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Alejandro Burga

Bio: Alejandro Burga is an academic researcher from Austrian Academy of Sciences. The author has contributed to research in topics: Caenorhabditis elegans & Genetic variation. The author has an hindex of 8, co-authored 14 publications receiving 560 citations. Previous affiliations of Alejandro Burga include Pontifical Catholic University of Chile & Pompeu Fabra University.

Papers
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Journal ArticleDOI
08 Dec 2011-Nature
TL;DR: The model and methodology provide a framework for dissecting the causes of incomplete penetrance and establish that inter-individual variation in both specific and more general buffering systems combine to determine the outcome inherited mutations in each individual.
Abstract: Many mutations, including those that cause disease, only have a detrimental effect in a subset of individuals. The reasons for this are usually unknown, but may include additional genetic variation and environmental risk factors. However, phenotypic discordance remains even in the absence of genetic variation, for example between monozygotic twins, and incomplete penetrance of mutations is frequent in isogenic model organisms in homogeneous environments. Here we propose a model for incomplete penetrance based on genetic interaction networks. Using Caenorhabditis elegans as a model system, we identify two compensation mechanisms that vary among individuals and influence mutation outcome. First, feedback induction of an ancestral gene duplicate differs across individuals, with high expression masking the effects of a mutation. This supports the hypothesis that redundancy is maintained in genomes to buffer stochastic developmental failure. Second, during normal embryonic development we find that there is substantial variation in the induction of molecular chaperones such as Hsp90 (DAF-21). Chaperones act as promiscuous buffers of genetic variation, and embryos with stronger induction of Hsp90 are less likely to be affected by an inherited mutation. Simultaneously quantifying the variation in these two independent responses allows the phenotypic outcome of a mutation to be more accurately predicted in individuals. Our model and methodology provide a framework for dissecting the causes of incomplete penetrance. Further, the results establish that inter-individual variation in both specific and more general buffering systems combine to determine the outcome inherited mutations in each individual.

189 citations

Journal ArticleDOI
06 Jan 2012-Science
TL;DR: It is shown that the stimulation of a stress response can reduce mutation penetrance in Caenorhabditis elegans, illustrating how transient environmental stimuli can induce protection against mutations, how environmental responses can underlie variable mutation buffering, and how a fitness trade-off may make variation in stress signaling advantageous.
Abstract: Mutations often have consequences that vary across individuals. Here, we show that the stimulation of a stress response can reduce mutation penetrance in Caenorhabditis elegans. Moreover, this induced mutation buffering varies across isogenic individuals because of interindividual differences in stress signaling. This variation has important consequences in wild-type animals, producing some individuals with higher stress resistance but lower reproductive fitness and other individuals with lower stress resistance and higher reproductive fitness. This may be beneficial in an unpredictable environment, acting as a "bet-hedging" strategy to diversify risk. These results illustrate how transient environmental stimuli can induce protection against mutations, how environmental responses can underlie variable mutation buffering, and how a fitness trade-off may make variation in stress signaling advantageous.

156 citations

Journal ArticleDOI
09 Jun 2017-Science
TL;DR: A selfish element causing embryonic lethality in crosses between wild strains of the nematode Caenorhabditis elegans is discovered and the results suggest that other essential genes identified by genetic screens may turn out to be components of selfish elements.
Abstract: Selfish genetic elements spread in natural populations and have an important role in genome evolution. We discovered a selfish element causing embryonic lethality in crosses between wild strains of the nematode Caenorhabditis elegans . The element is made up of sup-35 , a maternal-effect toxin that kills developing embryos, and pha-1 , its zygotically expressed antidote. pha-1 has long been considered essential for pharynx development on the basis of its mutant phenotype, but this phenotype arises from a loss of suppression of sup-35 toxicity. Inactive copies of the sup-35/pha-1 element show high sequence divergence from active copies, and phylogenetic reconstruction suggests that they represent ancestral stages in the evolution of the element. Our results suggest that other essential genes identified by genetic screens may turn out to be components of selfish elements.

