International Genetics and Genomics of Diseases

Base editing screens define the genetic landscape of cancer drug resistance mechanisms Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant ...

Scientists identify six novel genes linked to cancer risk Scientists at deCODE genetics/Amgen, and their collaborators have discovered six novel genes with rare germline variants that associate with cancer risk. The findings are published today in Nature Genetics under the title "Gene-based burden tests of rare germline variants identify six cancer susceptibility genes." A subset of cancers arises in individuals who are born with rare sequence variants that significantly alter their cancer risk. The discovery of such variants, like those in the BRCA1- and BRCA2 genes, has led to improved early cancer detection and the development of targeted therapies, ultimately reducing the cancer burden and improving prognosis of those carrying these mutations. In this study, the scientists analyzed three large genetic datasets from individuals of European descent, including 130,991 cancer patients and 733,486 controls. Through a gene-based burden association analysis across 22 different ...

A PD-L1 tropism-expanded oncolytic adenovirus enhanced gene delivery efficiency and anti-tumor effects Recombinant adenovirus serotype 5 (Ad5)-mediated virotherapy is a maturing technique in cancer treatment. However, the utility of adenovirus (Ad) has been limited by low expression of coxsackievirus and adenovirus receptor (CAR) in cancer cells resulting in poor infectivity of Ads. To overcome the problem, we aimed to develop a novel tropism-modified oncolytic adenovirus , ZD55-F-HI-sPD-1-EGFP, which contains the epitope of PD-1 (70-77aa) at the HI-loop of Ad fiber. Trimerization of Fiber-sPD-1 was confirmed by immunoblot analysis. ZD55-F-HI-sPD-1-EGFP shows a remarkable improvement in viral infection rate and gene transduction efficiency in the PD-L1-positive cancer cells. Competition assays with a PD-L1 protein reveals that cell internalization of ZD55-F-HI-sPD-1-EGFP is mediated by both CAR and PD-L1 at a high dose. The progeny virus production capacity showed that sPD-1 incorpo...

Genetic variants in melatonin receptor linked to idiopathic osteoporosis Osteoporosis is a common bone disorder characterized by low bone mass and increased fracture risk, usually affecting postmenopausal women and men over the age of 60. Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis that is seen in individuals under 50 years of age without any known metabolic or hormonal causes. Family histories of osteoporosis and childhood fractures suggest a genetic basis for IOP, though many cases remain unexplained despite previous genetic studies. In the study, "Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis," published in Science Translational Medicine, researchers examined melatonin receptor variants as a potential genetic cause of IOP. They focused on the variant rs374152717, found in an Ashkenazi family with IOP, and rs28383653, identified in unrelated IOP patients. Whole-exome sequencing was conducted on an Ashkenazi family ...

Stressed bees may experience human-like emotions Researchers from Newcastle University in Newcastle upon Tyne, England, have discovered that bumblebees’ responses to adverse events resemble human emotions. Findings of the study show that bees lower their expectations of rewards when they become agitated or stressed, which scientists say could impact their approach to pollination. The study offers significant evidence for judgement biases in bees.1,2 “Our study shows that bees are more pessimistic after stress as their behavior suggests that they do not expect to get rewards,” Vivek Nityananda, PhD, a Biotechnology and Biological Sciences Research Council (BBSRC) David Phillips research fellow who worked on the study, said in a university release.1 “Emotions are complex states and, in humans, involve a subjective understanding of what you are feeling. We might never know if bees feel something similar, however, what this research can say is that bees have similar responses when they are...

Turtle genome provides new clues on the evolution of vertebrates Scientists from the UAB and Iowa State University have generated the genome assemblies of two hidden-neck turtles, unpublished until now. The results, which revealed a new three-dimensional structure of the genome within the phylogenetic group of reptiles, birds and mammals, will contribute to the development of more effective turtle conservation strategies, and to the study of the evolution of the genome and chromosomal organisation of vertebrates. The study was led by researchers Aurora Ruiz-Herrera (UAB) and Nicole Valenzuela (Iowa State University), with the participation of researchers from the Institute of Evolutionary Biology (CSIC-UPF) and Earlham College. Published in Genome Research, it highlights the important role of chromatin, a three-dimensional structure into which genetic material folds and is packaged within the cell nucleus, in the regulation of gene function and its impact on evolution and speciation. ...

