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Health- and disease-related events may be of highly significance for patients and their relatives. Naming a medical diagnosis is one of them. It carries the inherent power of (re)configuring the individuals' life courses, which are moreover closely linked to those of their relatives, and especially blood families in the case of (hereditary) genetic diseases. Drawing on ethnographic observations and narratives from patients and relatives involved in some Belgian organizations concerned with genetic disorders, this paper is interested in the ways these concerned people make sense of the naming of a medical diagnosis event by (re)interpreting their past familial stories, trying...
Wellmer, Frank; Bowman, John L.; Davies, Brendan; Ferrándiz, Cristina; Fletcher, Jennifer C.; Franks, Robert G.; Graciet, Emmanuelle; Gregis, Veronica; Ito, Toshiro; Jack, Thomas P.; Jiao, Yuling; Kater, Martin M.; Ma, Hong; Meyerowitz, Elliot M.; Prunet, Nathanaël; Riechmann, José Luis
Almost three decades of genetic and molecular analyses have resulted in detailed insights into many of the processes that take place during flower development and in the identification of a large number of key regulatory genes that control these processes. Despite this impressive progress, many questions about how flower development is controlled in different angiosperm species remain unanswered. In this chapter, we discuss some of these open questions and the experimental strategies with which they could be addressed. Specifically, we focus on the areas of floral meristem development and patterning, floral organ specification and differentiation, as well as on the...
Association of genetic variation in IKZF1, ARID5B, CDKN2A, and CEBPE with the risk of acute lymphoblastic leukemia in Tunisian children and their contribution to racial differences in leukemia incidence
Gharbi, Hanene; Ben Hassine, Islem; Soltani, Ismail; Safra, Ines; Ouerhani, Slah; Othmen, Hind Bel Haj; Teber, Mouheb; Farah, Ahlem; Amouri, Hassiba; Toumi, Nourel Houda
Low incidence of clonality in cold water corals revealed through the novel use of standardized protocol adapted to deep sea sampling
Becheler, Ronan; Cassone, Anne-laure; Noël, Philippe; Mouchel, Olivier; Morrison, Cheryl L.; Arnaud-haond, Sophie
Sampling in the deep sea is a technical challenge, which has hindered the acquisition of robust datasets that are necessary to determine the fine-grained biological patterns and processes that may shape genetic diversity. Estimates of the extent of clonality in deep-sea species, despite the importance of clonality in shaping the local dynamics and evolutionary trajectories, have been largely obscured by such limitations. Cold-water coral reefs along European margins are formed mainly by two reef-building species, Lophelia pertusa and Madrepora oculata. Here we present a fine-grained analysis of the genotypic and genetic composition of reefs occurring in the Bay of Biscay,...
European colonization, not Polynesian arrival, impacted population size and genetic diversity in the critically endangered New Zealand Kākāpō.
Bergner, Laura M.; Dussex, Nicolas; Jamieson, Ian G.; Robertson, Bruce C.
Island endemic species are often vulnerable to decline and extinction following human settlement, and the genetic study of historical museum specimens can be useful in understanding these processes. The kākāpō (Strigops habroptilus) is a critically endangered New Zealand parrot that was formerly widespread and abundant. It is well established that both Polynesian and European colonization of New Zealand impacted the native avifauna, but the timeframe and severity of impacts have differed depending on species. Here, we investigated the relative importance of the 2 waves of human settlement on kākāpō decline, using microsatellites and mitochondrial DNA (mtDNA) to characterize recent kākāpō...
Shmakov, S.; Makarova, K. S.; Semenova, E.; Minakhin, L.; Severinov, K.; Koonin, E. V.; Regev, Aviv; Abudayyeh, Omar Osama; Gootenberg, Jonathan S; Konermann, Silvana M; Joung, Julia; Slaymaker, Ian; Cox, David Benjamin Turitz; Lander, Eric Steven; Zhang, Feng
The clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated genes (Cas) adaptive immune system defends microbes against foreign genetic elements via DNA or RNA-DNA interference. We characterize the class 2 type VI CRISPR-Cas effector C2c2 and demonstrate its RNA-guided ribonuclease function. C2c2 from the bacterium Leptotrichia shahii provides interference against RNA phage. In vitro biochemical analysis shows that C2c2 is guided by a single CRISPR RNA and can be programmed to cleave single-stranded RNA targets carrying complementary protospacers. In bacteria, C2c2 can be programmed to knock down specific mRNAs. Cleavage is mediated by catalytic residues in the two conserved Higher Eukaryotes...
