Publications by authors named "Luis M Franco"

41 Publications

A distributed circuit for associating environmental context with motor choice in retrosplenial cortex.

Sci Adv 2021 Aug 25;7(35). Epub 2021 Aug 25.

Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.

During navigation, animals often use recognition of familiar environmental contexts to guide motor action selection. The retrosplenial cortex (RSC) receives inputs from both visual cortex and subcortical regions required for spatial memory and projects to motor planning regions. However, it is not known whether RSC is important for associating familiar environmental contexts with specific motor actions. We test this possibility by developing a task in which motor trajectories are chosen based on the context. We find that mice exhibit differential predecision activity in RSC and that optogenetic suppression of RSC activity impairs task performance. Individual RSC neurons encode a range of task variables, often multiplexed with distinct temporal profiles. However, the responses are spatiotemporally organized, with task variables represented along a posterior-to-anterior gradient along RSC during the behavioral performance, consistent with histological characterization. These results reveal an anatomically organized retrosplenial cortical circuit for associating environmental contexts with appropriate motor outputs.
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http://dx.doi.org/10.1126/sciadv.abf9815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386923PMC
August 2021

A Deep Learning Pipeline for Nucleus Segmentation.

Cytometry A 2020 12 19;97(12):1248-1264. Epub 2020 Nov 19.

High-Throughput Imaging Facility (HiTIF), Center for Cancer Research (CCR), NCI/NIH, Bethesda, Maryland, USA.

Deep learning is rapidly becoming the technique of choice for automated segmentation of nuclei in biological image analysis workflows. In order to evaluate the feasibility of training nuclear segmentation models on small, custom annotated image datasets that have been augmented, we have designed a computational pipeline to systematically compare different nuclear segmentation model architectures and model training strategies. Using this approach, we demonstrate that transfer learning and tuning of training parameters, such as the composition, size, and preprocessing of the training image dataset, can lead to robust nuclear segmentation models, which match, and often exceed, the performance of existing, off-the-shelf deep learning models pretrained on large image datasets. We envision a practical scenario where deep learning nuclear segmentation models trained in this way can be shared across a laboratory, facility, or institution, and continuously improved by training them on progressively larger and varied image datasets. Our work provides computational tools and a practical framework for deep learning-based biological image segmentation using small annotated image datasets. Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.
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http://dx.doi.org/10.1002/cyto.a.24257DOI Listing
December 2020

Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration.

Blood 2020 12;136(23):2667-2678

Laboratory of Immune System Biology, and.

Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine-labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.
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http://dx.doi.org/10.1182/blood.2020005161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735160PMC
December 2020

Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism.

Proc Natl Acad Sci U S A 2020 07 29;117(28):16481-16491. Epub 2020 Jun 29.

Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892;

Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. We previously reported that neutrophils from reproductive-age males are more immature and less activated than their female counterparts. To further characterize the mechanisms that drive differential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Female neutrophils displayed significant up-regulation of type I IFN (IFN)-stimulated genes (ISGs). Single-cell RNA-sequencing analysis indicated that these differences are neutrophil specific, driven by a distinct neutrophil subset and related to maturation status. Neutrophil hyperresponsiveness to type I IFNs promoted enhanced responses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism compared to those from females and this was modulated by estradiol. Assessment of ISGs and neutrophil maturation genes in Klinefelter syndrome (47, XXY) males and in prepubescent children supported that differences in neutrophil phenotype between adult male and female neutrophils are hormonally driven and not explained by X chromosome gene dosage. Our results indicate that there are distinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.
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http://dx.doi.org/10.1073/pnas.2003603117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368314PMC
July 2020

PAX1 is essential for development and function of the human thymus.

Sci Immunol 2020 02;5(44)

Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function mutations as the cause of a syndromic form of SCID due to altered thymus development.
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http://dx.doi.org/10.1126/sciimmunol.aax1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189207PMC
February 2020

Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses.

J Exp Med 2019 02 23;216(2):384-406. Epub 2019 Jan 23.

Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.
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http://dx.doi.org/10.1084/jem.20180595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363437PMC
February 2019

Transcript- and protein-level analyses of the response of human eosinophils to glucocorticoids.

Sci Data 2018 12 4;5:180275. Epub 2018 Dec 4.

Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Memorial Drive, Building 4, Room 138, Bethesda, MD 20892, USA.

Glucocorticoids are first-line agents for the treatment of many eosinophil-associated disorders; however, their effects on human eosinophils remain poorly understood. To gain an unbiased, genome-wide view of the early transcriptional effects of glucocorticoids on human eosinophils in vivo, RNA sequencing was performed on purified blood eosinophils obtained before and 30, 60, and 120 minutes after administration of a single dose of oral prednisone (1 mg/kg) to three unrelated healthy subjects with hypereosinophilia of unknown significance. The resulting dataset is of high quality and suitable for differential expression analysis. Flow cytometry and qPCR were then performed on three additional cohorts of human subjects, to validate the key findings at the transcript and protein levels. The resulting datasets provide a resource for understanding the response of circulating human eosinophils to glucocorticoid administration.
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http://dx.doi.org/10.1038/sdata.2018.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278693PMC
December 2018

Human CARD9: A Critical Molecule of Fungal Immune Surveillance.

Front Immunol 2018 6;9:1836. Epub 2018 Aug 6.

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.

CARD9 is a signaling adaptor protein that is involved in the transduction of signals from a variety of innate pattern recognition receptors, including the C-type lectin receptors and intracellular NOD receptors and nucleic acid sensors. As a result, CARD9 has been shown in animal models to be an important regulator of immunity to bacteria, fungi, and viruses. Studies in humans with autosomal recessive CARD9 deficiency have indicated a highly specific role for this molecule in the activation of antifungal immune responses in the central nervous system, the oral mucosa, and the skin. Moreover, CARD9-dependent functions have recently been indicated to modulate the development of autoimmunity, inflammatory bowel diseases, and cancer. In this mini-review, we highlight the recent studies that have identified several novel functions of CARD9 in various disease contexts, and we summarize the contemporary understanding of the genetics and immunology of human CARD9 deficiency.
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http://dx.doi.org/10.3389/fimmu.2018.01836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088205PMC
September 2019

Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome.

Curr Biol 2017 Apr 30;27(8):1111-1123. Epub 2017 Mar 30.

Neuroelectronics Research Flanders (NERF), KU Leuven, Kapeldreef 75, 3001 Leuven, Belgium; Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Olav Kyrres gate 9, 7030 Trondheim, Norway. Electronic address:

Fragile X syndrome (FXS) patients present neuronal alterations that lead to severe intellectual disability, but the underlying neuronal circuit mechanisms are poorly understood. An emerging hypothesis postulates that reduced GABAergic inhibition of excitatory neurons is a key component in the pathophysiology of FXS. Here, we directly test this idea in a FXS Drosophila model. We show that FXS flies exhibit strongly impaired olfactory behaviors. In line with this, olfactory representations are less odor specific due to broader response tuning of excitatory projection neurons. We find that impaired inhibitory interactions underlie reduced specificity in olfactory computations. Finally, we show that defective lateral inhibition across projection neurons is caused by weaker inhibition from GABAergic interneurons. We provide direct evidence that deficient inhibition impairs sensory computations and behavior in an in vivo model of FXS. Together with evidence of impaired inhibition in autism and Rett syndrome, these findings suggest a potentially general mechanism for intellectual disability.
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http://dx.doi.org/10.1016/j.cub.2017.02.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405172PMC
April 2017

Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections--A Prospective Cohort Study.

PLoS Pathog 2015 Jun 12;11(6):e1004869. Epub 2015 Jun 12.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.

To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.
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http://dx.doi.org/10.1371/journal.ppat.1004869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466531PMC
June 2015

Breast adenocarcinoma recurring as small cell carcinoma in a patient with a germline BRCA2 mutation: clonal evolution unchecked.

Exp Hematol Oncol 2015 6;4(1). Epub 2015 Jan 6.

