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Forward genetics

Kentaro Noma, Yishi Jin
Forward genetic screening in model organisms is the workhorse to discover functionally important genes and pathways in many biological processes. In most mutagenesis-based screens, researchers have relied on the use of toxic chemicals, carcinogens, or irradiation, which requires designated equipment, safety setup, and/or disposal of hazardous materials. We have developed a simple approach to induce heritable mutations in C. elegans using germline-expressed histone-miniSOG, a light-inducible potent generator of reactive oxygen species...
November 14, 2016: Journal of Visualized Experiments: JoVE
Heidi S Fisher, Emily Jacobs-Palmer, Jean-Marc Lassance, Hopi E Hoekstra
An extensive array of reproductive traits varies among species, yet the genetic mechanisms that enable divergence, often over short evolutionary timescales, remain elusive. Here we examine two sister-species of Peromyscus mice with divergent mating systems. We find that the promiscuous species produces sperm with longer midpiece than the monogamous species, and midpiece size correlates positively with competitive ability and swimming performance. Using forward genetics, we identify a gene associated with midpiece length: Prkar1a, which encodes the R1α regulatory subunit of PKA...
December 2, 2016: Nature Communications
Steffen Just, Linda Raphel, Ina M Berger, Anja Bühler, Mirjam Keßler, Wolfgang Rottbauer
The molecular mechanisms that regulate cardiomyocyte proliferation during embryonic heart growth are not completely deciphered yet. In a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified the recessive embryonic-lethal zebrafish mutant line weiches herz (whz). Homozygous mutant whz embryos display impaired heart growth due to diminished embryonic cardiomyocyte proliferation resulting in cardiac hypoplasia and weak cardiac contraction. By positional cloning, we found in whz mutant zebrafish a missense mutation within the T-box 20 (Tbx20) transcription factor gene leading to destabilization of Tbx20 protein...
2016: PloS One
Lazaros Vasilikos, Lisanne M Spilgies, Janin Knop, WWei-Lynn Wong
Understanding how Inhibitors of APoptosis proteins (IAPs) regulate apoptosis and necroptosis has been fast-forwarded by the use of Smac mimetics to deplete or inhibit the IAPs, specifically cIAP1& 2 and XIAP. The loss or inhibition of cIAP1, cIAP2 and XIAP causes the majority of cells to be sensitized to death receptor induced cell death, particularly tumour necrosis factor (TNF). Mouse genetics shows that there is some functional redundancy and the use of Smac mimetics has allowed us to understand how changing the composition of proteins recruited to TNF receptor 1 upon TNF ligation can alter protein complex formation and activation of apoptosis or necroptosis, particularly when caspases are inhibited...
December 1, 2016: Immunology and Cell Biology
Casper-Emil T Pedersen, Kirk E Lohmueller, Niels Grarup, Peter Bjerregaard, Torben Hansen, Hans R Siegismund, Ida Moltke, Anders Albrechtsen
The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit here we show that the Inuit have undergone a severe ~20,000 year long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation...
November 30, 2016: Genetics
Sarah D Battenfield, Carlos Guzmán, R Chris Gaynor, Ravi P Singh, Roberto J Peña, Susanne Dreisigacker, Allan K Fritz, Jesse A Poland
Wheat ( L.) cultivars must possess suitable end-use quality for release and consumer acceptability. However, breeding for quality traits is often considered a secondary target relative to yield largely because of amount of seed needed and expense. Without testing and selection, many undesirable materials are advanced, expending additional resources. Here, we develop and validate whole-genome prediction models for end-use quality phenotypes in the CIMMYT bread wheat breeding program. Model accuracy was tested using forward prediction on breeding lines ( = 5520) tested in unbalanced yield trials from 2009 to 2015 at Ciudad Obregon, Sonora, Mexico...
July 2016: Plant Genome
Maciej Grzybek, Aleksandra Golonko, Marta Walczak, Pawel Lisowski
The reprogramming of human induced pluripotent stem cells (hiPSCs) proceeds in a stepwise manner with reprogramming factors binding and epigenetic composition changes during transition to maintain the epigenetic landscape, important for pluripotency. There arises a question as to whether the aberrant epigenetic state after reprogramming leads to epigenetic defects in induced stem cells causing unpredictable long term effects in differentiated cells. In this review, we present a comprehensive view of epigenetic alterations accompanying reprogramming, cell maintenance and differentiation as factors that influence applications of hiPSCs in stem cell based technologies...