Wang, Tim; Lander, Eric Steven; Sabatini, David
This protocol describes how to generate a single guide RNA (sgRNA) library for use in genetic screens. There are many online tools available for predicting sgRNA sequences with high target specificity and/or cleavage activity. Here, we refer the user to genome-wide sgRNA sequence predictions that we have developed for both the human and mouse and that are available from the Broad Institute website. Once a set of target genes and corresponding sgRNA sequences has been identified, customized oligonucleotide pools can be rapidly synthesized by a number of commercial vendors. Thereafter, as described here, the oligonucleotides can be efficiently cloned into...
Genetic Investigations of Sporadic Inclusion Body Myositis and Myopathies with Structural Abnormalities and Protein Aggregates in Muscle
The application of whole-exome sequencing (WES) has not only dramatically accelerated the discovery of pathogenic genes of Mendelian diseases, but has also shown promising findings in complex diseases. This thesis focuses on exploring genetic risk factors for a large series of sporadic inclusion body myositis (sIBM) cases, and identifying disease-causing genes for several groups of patients with abnormal structure and/or protein aggregates in muscle. Both conventional and advanced techniques were applied. Based on the International IBM Genetics Consortium (IIBMGC), the largest sIBM cohort of blood and muscle tissue for DNA analysis was collected as the initial part of this thesis....
BACKGROUND: Sickle Cell Anaemia (SCA) or homozygosity for the sickle haemoglobin gene (HbSS) is the most common genetic condition in the UK. A high prevalence of Sleep Disordered Breathing (SDB) in SCA is widely accepted but there is a lack of unselected population based studies. As Polysomnography (PSG) is expensive, screening for SDB using a robust tool, e.g. the Delta 12 (Δ12) index and 3% Oxygen Desaturation Indices (ODI) calculated from home pulse oximetry, should be validated. Elevated Cerebral Blood Flow Velocity (CBFV) is a predictor of stroke in SCA, and may be associated with SDB. METHODS AND RESULTS: Prevalence...
Tizei, PA; Csibra, E; Torres, L; Pinheiro, VB
Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules-gaining a deeper understanding of life in the process. Directed evolution is...
Boland, Torrey A.; McGuone, Declan; Jindal, Jenelle; Rocha, Marcelo; Cumming, Melissa; Rupprecht, Charles E.; Barbosa, Taciana Fernandes Souza; de Novaes Oliveira, Rafael; Chu, Catherine Jean; Cole, Andrew James; Kotait, Ivanete; Kuzmina, Natalia A.; Yager, Pamela A.; Kuzmin, Ivan V.; Hedley-Whyte, E. Tessa; Brown, Catherine M.; Rosenthal, Eric Scott
Eight years after emigrating from Brazil, an otherwise healthy man developed rabies. An exposure prior to immigration was reported. Genetic analysis revealed a canine rabies virus variant found only in the patient’s home country, and the patient had not traveled internationally since immigrating to the United States. We describe how epidemiological, phylogenetic, and viral sequencing data provided confirmation that rabies encephalomyelitis may present after a long, multiyear incubation period, a consideration that previously has been hypothesized without the ability to exclude a more recent exposure. Accordingly, rabies should be considered in the diagnosis of any acute encephalitis, myelitis, or encephalomyelitis.
Child Neurology: Exaggerated dermal melanocytosis in a hypotonic infant: A harbinger of GM1 gangliosidosis
Armstrong-Javors, Amy Elizabeth; Chu, Catherine Jean
Gangliosidoses are a group of rare lysosomal storage diseases (LySD) involving the accumulation of lipids in multiple organ systems, including the central and peripheral nervous systems. These disorders are inherited in an autosomal recessive pattern and are broadly grouped into 2 types. GM1 gangliosidoses (GM1) are due to a deficiency of the enzyme β-galactosidase, and GM2 diseases (Tay-Sachs, AB variant, and Sandhoff disease) are due to a deficiency of the enzyme β-hexosaminidase. GM1, first described biochemically by Dr. John S. O'Brien in the 1960s, is estimated to occur in 1 in 100,000–200,000 newborns.1 Despite being the first of the gangliosidoses...