Lester & Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM 660, Houston, Texas 77030 USA.

Background: Because up to 30% of breast cancer cases may relapse, understanding the biology of recurrent breast cancer is imperative in preventing these poor outcomes. Thus, we present this unusual case of a BRCA2 carrier who presented seven years after her initial diagnosis of breast adenocarcinoma with a new lump in the left axillary tail, which proved to be small cell carcinoma. The second cancer bore no morphologic or immunohistochemical resemblance to the first. However, we aimed to understand whether the two cancers could have been related.

Methods: We performed targeted Next Generation Sequencing on both cancer specimens in order to determine whether there was a genomic relationship between the two cancers.

Results: We found that the initial breast adenocarcinoma was positive for a heterozygous mutation in PIK3CA (c. 1624 G > A, p.E42K) and a heterozygous 13-basepair deletion in TP53 (c.639-651del, p.H214fs). The small cell cancer was positive for the same mutation in PIK3CA, but negative for the mutation in TP53.

Conclusion: We concluded that the small cell cancer may have arisen from a clone within the initial cancer, since they carried an identical genetic mutation. Furthermore, we postulate that the unusual morphology of the second cancer may be due, in part, to the patient's germline BRCA mutation.
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http://dx.doi.org/10.1186/2162-3619-4-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323278PMC
February 2015

Differential frequency-dependent antidromic resonance of the Schaffer collaterals and mossy fibers.

Brain Struct Funct 2016 05 11;221(4):1793-807. Epub 2015 Feb 11.

Department of Pharmacobiology, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios No. 235, 14330, Mexico D.F., Mexico.

To better understand information transfer along the hippocampal pathways and its plasticity, here we studied the antidromic responses of the dentate gyrus (DG) and CA3 to activation of the mossy fibers and Schaffer collaterals, respectively, in hippocampal slices from naïve and epileptic rats. We applied trains of 600 electrical stimuli at functionally meaningful frequencies (θ, β/γ and γ). The responses of the DG to θ frequency trains underwent rapid potentiation that lasted about 400 stimuli, after which they progressively returned to control value. At β/γ and γ frequencies, however, the initial potentiation was followed by a strong frequency-dependent depression within the first 50 stimuli. In kindled animals, the initial potentiation was stronger than in control preparations and the resonant phase at θ frequency lasted longer. In contrast, CA3 responses were exponentially depressed at all frequencies, but depression was significantly less intense at θ frequency in epileptic preparations. Failure of fibers to fire action potentials could account for some of the aforementioned characteristics, but waveforms of the intracellular action potentials also changed as the field responses did, i.e., half-duration and time-to-peak increased in both structures along the stimulation trains. Noteworthy, block of glutamate and GABA ionotropic receptors prevented resonance and reduced the depression of antidromic responses to β/γ and γ stimulation recorded in the DG, but not in CA3. We show that the different behavior in the information transfer along these pathways depends on the frequency at which action potentials are generated, excitability history and anatomical features, including myelination and tortuosity. In addition, the mossy fibers are endowed with ionotropic receptors and terminal active properties conferring them their sui generis non-passive antidromic responses.
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http://dx.doi.org/10.1007/s00429-015-1003-1DOI Listing
May 2016

Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males.

Int J Mol Epidemiol Genet 2014 22;5(3):164-76. Epub 2014 Oct 22.

Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA ; Section of Endocrinology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA.

Background: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear.

Goal: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males.

Methods: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction.

Results: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation.

Conclusions: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214264PMC
November 2014

The fungal aroma gene ATF1 promotes dispersal of yeast cells through insect vectors.

Cell Rep 2014 Oct 9;9(2):425-32. Epub 2014 Oct 9.

