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26.  Wnt6 is required for maxillary palp formation in Drosophila 
BMC Biology  2013;11:104.
Wnt6 is an evolutionarily ancient member of the Wnt family. In Drosophila, Wnt6 loss-of-function animals have not yet been reported, hence information about fly Wnt6 function is lacking. In wing discs, Wnt6 is expressed at the dorsal/ventral boundary in a pattern similar to that of wingless, an important regulator of wing size. To test whether Wnt6 also contributes towards wing size regulation, we generated Wnt6 knockout flies.
Wnt6 knockout flies are viable and have no obvious defect in wing size or planar cell polarity. Surprisingly, Wnt6 knockouts lack maxillary palps. Interestingly, Wnt6 is absent from the genome of hemipterans, correlating with the absence of maxillary palps in these insects.
Wnt6 is important for maxillary palp development in Drosophila, and phylogenetic analysis indicates that loss of Wnt6 may also have led to loss of maxillary palps on an evolutionary time scale.
PMCID: PMC3854539  PMID: 24090348
Drosophila; Wnt6; Maxillary palps
27.  Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease 
BMC Biology  2013;11:100.
Monogenic gain-of-function protein aggregation diseases, including Huntington’s disease, exhibit substantial variability in age of onset, penetrance, and clinical symptoms, even between individuals with similar or identical mutations. This difference in phenotypic expression of proteotoxic mutations is proposed to be due, at least in part, to the variability in genetic background. To address this, we examined the role of natural variation in defining the susceptibility of genetically diverse individuals to protein aggregation and toxicity, using the Caenorhabditis elegans polyglutamine model.
Introgression of polyQ40 into three wild genetic backgrounds uncovered wide variation in onset of aggregation and corresponding toxicity, as well as alteration in the cell-specific susceptibility to aggregation. To further dissect these relationships, we established a panel of 21 recombinant inbred lines that showed a broad range of aggregation phenotypes, independent of differences in expression levels. We found that aggregation is a transgressive trait, and does not always correlate with measures of toxicity, such as early onset of muscle dysfunction, egg-laying deficits, or reduced lifespan. Moreover, distinct measures of proteotoxicity were independently modified by the genetic background.
Resistance to protein aggregation and the ability to restrict its associated cellular dysfunction are independently controlled by the natural variation in genetic background, revealing important new considerations in the search for targets for therapeutic intervention in conformational diseases. Thus, our C. elegans model can serve as a powerful tool to dissect the contribution of natural variation to individual susceptibility to proteotoxicity.
Please see related commentary by Kaeberlein,
PMCID: PMC3816611  PMID: 24079614
Protein aggregation; Polyglutamine; Conformational disease; Genetic modifier; Natural variation
28.  Deciphering the role of natural variation in age-related protein homeostasis 
BMC Biology  2013;11:102.
Understanding the genetic basis of age-related diseases is a critical step toward developing therapies that promote healthy aging. Numerous genes have been identified that modulate lifespan, but the influence of natural variation in aging has not been well studied. A new report utilizing a transgenic protein aggregation model in Caenorhabditis elegans has provided important tools and insights into the relationship between natural genetic variation, protein aggregation, and age-related pathology.
See research article:
PMCID: PMC3849513  PMID: 24228595
29.  Q&A: Evolutionary capacitance 
BMC Biology  2013;11:103.
PMCID: PMC3849687  PMID: 24228631
30.  The Oct1 homolog Nubbin is a repressor of NF-κB-dependent immune gene expression that increases the tolerance to gut microbiota 
BMC Biology  2013;11:99.
Innate immune responses are evolutionarily conserved processes that provide crucial protection against invading organisms. Gene activation by potent NF-κB transcription factors is essential both in mammals and Drosophila during infection and stress challenges. If not strictly controlled, this potent defense system can activate autoimmune and inflammatory stress reactions, with deleterious consequences for the organism. Negative regulation to prevent gene activation in healthy organisms, in the presence of the commensal gut flora, is however not well understood.
