypothesis.
Rapid adaptive radiation poses two distinct questions apart from speciation and adaptation: What happens after one speciation event and how do some lineages continue speciating through a rapid burst? ...We review major features of rapid radiations and their mismatch with theoretical models and speciation mechanisms. The paradox is that the hallmark rapid burst pattern of adaptive radiation is contradicted by most speciation models, which predict continuously decelerating diversification and niche subdivision. Furthermore, it is unclear if and how speciation-promoting mechanisms such as magic traits, phenotype matching, and physical linkage of coadapted alleles promote rapid bursts of speciation. We review additional mechanisms beyond ecological opportunity to explain rapid radiations: (
a
) ancient adaptive alleles and the transporter hypothesis, (
b
) sexual signal complexity, (
c
) fitness landscape connectivity, (
d
) diversity begets diversity, and (
e
) plasticity first. We propose new questions and predictions connecting microevolutionary processes to macroevolutionary patterns through the study of rapid radiations.
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