Laboratory for Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Gaston Geenslaan 1, 3001 Leuven (Heverlee), Belgium; VIB Laboratory of Systems Biology, Gaston Geenslaan 1, 3001 Leuven (Heverlee), Belgium. Electronic address:

Yeast cells produce various volatile metabolites that are key contributors to the pleasing fruity and flowery aroma of fermented beverages. Several of these fruity metabolites, including isoamyl acetate and ethyl acetate, are produced by a dedicated enzyme, the alcohol acetyl transferase Atf1. However, despite much research, the physiological role of acetate ester formation in yeast remains unknown. Using a combination of molecular biology, neurobiology, and behavioral tests, we demonstrate that deletion of ATF1 alters the olfactory response in the antennal lobe of fruit flies that feed on yeast cells. The flies are much less attracted to the mutant yeast cells, and this in turn results in reduced dispersal of the mutant yeast cells by the flies. Together, our results uncover the molecular details of an intriguing aroma-based communication and mutualism between microbes and their insect vectors. Similar mechanisms may exist in other microbes, including microbes on flowering plants and pathogens.
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http://dx.doi.org/10.1016/j.celrep.2014.09.009DOI Listing
October 2014

Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.

Cell 2014 Apr;157(3):636-50

Department of Radiology, MR Center of Excellence, Medical University of Vienna, Vienna 1090, Austria.

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.
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http://dx.doi.org/10.1016/j.cell.2014.02.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146440PMC
April 2014

Variable levels of tissue mosaicism can confound the interpretation of chromosomal microarray results from peripheral blood.

Eur J Med Genet 2014 May-Jun;57(6):264-6. Epub 2014 Mar 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Chromosomal microarray analysis (CMA) has significantly increased the ability to diagnose medical conditions caused by copy-number variation in the human genome. Given that the regions involved in copy-number abnormalities often encompass multiple genes, it has been common practice in recent years to compare the phenotypes of individuals with specific copy-number alterations identified by CMA, with the goal of identifying the critical regions for particular elements of a disease phenotype. It is rarely mentioned that this practice relies heavily on the assumption that the absence of mosaicism on CMA from a peripheral blood sample (the most common source of DNA in current clinical practice) reflects the absence of mosaicism in other tissues. We report here a case that violates that assumption. A 28-year-old male with Charcot-Marie-Tooth disease was found by CMA to have a duplication of 17p12 along with two other abnormalities: A duplication of 12p13.33 translocated to the long arm of chromosome 3 and an interstitial duplication of 12p11.23. The patient did not have any clinical features suggestive of 12p duplication syndrome. Chromosomal microarray analysis on skin fibroblasts revealed the duplications at 17p12 and 12p11.23, but not the terminal duplication of 12p13.33. FISH analysis on skin fibroblasts confirmed the presence of very low levels of mosaicism for the terminal 12p duplication. The case illustrates how the absence of mosaicism in blood is not always indicative of the absence of mosaicism in other tissues. Even in an era of high-throughput, highly accurate DNA-based tests, it is important to remember the limitations of testing before drawing conclusions about the relationship between a test results and a clinical phenotype.
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http://dx.doi.org/10.1016/j.ejmg.2014.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859793PMC
February 2015

WNT signaling pathway gene polymorphisms and risk of hepatic fibrosis and inflammation in HCV-infected patients.

PLoS One 2013 30;8(12):e84407. Epub 2013 Dec 30.

Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, United States of America ; Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuEST), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, United States of America ; Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, Texas, United States of America ; Texas Medical Center Digestive Disease Center, Houston, Texas, United States of America ; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.

Background: Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population.

Methods: We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis.

Results: Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation.

Conclusions: Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875538PMC
February 2015

Replicative mechanisms for CNV formation are error prone.

Nat Genet 2013 Nov 22;45(11):1319-26. Epub 2013 Sep 22.

1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Centro de Pesquisas René Rachou-FIOCRUZ, Belo Horizonte, Brazil.

We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex copy number variants. These single-nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR.
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http://dx.doi.org/10.1038/ng.2768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821386PMC
November 2013

Integrative genomic analysis of the human immune response to influenza vaccination.

Elife 2013 Jul 16;2:e00299. Epub 2013 Jul 16.

Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , United States ; Department of Medicine , Baylor College of Medicine , Houston , United States.