We show that the Drosophila homolog of mammalian Oct1/POU2F1 transcription factor, called Nubbin (Nub), is a repressor of NF-κB/Relish-driven antimicrobial peptide gene expression in flies. In nub1 mutants, which lack Nub-PD protein, excessive expression of antimicrobial peptide genes occurs in the absence of infection, leading to a significant reduction of the numbers of cultivatable gut commensal bacteria. This aberrant immune gene expression was effectively blocked by expression of Nub from a transgene. We have identified an upstream regulatory region, containing a cluster of octamer sites, which is required for repression of antimicrobial peptide gene expression in healthy flies. Chromatin immunoprecipitation experiments demonstrated that Nub binds to octamer-containing promoter fragments of several immune genes. Gene expression profiling revealed that Drosophila Nub negatively regulates many genes that are involved in immune and stress responses, while it is a positive regulator of genes involved in differentiation and metabolism.
This study demonstrates that a large number of genes that are activated by NF-κB/Relish in response to infection are normally repressed by the evolutionarily conserved Oct/POU transcription factor Nub. This prevents uncontrolled gene activation and supports the existence of a normal gut flora. We suggest that Nub protein plays an ancient role, shared with mammalian Oct/POU transcription factors, to moderate responses to immune challenge, thereby increasing the tolerance to biotic stress.
PMCID: PMC3849502  PMID: 24010524
Antimicrobial peptides; Drosophila; Gene regulation; Host-pathogen interaction; Immune signaling; Innate immunity; NF-kappaB; Oct /POU transcription factors; Stress response
31.  Diversity is maintained by seasonal variation in species abundance 
BMC Biology  2013;11:98.
Some of the most marked temporal fluctuations in species abundances are linked to seasons. In theory, multispecies assemblages can persist if species use shared resources at different times, thereby minimizing interspecific competition. However, there is scant empirical evidence supporting these predictions and, to the best of our knowledge, seasonal variation has never been explored in the context of fluctuation-mediated coexistence.
Using an exceptionally well-documented estuarine fish assemblage, sampled monthly for over 30 years, we show that temporal shifts in species abundances underpin species coexistence. Species fall into distinct seasonal groups, within which spatial resource use is more heterogeneous than would be expected by chance at those times when competition for food is most intense. We also detect seasonal variation in the richness and evenness of the community, again linked to shifts in resource availability.
These results reveal that spatiotemporal shifts in community composition minimize competitive interactions and help stabilize total abundance.
PMCID: PMC3856667  PMID: 24007204
Species coexistence; Biodiversity; Fluctuation mediated coexistence; Storage effect; Stability
32.  Modeling the within-host dynamics of HIV infection 
BMC Biology  2013;11:96.
The new field of viral dynamics, based on within-host modeling of viral infections, began with models of human immunodeficiency virus (HIV), but now includes many viral infections. Here we review developments in HIV modeling, emphasizing quantitative findings about HIV biology uncovered by studying acute infection, the response to drug therapy and the rate of generation of HIV variants that escape immune responses. We show how modeling has revealed many dynamical features of HIV infection and how it may provide insight into the ultimate cure for this infection.
PMCID: PMC3765939  PMID: 24020860
34.  Low-dose radiation, scientific scrutiny, and requirements for demonstrating effects 
BMC Biology  2013;11:92.
Recent nuclear accidents have prompted renewed interest in the fitness consequences of low-dose radiation. Hiyama et al. provided information on such effects in the Japanese pale grass blue butterfly in a paper that has been viewed more than 300,000 times, prompting a barrage of criticism. These exchanges highlight the role of scrutiny in studies with potential effects on humans, but also raise questions about minimum requirements for demonstrating biological effects.
PMCID: PMC3765500  PMID: 23987799
35.  From aging worms to the influence of the microbiota: an interview with David Weinkove 
BMC Biology  2013;11:94.
PMCID: PMC3765615  PMID: 23984877
36.  Tony Pawson and the germination and flowering of cell signaling: an appreciation 
BMC Biology  2013;11:95.
PMCID: PMC3765445  PMID: 24502764
37.  Gene-environment and protein-degradation signatures characterize genomic and phenotypic diversity in wild Caenorhabditis elegans populations 
BMC Biology  2013;11:93.