November 23, 2016: Neurobiology of Disease
Bruce Beutler
As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps...
December 2016: Best Practice & Research. Clinical Haematology
William Blum
The question posed above assumes that we are going nowhere in therapies for myelodysplastic syndromes (MDS) and asks, why? Yet, in recent years novel and effective therapies for MDS indeed have begun to emerge, particularly in patients with lower-risk disease. Beyond this, however, most of the progress has been limited to advances in allogeneic transplantation for higher-risk patients. This discussion will focus first on areas where we have moved beyond "stagnation," including these advances in supportive care for lower-risk patients and in emerging transplant gains...
December 2016: Best Practice & Research. Clinical Haematology
Madhurankhi Goswami, Purnita Bhattacharyya, Prosun Tribedi
A population exhibiting Allee effect shows a positive correlation between population fitness and population size or density. Allee effect decides the extinction or conservation of a microbial population and thus appears to be an important criterion in population ecology. The underlying factor of Allee effect that decides the stabilization and extinction of a particular population density is the threshold or the critical density of their abundance. According to Allee, microbial populations exhibit a definite, critical or threshold density, beyond which the population fitness of a particular population increases with the rise in population density and below it, the population fitness goes down with the decrease in population density...
November 25, 2016: Archives of Microbiology
Thomas A Delomas, Konrad Dabrowski
Haploid gynogenetic screens increase the efficiency of forward genetic screens and linkage analysis in fish. Typically, UV-irradiated zebrafish sperm is used to activate zebrafish oocytes for haploid screens. We describe the use of UV-irradiated common carp sperm to activate haploid gynogenetic zebrafish development. Carp × zebrafish hybrids are shown to have a characteristic set of features during embryonic development and exhibit functional development of several tissues (muscle, heart and nervous system)...
November 2016: Biology Letters
Norimasa Iwanami, Katarzyna Sikora, Andreas S Richter, Maren Mönnich, Lucia Guerri, Cristian Soza-Ried, Divine-Fondzenyuy Lawir, Fernando Mateos, Isabell Hess, Connor P O'Meara, Michael Schorpp, Thomas Boehm
Lymphocytes represent basic components of vertebrate adaptive immune systems, suggesting the utility of non-mammalian models to define the molecular basis of their development and differentiation. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. The identification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication and/or repair pathways known from studies of immunocompromised mammals provided an evolutionary cross-validation of the screen design...
November 22, 2016: Cell Reports
Xin Wang, Limin Hao, Taixiang Saur, Katelyn Joyal, Ying Zhao, Desheng Zhai, Jie Li, Mochtar Pribadi, Giovanni Coppola, Bruce M Cohen, Edgar A Buttner
An abnormally expanded GGGGCC repeat in C9ORF72 is the most frequent causal mutation associated with amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD). Both gain-of-function (gf) and loss-of-function (lf) mechanisms have been involved in C9ORF72 related ALS/FTLD. The gf mechanism of C9ORF72 has been studied in various animal models but not in C. elegans. In the present study, we described mutant C9ORF72 modeling in C. elegans and report the finding of two suppressor genes. We made transgenes containing 9 or 29 repeats of GGGGCC in C9ORF72, driven by either the hsp-16 promoters or the unc-119 promoter...
2016: Frontiers in Molecular Neuroscience
Takehito Nakazawa, Ayako Izuno, Rina Kodera, Yasumasa Miyazaki, Masahiro Sakamoto, Yuji Isagi, Yoichi Honda
White-rot fungi play an important role in the global carbon cycle because they are the species that almost exclusively biodegrade wood lignin in nature. Lignin peroxidases (LiPs), manganese peroxidases (MnPs), and versatile peroxidases (VPs) are considered key players in the ligninolytic system. Apart from LiPs, MnPs, and VPs, however, only few other factors involved in the ligninolytic system have been investigated using molecular genetics, implying the existence of unidentified elements. By combining classical genetic techniques with next-generation sequencing technology, we successfully showed an efficient forward genetics approach to identify mutations causing defects in the ligninolytic system of the white-rot fungus Pleurotus ostreatus...
