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Current Opinion in Genetics & Development

Barbara Mair, Jason Moffat, Charles Boone, Brenda J Andrews
The genotype-to-phenotype relationship in health and disease is complex and influenced by both an individual's environment and their unique genome. Personal genetic variants can modulate gene function to generate a phenotype either through a single gene effect or through genetic interactions involving two or more genes. The relevance of genetic interactions to disease phenotypes has been particularly clear in cancer research, where an extreme genetic interaction, synthetic lethality, has been exploited as a therapeutic strategy...
April 8, 2019: Current Opinion in Genetics & Development
Stephen J Pettitt, Christopher J Lord
The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now been approved for use in a wider group of gynaecological cancers as well as for the treatment of BRCA-gene mutant breast cancer. Despite these advances, resistance to PARPi is a common clinical phenotype. Understanding, at the molecular level, how tumour cells respond to PARPi has the potential to inform how these drugs should be used clinically and since the discovery of this drug class, multiple different functional genomic strategies have been employed to dissect PARPi sensitivity and resistance...
April 4, 2019: Current Opinion in Genetics & Development
Anirudh Prahallad, Michael Rugaard Jensen, Emilie Anne Chapeau
Acquired resistance is a major limitation for the successful treatment of cancer patients. Although numerous efficacious cancer therapeutics have been developed in the past decades, resistance arises due to a variety of reasons including tumoral genetic alterations, or modulation of factors in the tumor environment. Understanding the mechanistic reasons for tumor relapse supports the identification of novel combination therapies that could lead to more durable responses. Here, we will review large-scale in vivo screens in pre-clinical cancer models that employed genetic and pharmacological agents toward elucidating acquired drug resistance and informing on beneficial combinations to be tested in clinical trials...
April 3, 2019: Current Opinion in Genetics & Development
Matthias Hinterndorfer, Johannes Zuber
Drug development remains a slow and expensive process, while the effective use of established therapeutics is widely hampered by our limited understanding of response and resistance mechanisms. Functional-genetic tools such as CRISPR/Cas9, advanced RNAi methods, and targeted protein degradation, together with other emerging technologies such as time-resolved and single-cell transcriptomics, fundamentally change the way we can search for candidate therapeutic targets and evaluate them before drug development...
April 2, 2019: Current Opinion in Genetics & Development
Yuen-Yi Tseng, Jesse S Boehm
Precision cancer medicine is based on the ability to predict the dependencies of a given tumor from its molecular makeup. These dependencies can be exploited with targeted, cytotoxic and/or immunity-inducing therapeutics. Ongoing efforts to perform genomic and cellular analyses on clinically annotated patient tumors are powerful, but bounded to existing therapies and focused cohorts. Here, we describe how living tumor material is increasingly being used in the generation of a systematic laboratory-based functional map of cancer dependencies (a 'Cancer Dependency Map')...
March 28, 2019: Current Opinion in Genetics & Development
Maja Kneissig, Sara Bernhard, Zuzana Storchova
Cancer cells differ from healthy cells by genetic information that is massively altered not only by point mutations and small insertions and deletions, but also by large scale changes such as chromosomal rearrangements as well as gains and losses of individual chromosomes or entire chromosome sets. How exactly large-scale chromosomal abnormalities contribute to tumorigenesis has been difficult to study. Remarkable progress has been recently made thanks to in vitro models that mimic large-scale chromosomal aberrations and allow their systematic analysis...
March 25, 2019: Current Opinion in Genetics & Development
Amaia Lujambio, Ana Banito
Cellular senescence is implicated in numerous biological processes, and can play pleiotropic, sometimes opposing, roles in cancer. Several triggers, cell types, contexts, and senescence-associated phenotypes introduce a multitude of possibilities when studying this process and its biological consequences. Recent studies continue to characterize cellular senescence at different levels, using a combination of functional screens, in silico analysis, omics characterizations and more targeted studies. However, a comprehensive analysis of its context-dependent effects and multiple phenotypes is required...
March 13, 2019: Current Opinion in Genetics & Development
Ultan McDermott
In the last decade, we have witnessed tremendous advances in our understanding of the landscape of the molecular alterations that underpin many of the most prevalent cancers, in the use of automated high throughput platforms for high-throughput drug screens in cancer cells, in the creation of more clinically relevant cancer cell models, in the application of CRISPR genetic screens for novel target identification, and lastly in the development of more useful computational approaches in the pursuit of biomarkers of drug response...
March 7, 2019: Current Opinion in Genetics & Development
Hervé Tiriac, Dennis Plenker, Lindsey A Baker, David A Tuveson
Despite recent advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) still retains the worst survival rate of common malignancies. Late diagnosis and lack of curative therapeutic options are the most pressing clinical problems for this disease. Therefore, there is a need for patient models and biomarkers that can be applied in the clinic to identify the most effective therapy for a patient. Pancreatic ductal organoids are ex-vivo models of PDAC that can be established from very small biopsies, enabling the study of localized, advanced, and metastatic patients...