Chu, Catherine Jean; Major, Philippe; Camposano, Susana; Muzykewicz, David; Thiele, Elizabeth Anne
Background: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. Methods: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. Results: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure;...
Reiff, Marian; Bernhardt, Barbara A; Mulchandani, Surabhi
New technologies have given us the ability to detect genomic variation at resolutions 50-100 times greater than earlier tests. The good news is that we can now detect variations that help explain developmental delays, autism, or multiple congenital anomalies in up to 20% of children. The bad news is that we can also detect small missing or extra pieces of chromosomes that remain unexplained: that is, we don’t know whether they have any clinical significance at all. The rapid pace of technological change may have outpaced the lab’s ability to interpret, providers’ abilities to explain, and patients’ abilities to understand...
Bernhardt, Barbara A; Pyeritz, Reed E
In families with genetic disorders due to a known genetic mutation, presymptomatic genetic testing can lead to early detection and treatment of inherited disorders that may manifest later in life. The health benefits for family members at increased risk, however, is limited by the predictive value of the genetic test, the availability of effective treatments, and individuals’ and families’ willingness to undergo genetic testing in the first place. This Issue Brief describes the case of a genetic condition for which genetic screening of family members is clearly useful, and just as clearly underused. It explores the barriers to the use...
Preventive Surgery is Associated with Reduced Cancer Risk and Mortality in Women with BRCA1 and BRCA2 Mutations
Domchek, Susan M; Rebbeck, Timothy R
Women who have inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have a substantially elevated risk of developing breast and ovarian cancer. For more than 10 years, researchers have studied whether preventive surgery (to remove breasts, ovaries, and/or fallopian tubes) can reduce the cancer and mortality risk in BRCA1/2 mutation carriers. This Issue Brief summarizes the results of the latest, largest, multinational study on the effects of preventive surgery in these women. The results are consistent with earlier studies and provide strong evidence for the use of preventive surgery as an effective approach to managing this genetic risk.
Halbert, Chanita Hughes
Genetic testing for susceptibility to breast and ovarian cancer (BRCA1/2 testing) has been available in clinical settings since 1996. Increasingly, such testing is helping women at increased risk make decisions about breast cancer screening and prevention. African American women have participated in genetic counseling and testing programs less than white women, despite greater rates of early onset disease and higher breast cancer mortality. The barriers and motivations for genetic testing among African American women are not well understood. This Issue Brief summarizes a series of studies that systematically explore African American women’s beliefs and intentions about BRCA1/2 testing. The findings...
Recently, the Food and Drug Administration approved a new drug, varenicline, to help people quit smoking. It is the first new smoking cessation drug in nearly a decade, and joins just two other pharmacotherapy approaches [nicotine replacement therapies (NRTs) and bupropion] that have been proven effective for the treatment of tobacco dependence. However, even the most effective treatments help just one in four smokers quit longterm. Smoking is the single most preventable cause of death in the U.S., killing nearly 440,000 Americans each year. Nearly 45 million Americans smoke, and about 32 million of them would like to quit. Evolving...
Rebbeck, Timothy R
In 2005, more than 200,000 new cases of prostate cancer will be detected in the United States, and about 30,000 men will die from the disease. African American men are particularly hard-hit, dying from this disease at more than twice the rate of European Americans. The reasons for this racial/ethnic disparity are largely unknown, but probably involve an interaction among genetic, environmental, and social factors. This Issue Brief reviews current knowledge about the genetic basis of prostate cancer and summarizes ongoing research at Penn that investigates the role of genetics in prostate cancer treatment and outcomes.
For more than a decade, reports have indicated that the supply of child neurologists is inadequate to provide care for the growing number of children with acquired and genetic neurological conditions. It is critical to understand how the shortages affect the practice of child neurology, the attitudes of child neurologists, and ability of the field to attract new members. This Issue Brief examines these workforce issues, and profiles the attitudes and practice characteristics of child neurologists and trainees.