Analyzing and understanding the relationship between genotypes and phenotypes is at the heart of genetics. Research on the nematode Caenorhabditis elegans has been instrumental for unraveling genotype-phenotype relations, and has important implications for understanding the biology of mammals, but almost all studies, including forward and reverse genetic screens, are limited by investigations in only one canonical genotype. This hampers the detection and functional analysis of allelic variants, which play a key role in controlling many complex traits. It is therefore essential to explore the full potential of the natural genetic variation and evolutionary context of the genotype-phenotype map in wild C. elegans populations.
We used multiple wild C. elegans populations freshly isolated from local sites to investigate gene sequence polymorphisms and a multitude of phenotypes including the transcriptome, fitness, and behavioral traits. The genotype, transcriptome, and a number of fitness traits showed a direct link with the original site of the strains. The separation between the isolation sites was prevalent on all chromosomes, but chromosome V was the largest contributor to this variation. These results were supported by a differential food preference of the wild isolates for naturally co-existing bacterial species. Comparing polymorphic genes between the populations with a set of genes extracted from 19 different studies on gene expression in C. elegans exposed to biotic and abiotic factors, such as bacteria, osmotic pressure, and temperature, revealed a significant enrichment for genes involved in gene-environment interactions and protein degradation.
We found that wild C. elegans populations are characterized by gene-environment signatures, and we have unlocked a wealth of genotype-phenotype relations for the first time. Studying natural isolates provides a treasure trove of evidence compared with that unearthed by the current research in C. elegans, which covers only a diminutive part of the myriad of genotype-phenotype relations that are present in the wild.
PMCID: PMC3846632  PMID: 23957880
Gene-environment interactions; Genotype-phenotype relations; Wild C. elegans strains; Transcriptomic diversity
38.  Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitro evidence 
BMC Biology  2013;11:91.
Subterranean blind mole rats (Spalax) are hypoxia tolerant (down to 3% O2), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of Spalax research, spontaneous tumors have never been recorded among thousands of individuals. Here we addressed the questions of (1) whether Spalax is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from Spalax possess tumor-suppressive activity.
Treating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed Spalax high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among Spalax no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2 Spalax individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment. In vitro experiments showed an extraordinary ability of normal Spalax cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated Spalax 3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with Spalax fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to Spalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or Acomys. Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.
This report provides pioneering evidence that Spalax is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of Spalax normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing Spalax to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.
PMCID: PMC3750378  PMID: 23937926
39.  Transcription of a protein-coding gene on B chromosomes of the Siberian roe deer (Capreolus pygargus) 
BMC Biology  2013;11:90.
Most eukaryotic species represent stable karyotypes with a particular diploid number. B chromosomes are additional to standard karyotypes and may vary in size, number and morphology even between cells of the same individual. For many years it was generally believed that B chromosomes found in some plant, animal and fungi species lacked active genes. Recently, molecular cytogenetic studies showed the presence of additional copies of protein-coding genes on B chromosomes. However, the transcriptional activity of these genes remained elusive. We studied karyotypes of the Siberian roe deer (Capreolus pygargus) that possess up to 14 B chromosomes to investigate the presence and expression of genes on supernumerary chromosomes.
Here, we describe a 2 Mbp region homologous to cattle chromosome 3 and containing TNNI3K (partial), FPGT, LRRIQ3 and a large gene-sparse segment on B chromosomes of the Siberian roe deer. The presence of the copy of the autosomal region was demonstrated by B-specific cDNA analysis, PCR assisted mapping, cattle bacterial artificial chromosome (BAC) clone localization and quantitative polymerase chain reaction (qPCR). By comparative analysis of B-specific and non-B chromosomal sequences we discovered some B chromosome-specific mutations in protein-coding genes, which further enabled the detection of a FPGT-TNNI3K transcript expressed from duplicated genes located on B chromosomes in roe deer fibroblasts.
Discovery of a large autosomal segment in all B chromosomes of the Siberian roe deer further corroborates the view of an autosomal origin for these elements. Detection of a B-derived transcript in fibroblasts implies that the protein coding sequences located on Bs are not fully inactivated. The origin, evolution and effect on host of B chromosomal genes seem to be similar to autosomal segmental duplications, which reinforces the view that supernumerary chromosomal elements might play an important role in genome evolution.
PMCID: PMC3751663  PMID: 23915065
B chromosomes; Segmental duplications; Gene duplications; Karyotype evolution; Cervidae
40.  Organization and regulation of intracellular plasma membrane-connected HIV-1 assembly compartments in macrophages 
BMC Biology  2013;11:89.