81 citations

Journal ArticleDOI
02 Jun 2017-Science
TL;DR: A comparative and predictive genomics approach is developed that uses the genome sequences of P. harrisi and its flighted relatives to find candidate genetic variants that likely contributed to the evolution of loss of flight.
Abstract: INTRODUCTION Changes in the size and proportion of limbs and other structures have played a key role in the evolution of species One common class of limb modification is recurrent wing reduction and loss of flight in birds Indeed, Darwin used the occurrence of flightless birds as an argument in favor of his theory of natural selection Loss of flight has evolved repeatedly and is found among 26 families of birds in 17 different orders Despite the frequency of these modifications, we have a limited understanding of their underpinnings at the genetic and molecular levels RATIONALE To better understand the evolution of changes in limb size, we studied a classic case of recent loss of flight in the Galapagos cormorant ( Phalacrocorax harrisi ) Cormorants are large water birds that live in coastal areas or near lakes, and P harrisi is the only flightless cormorant among approximately 40 extant species The entire population is distributed along the coastlines of Isabela and Fernandina islands in the Galapagos archipelago P harrisi has a pair of short wings, which are smaller than those of any other cormorant The extreme reduction of the wings and pectoral skeleton observed in P harrisi is an attractive model for studying the evolution of loss of flight because it occurred very recently; phylogenetic evidence suggests that P harrisi diverged from its flighted relatives within the past 2 million years We developed a comparative and predictive genomics approach that uses the genome sequences of P harrisi and its flighted relatives to find candidate genetic variants that likely contributed to the evolution of loss of flight RESULTS We sequenced and de novo assembled the whole genomes of P harrisi and three closely related flighted cormorant species We identified thousands of coding variants exclusive to P harrisi and classified them according to their probability of altering protein function based on conservation Variants most likely to alter protein function were significantly enriched in genes mutated in human skeletal ciliopathies, including Ofd1 , Evc , Wdr34 , and Ift122 We carried out experiments in Caenorhabditis elegans to confirm that a missense variant present in the Galapagos cormorant IFT122 protein is sufficient to affect ciliary function The primary cilium is essential for Hedgehog (Hh) signaling in vertebrates, and individuals affected by ciliopathies have small limbs and ribcages, mirroring the phenotype of P harrisi We also identified a 4–amino acid deletion in the regulatory domain of Cux1 , a highly conserved transcription factor that has been experimentally shown to regulate limb growth in chicken The four missing amino acids are perfectly conserved in all birds and mammals sequenced to date We tested the consequences of this deletion in a chondrogenic cell line and showed that it impairs the ability of CUX1 to transcriptionally up-regulate cilia-related genes (some of which contain function-altering variants in P harrisi ) and to promote chondrogenic differentiation Finally, we show that positive selection may have played a role in the fixation of the variants associated with loss of flight in P harrisi CONCLUSION Our results indicate that the combined effect of variants in genes necessary for the correct transcriptional regulation and function of the primary cilium likely contributed to the evolution of highly reduced wings and other skeletal adaptations associated with loss of flight in P harrisi Our approach may be generally useful for identification of variants underlying evolutionary novelty from genomes of closely related species

62 citations

Journal ArticleDOI
TL;DR: It is argued that, although the ‘typical’ phenotypic outcome of an individual's genome can be predicted, it is much more difficult to predict the actual outcome for a particular individual.
Abstract: One promise of personalized medicine is that it will be possible to make useful predictions about the phenotypes of individuals from their complete genome sequences (e.g. concerning their susceptibility to disease). However, to what extent is knowledge about an individual's genotype, together with information about the environment that they have experienced, sufficient to predict phenotypic variation? In the present review, we argue that, although the 'typical' phenotypic outcome of an individual's genome can be predicted, it is much more difficult to predict the actual outcome for a particular individual. We highlight three reasons for this. First, the outcome of mutations can be influenced by random (stochastic) processes. Second, genetic variation present in one generation can influence phenotypic traits in the next generation, even if individuals do not inherit this variation. Third, the environment experienced by one generation can influence phenotypic variation in the next generation. These contributions to phenotypic variation have long been appreciated by quantitative geneticists, although they have only recently been studied at the molecular level. Taken together, they mean that, in many cases, the genotypes of individuals and the environment that they experience may not be sufficient to determine their phenotypes. A more comprehensive genotype-to-phenotype model will be required to make accurate predictions about the biology of individuals.