Identification of the host genetic factors that contribute to variation in vaccine responsiveness may uncover important mechanisms affecting vaccine efficacy. We carried out an integrative, longitudinal study combining genetic, transcriptional, and immunologic data in humans given seasonal influenza vaccine. We identified 20 genes exhibiting a transcriptional response to vaccination, significant genotype effects on gene expression, and correlation between the transcriptional and antibody responses. The results show that variation at the level of genes involved in membrane trafficking and antigen processing significantly influences the human response to influenza vaccination. More broadly, we demonstrate that an integrative study design is an efficient alternative to existing methods for the identification of genes involved in complex traits. DOI:http://dx.doi.org/10.7554/eLife.00299.001.
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http://dx.doi.org/10.7554/eLife.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713456PMC
July 2013

MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.

Hum Mol Genet 2013 Nov 16;22(21):4339-48. Epub 2013 Jun 16.

Department of Molecular and Human Genetics.

Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.
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http://dx.doi.org/10.1093/hmg/ddt283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792692PMC
November 2013

Neural circuits mediating olfactory-driven behavior in fish.

Front Neural Circuits 2013 11;7:62. Epub 2013 Apr 11.

Neuroelectronics Research Flanders Leuven, Belgium ; Vlaams Instituut voor Biotechnologie Leuven, Belgium.

The fish olfactory system processes odor signals and mediates behaviors that are crucial for survival such as foraging, courtship, and alarm response. Although the upstream olfactory brain areas (olfactory epithelium and olfactory bulb) are well-studied, less is known about their target brain areas and the role they play in generating odor-driven behaviors. Here we review a broad range of literature on the anatomy, physiology, and behavioral output of the olfactory system and its target areas in a wide range of teleost fish. Additionally, we discuss how applying recent technological advancements to the zebrafish (Danio rerio) could help in understanding the function of these target areas. We hope to provide a framework for elucidating the neural circuit computations underlying the odor-driven behaviors in this small, transparent, and genetically amenable vertebrate.
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http://dx.doi.org/10.3389/fncir.2013.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622886PMC
May 2014

A mosaic 2q24.2 deletion narrows the critical region to a 0.4 Mb interval that includes TBR1, TANK, and PSMD14.

Am J Med Genet A 2013 Apr 26;161A(4):841-4. Epub 2013 Feb 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Interstitial deletions involving 2q24 have been associated with a wide range of phenotypes including intellectual disability and short stature. To date, the smallest common region among reported cases of deletions in this region is approximately 2.65 Mb and contains 15 genes. In the present case report, we describe an 18-year-old male with mild intellectual disability, short stature, and mosaicism for a 0.422 Mb deletion on 2q24.2 that was diagnosed by comparative genomic hybridization and confirmed with fluorescent in situ hybridization (FISH). This deletion, which is present in approximately 61% of cells, includes three genes: TBR1, TANK, and PSMD14. The findings suggest that the critical region for intellectual disability and short stature in 2q24.2 can be narrowed to a 0.422 Mb segment. TBR1, a transcription factor involved in early cortical development, is a strong candidate for the intellectual disability phenotype seen in our patient and in patients with larger deletions in this region of the genome.
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http://dx.doi.org/10.1002/ajmg.a.35751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868782PMC
April 2013

Antibody correlates and predictors of immunity to naturally occurring influenza in humans and the importance of antibody to the neuraminidase.

J Infect Dis 2013 Mar 10;207(6):974-81. Epub 2013 Jan 10.

Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM280, Houston, TX 77030, USA.

Background: Serum antibody to the hemagglutinin (HA) of influenza viruses is a correlate and predictor of immunity to influenza in humans; the relative values of other correlates are uncertain.

Methods: Serum and nasal secretions (NS) were collected in fall and spring of 2009-2011 from healthy adults who were monitored for acute respiratory illness (ARI). Serum samples were tested for hemagglutination-inhibition (HAI) antibody increase and secretions for virus if ill; enrollment sera were also tested for neuraminidase-inhibiting (NI) antibody and NS for neutralizing (neut), NI, immunoglobulin A (IgA), and immunoglobulin G (IgG) anti-HA antibody.