In HIV-1-infected human monocyte-derived macrophages (MDMs), virus particles assemble primarily on intracellularly sequestered plasma membrane domains termed intracellular plasma membrane-connected compartments (IPMCs). Despite their clear role in virus formation, little is known of the organization, composition, dynamics or function of these compartments.
We have used amphipathic membrane dyes to reveal the complex three-dimensional structure of IPMCs in whole MDMs and to visualize connections between IPMCs and the cell surface. The observation of similar IPMC structures in both infected and uninfected cells indicates that these compartments are not induced by virus infection, but are present constitutively in MDMs. By expressing a phospholipase Cδ pleckstrin homology domain linked to green fluorescent protein, we demonstrate that IPMCs contain phosphatidylinositol 4,5-bisphosphate. Live cell imaging of cells expressing this probe shows that IPMCs are dynamic, but relatively stable, sub-domains of the plasma membrane. As recent electron microscopy studies indicated that portions of IPMCs are coated with β2 integrin-containing focal adhesion-like complexes linked to actin, we investigated whether the actin cytoskeleton is required for the organization of IPMCs. In MDMs treated with the actin polymerization inhibitor latrunculin, the normally compact IPMCs dispersed into smaller structures that remained connected to the plasma membrane. Moreover, latrunculin enhanced the release of preformed, mature HIV-1 particles from infected MDMs.
IPMCs are constitutive features of MDMs that are continuous with the plasma membrane and are used as unique sites for the assembly of new virions following infection by HIV-1. A functionally intact actin cytoskeleton is required to maintain the organization of the IPMCs and, in HIV-1-infected cells, perturbation of the actin cytoskeleton influences both the organization of the compartment and the release of sequestered virus.
PMCID: PMC3751737  PMID: 23915020
Actin cytoskeleton; Compartment; HIV-1; IPMC; MDM
41.  Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain 
BMC Biology  2013;11:88.
Thiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class of antidiabetic agents, decreases the activity of the MRC. In isolated mitochondria from mouse liver, we measured the effects of PGZ treatment on MRC complex activities, fully-assembled complex I and its subunits, gene expression of complex I and III subunits, and [3H]PGZ binding to mitochondrial complexes.
In vitro, PGZ decreased activity of complexes I and III of the MRC, but in vivo only complex I activity was decreased in mice treated for 12 weeks with 10 mg/kg/day of PGZ. In vitro treatment of isolated liver mitochondria with PGZ disassembled complex I, resulting in the formation of several subcomplexes. In mice treated with PGZ, fully assembled complex I was increased and two additional subcomplexes were found. Formation of supercomplexes CI+CIII2+CIVn and CI+CIII2 decreased in mouse liver mitochondria exposed to PGZ, while formation of these supercomplexes was increased in mice treated with PGZ. Two-dimensional analysis of complex I using blue native/sodium dodecyl sulfate polyacrylamide gel electrophoresis (BN/SDS-PAGE) showed that in vitro PGZ induced the formation of four subcomplexes of 600 (B), 400 (C), 350 (D), and 250 (E) kDa, respectively. Subcomplexes B and C had NADH:dehydrogenase activity, while subcomplexes C and D contained subunits of complex I membrane arm. Autoradiography and coimmunoprecipitation assays showed [3H]PGZ binding to subunits NDUFA9, NDUFB6, and NDUFA6. Treatment with PGZ increased mitochondrial gene transcription in mice liver and HepG2 cells. In these cells, PGZ decreased intracellular ATP content and enhanced gene expression of specific protein 1 and peroxisome-proliferator activated receptor (PPAR)γ coactivator 1α (PGC-1α).
PGZ binds complex I subunits, which induces disassembly of this complex, reduces its activity, depletes cellular ATP, and, in mice and HepG2 cells, upregulates nuclear DNA-encoded gene expression of complex I and III subunits.
PMCID: PMC3751493  PMID: 23915000
ATP; Mitochondrial respiratory chain; Pioglitazone; Proteomic; Thiazolidinediones
43.  Viral phylogeny in court: the unusual case of the Valencian anesthetist 
BMC Biology  2013;11:83.