November 21, 2016: Environmental Microbiology
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level...
November 21, 2016: Nature Medicine
Wang Nan, Zhao Shizhen, Lv Menghua, Xiang Fengning, Li Shuo
The yield of soybean is substantially reduced when the crop is grown in salinity-affected soil. This review summarizes the progress achieved in defining the genetic basis of salinity tolerance. Both forward (uncovering the genetic basis of a phenotype by exploiting natural or induced mutations) and reverse (defining the phenotype which arises as a result of an altered DNA sequence) genetics methods have been used to reveal the function of key salinity response genes. Quantitative trait locus analysis has identified six regions of the genome which harbor loci influencing salinity tolerance, and positional cloning has succeeded in isolating one important salt tolerant gene...
November 20, 2016: Yi Chuan, Hereditas
Asa Rahimi, Gursev Anmole, Maribel Soto-Nava, Tania Escamilla-Gomez, Tristan Markle, Steven W Jin, Guinevere Q Lee, P Richard Harrigan, David R Bangsberg, Jeffrey Martin, Santiago Avila-Rios, Gustavo Reyes-Teran, Mark A Brockman, Zabrina L Brumme
The HIV-1 accessory protein Vpu exhibits high inter- and intra- subtype genetic diversity that may influence Vpu function and possibly contribute to HIV-1 pathogenesis. However, scalable methods to evaluate genotype/phenotype relationships in natural Vpu sequences are limited, particularly those expressing the protein in CD4+ T-cells, the natural target of HIV-1 infection. A major impediment to assay scalability is the extensive genetic diversity within, and immediately upstream of, Vpu's initial 5' coding region, which has necessitated the design of oligonucleotide primers specific for each individual HIV-1 isolate (or subtype)...
November 16, 2016: Journal of Virological Methods
Elena Babiychuk, Khai Trinh Hoang, Klaas Vandepoele, Eveline Van De Slijke, Danny Geelen, Geert De Jaeger, Junichi Obokata, Sergei Kushnir
The evolutionarily conserved 12-subunit RNA polymerase II (Pol II) is a central catalytic component that drives RNA synthesis during the transcription cycle that consists of transcription initiation, elongation, and termination. A diverse set of general transcription factors, including a multifunctional TFIIF, govern Pol II selectivity, kinetic properties, and transcription coupling with posttranscriptional processes. Here, we show that TFIIF of Arabidopsis (Arabidopsis thaliana) resembles the metazoan complex that is composed of the TFIIFα and TFIIFβ polypeptides...
November 10, 2016: Plant Journal: for Cell and Molecular Biology
P Milanesi, R Holderegger, K Bollmann, F Gugerli, F Zellweger
Estimating connectivity among fragmented habitat patches is crucial for evaluating the functionality of ecological networks. However, current estimates of landscape resistance to animal movement and dispersal lack landscape-level data on local habitat structure. Here, we used a landscape genetics approach to show that high-fidelity habitat structure maps derived from Light Detection and Ranging (LiDAR) data critically improve functional connectivity estimates compared to conventional land cover data. We related pairwise genetic distances of 128 capercaillie (Tetrao urogallus) genotypes to least-cost path distances at multiple scales derived from land cover data...
November 11, 2016: Ecology
Emmanuel Paradis, Thierry Gosselin, Niklaus J Grünwald, Thibaut Jombart, Stéphanie Manel, Hilmar Lapp
As a scientific field, population genetics, despite its relatively young age, occupies a central place in biology. It was considered early on, well before the foundation of molecular genetics, as the way forward to solve the forces behind the evolution of species (Fisher 1930). Today, many pressing issues in understanding or predicting biological responses are investigated through population genetics approaches, for example the adaptation of populations of animals or plants facing human-mediated global changes such as habitat destruction or climate warming (Fordham et al...
November 14, 2016: Molecular Ecology Resources
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