45 citations


Cited by
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Journal Article

1,091 citations

Journal ArticleDOI
Mary E. Dickinson, Ann M. Flenniken, Xiao Ji1, Lydia Teboul2, Michael D. Wong, Jacqueline K. White3, Terrence F. Meehan4, Wolfgang Weninger5, Henrik Westerberg2, Hibret A. Adissu6, Candice N. Baker, Lynette Bower7, James M. Brown2, L. Brianna Caddle, Francesco Chiani8, Dave Clary7, James Cleak2, Mark J. Daly9, James M. Denegre, Brendan Doe3, Mary E. Dolan, Sarah M. Edie, Helmut Fuchs, Valerie Gailus-Durner, Antonella Galli3, Alessia Gambadoro8, Juan Gallegos10, Shiying Guo11, Neil R. Horner2, Chih-Wei Hsu, Sara Johnson2, Sowmya Kalaga, Lance C. Keith, Louise Lanoue7, Thomas N. Lawson2, Monkol Lek9, Monkol Lek12, Manuel Mark13, Susan Marschall, Jeremy Mason4, Melissa L. McElwee, Susan Newbigging6, Lauryl M. J. Nutter6, Kevin A. Peterson, Ramiro Ramirez-Solis3, Douglas J. Rowland7, Edward Ryder3, Kaitlin E. Samocha9, Kaitlin E. Samocha12, John R. Seavitt10, Mohammed Selloum13, Zsombor Szoke-Kovacs2, Masaru Tamura, Amanda G. Trainor7, Ilinca Tudose4, Shigeharu Wakana, Jonathan Warren4, Olivia Wendling13, David B. West14, Leeyean Wong, Atsushi Yoshiki, Daniel G. MacArthur9, Daniel G. MacArthur12, Glauco P. Tocchini-Valentini8, Xiang Gao11, Paul Flicek4, Allan Bradley3, William C. Skarnes3, Monica J. Justice, Helen Parkinson4, Mark W. Moore, Sara Wells2, Robert E. Braun, Karen L. Svenson, Martin Hrabé de Angelis15, Yann Herault13, Timothy J. Mohun16, Ann-Marie Mallon2, R. Mark Henkelman, Steve D.M. Brown2, David J. Adams3, Kevin C K Lloyd7, Colin McKerlie6, Arthur L. Beaudet10, Maja Bucan1, Stephen A. Murray 
22 Sep 2016-Nature
TL;DR: It is shown that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts and reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background.
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

928 citations

Journal ArticleDOI
TL;DR: The red harvester ant is a child of the Enlightenment, paying homage to Bacon and Newton but most of all to Condorcet, who trod the same intellectual path (and who came to grief in the Revolution for reasons probably not unrelated to his philosophy).
Abstract: When the red harvester ant is threatened, nestmates rush to its assistance. The message is a chemical one. Distress is communicated and help summoned by the potential victim ejecting a tiny cocktail of alkanes and terpenoids. Professor E 0 Wilson, who made this discovery, is a distinguished zoologist whose writings have twice been awarded Pulitzer Prizes. His interests extend far beyond entomology, however. Why should human communication be qualitatively different from that of the ant, in being achieved by definable, physicochemical processes? And, if this is the case, surely the same must be true of other social phenomena? Having conceded so much, on what grounds can we exclude other products of human activity such as the social sciences, arts, humanities and ethics? In a mechanistic universe, the whole of human civilization is the ultimate product of the interaction between genes and environment, incredibly complex, as Wilson admits, but susceptible to fundamentally the same analytic techniques as communication in the harvester ant. Consilience (literally, a 'jumping together') is the notion that a common groundwork of explanation applies not only to the sciences but also to the arts, ethics and religion. In his book Consiliencel Wilson applies a combination of broad learning and a style of baroque exuberance to put the case for such a unity of knowledge. Wilson is thus, as he makes clear, a child of the Enlightenment, paying homage to Bacon and Newton but most of all to Condorcet, who trod the same intellectual path (and who came to grief in the Revolution for reasons probably not unrelated to his philosophy). He mourns the triumph at the end of the eighteenth century of revelatory religion fearful of the outcomes of science, and most of all of Romanticism although regrettably overlooking the

829 citations

Journal ArticleDOI
TL;DR: Some of the limitations and pitfalls of prediction analysis are discussed and how naive implementations can lead to severe bias and misinterpretation of results are shown.
Abstract: The success of genome-wide association studies (GWASs) has led to increasing interest in making predictions of complex trait phenotypes, including disease, from genotype data. Rigorous assessment of the value of predictors is crucial before implementation. Here we discuss some of the limitations and pitfalls of prediction analysis and show how naive implementations can lead to severe bias and misinterpretation of results.

657 citations