A large and complex outbreak of hepatitis C virus in Valencia, Spain that began 25 years ago led to the prosecution and conviction of an anesthetist who was accused of infecting hundreds of his patients. Evolutionary analyses of viral gene sequences were presented as evidence in the trial, and these are now described in detail by González-Candelas and colleagues in a paper published in BMC Biology. Their study illustrates the challenges and opportunities that arise from the use of phylogenetic inference in criminal trials concerning virus transmission.
See research article:
PMCID: PMC3717106  PMID: 24059471
44.  Molecular evolution in court: analysis of a large hepatitis C virus outbreak from an evolving source 
BMC Biology  2013;11:76.
Molecular phylogenetic analyses are used increasingly in the epidemiological investigation of outbreaks and transmission cases involving rapidly evolving RNA viruses. Here, we present the results of such an analysis that contributed to the conviction of an anesthetist as being responsible for the infection of 275 of his patients with hepatitis C virus.
We obtained sequences of the NS5B and E1-E2 regions in the viral genome for 322 patients suspected to have been infected by the doctor, and for 44 local, unrelated controls. The analysis of 4,184 cloned sequences of the E1-E2 region allowed us to exclude 47 patients from the outbreak. A subset of patients had known dates of infection. We used these data to calibrate a relaxed molecular clock and to determine a rough estimate of the time of infection for each patient. A similar analysis led to an estimate for the time of infection of the source. The date turned out to be 10 years before the detection of the outbreak. The number of patients infected was small at first, but it increased substantially in the months before the detection of the outbreak.
We have developed a procedure to integrate molecular phylogenetic reconstructions of rapidly evolving viral populations into a forensic setting adequate for molecular epidemiological analysis of outbreaks and transmission events. We applied this procedure to a large outbreak of hepatitis C virus caused by a single source and the results obtained played a key role in the trial that led to the conviction of the suspected source.
PMCID: PMC3717074  PMID: 23870105
HCV; Outbreak; Forensics; Molecular epidemiology; Nosocomial transmission; Compartmentalization; Maximum likelihood; Dating transmission events; Viral evolution
45.  Integration-deficient lentivectors: an effective strategy to purify and differentiate human embryonic stem cell-derived hepatic progenitors 
BMC Biology  2013;11:86.
Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods.
We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive cells expressed hepatoblast markers such as α-fetoprotein and cytokeratin 19. When further cultured for 16 days, these cells underwent differentiation into more mature cells and exhibited hepatocyte properties such as albumin secretion. Moreover, they were devoid of vector DNA integration.
We have developed an effective strategy to purify human hepatic cells from cultures of differentiating hPSCs, producing a novel tool that could be used not only for cell therapy but also for in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either pluripotent or adult stem cells.
PMCID: PMC3751548  PMID: 23870169
Tissue-specific progenitor cells; Hepatoblasts; Purification; Non-integrating lentiviral vectors
46.  Brain H2A.Z: the long and the short 
BMC Biology  2013;11:84.
The role of histone variants and their specific post-translational modifications (PTMs) in the epigenetic regulation of gene expression is still poorly understood. A paper published by Simonet and colleagues in Epigenetics and Chromatin describes a new H2A.Z subtype that is specific for brain and pituitary in the carp and provides additional information about the functional epigenetic complexity of the PTMs associated with histone H2A.Z.
See research article:
PMCID: PMC3716961  PMID: 23866047
47.  Juvenile hormone regulation of Drosophila aging 
BMC Biology  2013;11:85.
Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the hormone’s source. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet address whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging.
A tissue specific driver inducing an inhibitor of a protein phosphatase was used to ablate the corpora allata while permitting normal development of adult flies. Corpora allata knockout adults had greatly reduced fecundity, inhibited oogenesis, impaired adult fat body development and extended lifespan. Treating these adults with the juvenile hormone analog methoprene restored all traits toward wildtype. Knockout females remained relatively long-lived even when crossed into a genotype that blocked all egg production. Dietary restriction further extended the lifespan of knockout females. In an analysis of expression profiles of knockout females in fertile and sterile backgrounds, about 100 genes changed in response to loss of juvenile hormone independent of reproductive state.
Reduced juvenile hormone alone is sufficient to extend the lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of the vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of egg production. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity.