‘Anonymous’ genetic databases vulnerable to privacy leaks A study has raised concerns that a type of genetic database that is increasingly popular with researchers could be exploited to reveal the identities of its participants, or link private health information to their public genetic profiles. Single-cell data sets can contain information on gene expression in millions of cells collected from thousands of people. They are often freely accessible, providing a valuable resource for researchers who study the effects of diseases at a cellular level. The data are supposed to be anonymized, but a study published on 2 October in Cell shows how genetic data from one study “can be exploited to uncover private information about individuals in another study”, the authors write. The findings highlight the difficulty of balancing the interests of researchers with the privacy of donors. “Our genomes are very identifying. They can tell a lot about us, our traits, our predisposition to diseases,” s...

Scientists discover unexpected link between genes involved in human brain evolution and developmental disorders The human brain stands out among mammals for its remarkably prolonged development. Synapses – critical connections between neurons of the cerebral cortex, the brain’s main hub for cognition – take years to mature in humans, compared to just months in species like macaques or mice. This extended development, also known as neoteny, is thought to be central to humans' advanced cognitive and learning abilities. On the other hand, it has been hypothesized that disruptions of brain neoteny could be linked to neurodevelopmental disorders such as intellectual disability and autism spectrum disorder. The lab of Pierre Vanderhaeghen at the VIB-KU Leuven Center for Brain & Disease Research previously discovered that the prolonged development of the human cerebral cortex is mainly due to human-specific molecular mechanisms in neurons. Now, they are investigating these molecular t...

What is genomic prediction and can embryos really be ‘screened for IQ’? A startup in the US, Heliospect, appears to be preparing to launch a service to enable parents to select ‘desirable’ traits There is broad scientific consensus that intelligence is partly inherited and that genes play a significant role. But pinning this incredibly complex trait down to precise contributions from specific genes is a far more thorny scientific challenge – and claims of being able to produce meaningful IQ “gains” in the context of embryo screening are widely viewed as contentious. Despite the science being unsettled, it has emerged that at least one company, the US startup Heliospect, appears to be preparing to publicly launch a service that allows parents who have conceived several embryos through IVF to select those most likely to have “desirable” traits, such as height and IQ. Complex traits, such as IQ, are not determined by a single mutation, but are influenced by the tiny contributions of thous...

Bacterial cells transmit memories to offspring Bacterial cells can “remember” brief, temporary changes to their bodies and immediate surroundings, a new Northwestern University and University of Texas-Southwestern study has found. And, although these changes are not encoded in the cell’s genetics, the cell still passes memories of them to its offspring — for multiple generations. Not only does this discovery challenge long-held assumptions of how the simplest organisms transmit and inherit physical traits, it also could be leveraged for new medical applications. For example, researchers could circumvent antibiotic resistance by subtly tweaking a pathogenic bacterium to render its offspring more sensitive to treatment for generations. “A central assumption in bacterial biology is that heritable physical characteristics are determined primarily by DNA,” said Northwestern’s Adilson Motter , the study’s senior author. “But, from the perspective of complex systems, we know that information ...

Genetic insights transform treatment for children with developmental disorders Thousands of children with severe developmental disorders have benefited from more targeted treatments and support with genetic insights from the large-scale Deciphering Developmental Disorders (DDD) study, finds a new study. Researchers from the University of Exeter and the Royal Devon University Healthcare NHS Foundation Trust followed up on the impact of those diagnosed as part of the DDD study, a collaboration between the NHS and the Wellcome Sanger Institute. This large-scale project, which began over a decade ago, has led to life-changing diagnoses for over 5,500 families across the UK and Ireland and the discovery of 60 new genetic conditions. The findings, published in Genetics in Medicine Open (14 October), reveal that over a thousand of those diagnosed were able to alter their treatment or undergo further medical testing based on their genetic findings, significantly improving their quality of life...

New Genetic Insights Into Alopecia Areata Alopecia areata has a genetic relationship with trace elements, serum metabolites, and inflammatory factors that highlights the potential value of targeted therapeutic strategies and preventive measures, according to a study published in Skin Research and Technology .1 Genetics, environmental factors, and immune dysregulation influence alopecia areata development. There is an increased risk between alopecia areata and atopy and allergies such as hay fever, eczema, asthma, and allergies to pollen, dust, and cats.2 Hypothyroidism has also been found to contribute to the development of alopecia areata among patients.3 Currently, there is little research that explores the association between developing alopecia areata and the progression of trace elements, serum modalities, and inflammatory cytokines that could be influencing the onset of the disease.1 Trace elements are essential building blocks for cells that play a crucial role in processes lik...