March 4, 2019: Current Opinion in Genetics & Development
Claudia Scholl, Stefan Fröhling
Catalyzed by the ability to develop precision therapies targeting the unique genetic changes that drive individual tumors, sequencing patients' tumor genomes is an increasingly common practice in oncology. In most cancer types, however, a limited number of common mutations are accompanied by a plethora of low-frequency variants whose functional consequences and clinical actionability are often unknown. We here illustrate that this 'long tail' of infrequent molecular alterations includes oncogenic drivers of biological significance that can be the genetic basis of extraordinary responses to systemic cancer therapies...
March 4, 2019: Current Opinion in Genetics & Development
Brenna M Henn, Lluis Quintana-Murci
No abstract text is available yet for this article.
December 2018: Current Opinion in Genetics & Development
Francesco Montinaro, Cristian Capelli
The genomic variability of Southern African groups is characterized by an exceptional degree of diversity, which is the result of long-term local evolutionary history, migrations and gene-flow. Over the last few years several investigations have identified and described signatures related to these processes, revealing how ancient and more recent events have shaped the structure and ancestry composition of local populations. Here we discuss recent insights into the genetic history of the Southernmost part of the African continent provided by the analysis of modern and ancient genomes...
December 2018: Current Opinion in Genetics & Development
Brenna M Henn, Teresa E Steele, Timothy D Weaver
Accumulating genomic, fossil and archaeological data from Africa have led to a renewed interest in models of modern human origins. However, such discussions are often discipline-specific, with limited integration of evidence across the different fields. Further, geneticists typically require explicit specification of parameters to test competing demographic models, but these have been poorly outlined for some scenarios. Here, we describe four possible models for the origins of Homo sapiens in Africa based on published literature from paleoanthropology and human genetics...
December 2018: Current Opinion in Genetics & Development
Aaron P Ragsdale, Claudia Moreau, Simon Gravel
Evolutionary, biological, and demographic processes together shape observed variation in populations. Understanding how these processes influence variation allows us to infer past demography and the nature of selection in populations. Forward in time models such as the diffusion approximation provide a powerful tool for performing inference based on the distribution of allele frequencies. Here, we discuss recent computational developments and their application to reconstructing human demographic history. Using whole-genome sequence data for 797 French Canadian individuals, we assess the neutrality of synonymous variants and show that selection can bias inferred demography, mutation rates, and distributions of fitness effects...
December 2018: Current Opinion in Genetics & Development
Melissa Ilardo, Rasmus Nielsen
Modern humans inhabit most of earth's harshest environments and display a wide array of lifestyles. Biological adaptations, in addition to technological innovations, have enabled these geographical and cultural explorations. The study of these adaptations helps not only to fundamentally understand our evolution as a species, but also may have increasing relevance as genomics transforms fields such as personalized medicine. Here we review three cultural and environmental shifts that have brought about adaptations in modern humans; the arctic, high altitudes, and a subsistence dependent on breath-hold diving...
December 2018: Current Opinion in Genetics & Development
Connie J Mulligan
Epigenetic variation represents a unique aspect of human biological variation that can shed light on our evolutionary history as well as the etiology of human disease. DNA methylation is the most commonly studied type of epigenetic modification and can alter gene expression without changing the underlying DNA sequence. DNA methylation occurs throughout all living organisms although its function seems to have evolved from genome defense in fungi, bacteria and plants to a more complex role in gene regulation and cellular differentiation in animals...
December 2018: Current Opinion in Genetics & Development
Iosif Lazaridis
I review the evolutionary history of human populations in Europe with an emphasis on what has been learned in recent years through the study of ancient DNA. Human populations in Europe ∼430-39kya (archaic Europeans) included Neandertals and their ancestors, who were genetically differentiated from other archaic Eurasians (such as the Denisovans of Siberia), as well as modern humans. Modern humans arrived to Europe by ∼45kya, and are first genetically attested by ∼39kya when they were still mixing with Neandertals...
December 2018: Current Opinion in Genetics & Development
Georgina A Stooke-Vaughan, Otger Campàs
During embryogenesis, tissues and organs are progressively shaped into their functional morphologies. While the information about tissue and organ shape is encoded genetically, the sculpting of embryonic structures in the 3D space is ultimately a physical process. The control of physical quantities involved in tissue morphogenesis originates at cellular and subcellular scales, but it is their emergent behavior at supracellular scales that guides morphogenetic events. In this review, we highlight the physical quantities that can be spatiotemporally tuned at supracellular scales to sculpt tissues and organs during embryonic development of animal species, and connect them to the cellular and molecular mechanisms controlling them...
October 31, 2018: Current Opinion in Genetics & Development
Ludovica Molinaro, Luca Pagani
Since the discovery of the first hominin fossils, East Africa has been in the spotlight of palaeo-anthropological investigation for its role as a potential cradle of humanity and as a gateway out of Africa. With the advent of the genomic era an ever increasing amount of information has started to complement this notion, and to place the area within a broader, Pan-African scenario. Here we examine the most recent genetic and fossil results that recapitulate the last hundreds of thousands of years of human evolution in the area, and point to a number of uncharted avenues that may complement the emerging scenario in the coming years...
October 23, 2018: Current Opinion in Genetics & Development
Knut Woltjen, Alex Bortvin
No abstract text is available yet for this article.
October 2018: Current Opinion in Genetics & Development
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