PMCID: PMC3726347  PMID: 23866071
Juvenile hormone; Drosophila; Lifespan; Fecundity; Fat body; Gene expression
48.  The genetics of infectious disease susceptibility: has the evidence for epistasis been overestimated? 
BMC Biology  2013;11:79.
Interactions amongst genes, known as epistasis, are assumed to make a substantial contribution to the genetic variation in infectious disease susceptibility, but this claim is controversial. Here, we focus on the debate surrounding the evolutionary importance of interactions between resistance loci and argue that its role in explaining overall variance in disease outcomes may have been overestimated.
PMCID: PMC3711976  PMID: 23855805
49.  Eye regression in blind Astyanax cavefish may facilitate the evolution of an adaptive behavior and its sensory receptors 
BMC Biology  2013;11:81.
The forces driving the evolutionary loss or simplification of traits such as vision and pigmentation in cave animals are still debated. Three alternative hypotheses are direct selection against the trait, genetic drift, and indirect selection due to antagonistic pleiotropy. Recent work establishes that Astyanax cavefish exhibit vibration attraction behavior (VAB), a presumed behavioral adaptation to finding food in the dark not exhibited by surface fish. Genetic analysis revealed two regions in the genome with quantitative trait loci (QTL) for both VAB and eye size. These observations were interpreted as genetic evidence that selection for VAB indirectly drove eye regression through antagonistic pleiotropy and, further, that this is a general mechanism to account for regressive evolution. These conclusions are unsupported by the data; the analysis fails to establish pleiotropy and ignores the numerous other QTL that map to, and potentially interact, in the same regions. It is likely that all three forces drive evolutionary change. We will be able to distinguish among them in individual cases only when we have identified the causative alleles and characterized their effects.
PMCID: PMC3726320  PMID: 23844714
Astyanax; Regressive evolution; Eye loss; Cavefish; QTL; Antagonistic pleiotropy; VAB
50.  Evolution of an adaptive behavior and its sensory receptors promotes eye regression in blind cavefish: response to Borowsky (2013) 
BMC Biology  2013;11:82.
Vibration attraction behavior (VAB) is the swimming of fish toward an oscillating object, a behavior that is likely adaptive because it increases foraging efficiency in darkness. VAB is seen in a small proportion of Astyanax surface-dwelling populations (surface fish) but is pronounced in cave-dwelling populations (cavefish). In a recent study, we identified two quantitative trait loci for VAB on Astyanax linkage groups 2 and 17. We also demonstrated that a small population of superficial neuromast sensors located within the eye orbit (EO SN) facilitate VAB, and two quantitative trait loci (QTL) were identified for EO SN that were congruent with those for VAB. Finally, we showed that both VAB and EO SN are negatively correlated with eye size, and that two (of several) QTL for eye size overlap VAB and EO SN QTLs. From these results, we concluded that the adaptive evolution of VAB and EO SN has contributed to the indirect loss of eyes in cavefish, either as a result of pleiotropy or tight physical linkage of the mutations underlying these traits. In a subsequent commentary, Borowsky argues that there is poor experimental support for our conclusions. Specifically, Borowsky states that: (1) linkage groups (LGs) 2 and 17 harbor QTL for many traits and, therefore, no evidence exists for an exclusive interaction among the overlapping VAB, EO SN and eye size QTL; (2) some of the QTL we identified are too broad (>20 cM) to support the hypothesis of correlated evolution due to pleiotropy or hitchhiking; and (3) VAB is unnecessary to explain the indirect evolution of eye-loss since the negative polarity of numerous eye QTL is consistent with direct selection against eyes. Borowsky further argues that (4) it is difficult to envision an evolutionary scenario whereby VAB and EO SN drive eye loss, since the eyes must first be reduced in order to increase the number of EO SN and, therefore, VAB. In this response, we explain why the evidence of one trait influencing eye reduction is stronger for VAB than other traits, and provide further support for a scenario whereby elaboration of VAB in surface fish may precede complete eye-loss.
PMCID: PMC3726343  PMID: 23844745
Animal behavior; Regressive evolution; Constructive evolution; Neuromast; Tradeoff; Pleiotropy; Quantitative trait locus; Eye; QTL cluster; Adaptation

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