Results: Serum anti-HA and anti-neuraminidase (NA) antibody titers to 2009(H1N1) pandemic influenza virus (pH1N1) correlated with titers in NS (including IgA and IgG antibody). Increasing anti-HA and anti-NA titers in serum and NS tests all correlated with reducing infection and infection-associated illness. Multivariate analyses indicated serum HAI and NI each independently predicted immunity to infection and infection-associated illness. Only serum NI independently predicted reduced illness among infected subjects.

Conclusions: Increasing anti-HA and NA antibody in serum and secretions correlated with reducing pH1N1 influenza virus infection and illness in healthy young adults. Both anti-HA and anti-NA antibody are independent predictors of immunity to influenza; ensuring induction of both by vaccination is desirable.
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http://dx.doi.org/10.1093/infdis/jis935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633450PMC
March 2013

The practice of adult genetics: a 7-year experience from a single center.

Am J Med Genet A 2013 Jan 13;161A(1):89-93. Epub 2012 Dec 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

The purpose of our study is to familiarize the reader with genetic disorders commonly seen in adults and identify challenges and barriers that limit provision of services. We conducted a retrospective chart analysis of patients seen in the adult Genetics clinics from January 2004 to December 2010 in a metropolitan medical center consisting of an academic private clinic and a county hospital clinic. During the study period, a total of 1,552 patients (n = 1,108 private clinic patients; n = 444 county clinic patients) were evaluated and managed. Of these, 790 and 280 were new patient visits at the private clinic and county clinic, respectively. Approximately 35% (374/1,070) of new patients were seen for cancer-related indications, while neurological indications accounted for approximately 14% (153/1,070) in both clinics. Cardiology-related indications accounted for approximately 13% (145/1,070) of patients, followed closely by chromosomal and syndromic indications for which almost 9% (96/1,070) of new patients were seen. Approximately 8% (90/1,070) of new patients were seen for musculoskeletal indications. We saw increased clinic growth during the study period and found that the most common indications for referral are: (1) Personal/family history of cancer (2) neurological (3) cardiovascular (CV) (4) chromosomal/syndromic and (5) musculoskeletal. A number of challenges were identified, including coordination of services, feasibility of testing, and an overall higher complexity of care with increased clinic scheduling time requirements. Through this review, we demonstrate the demand for adult genetics services and propose some guidelines to address the challenges of management in the adult genetics patient population.
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http://dx.doi.org/10.1002/ajmg.a.35684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859647PMC
January 2013

Global gene expression profiling in infants with acute respiratory syncytial virus broncholitis demonstrates systemic activation of interferon signaling networks.

Pediatr Infect Dis J 2013 Feb;32(2):e68-76

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Respiratory syncytial virus (RSV) is a leading cause of pediatric lower respiratory tract infections and has a high impact on pediatric emergency department utilization. Variation in host response may influence the pathogenesis and disease severity. We evaluated global gene expression profiles to better understand the systemic host response to acute RSV bronchiolitis in infants and young children.

Methods: Patients (age ≤ 24 months) who were clinically diagnosed with acute bronchiolitis and who had a positive rapid test for RSV assay were recruited from the Texas Children's Hospital emergency department. Global gene expression of peripheral whole blood cells were analyzed in 21 cases and 37 age-matched healthy controls. Transcripts exhibiting significant upregulation and downregulation as a result of RSV infection were identified and confirmed in a subset of samples using RNA sequencing. The potential pathways affected were analyzed.

Results: Blood was obtained from patients with acute RSV bronchiolitis (mean age 6 months). Of these, 43% were admitted to the hospital, 52% were given intravenous fluids and 24% received oxygen. Highly significant expression differences were detected in a discovery cohort of White infants (N = 33) and validated in an independent group of African-American infants (N = 19). Individuals with mild disease (N = 15) could not be distinguished from subjects with clinically moderate disease (N = 5). Pathway enrichment analyses of the differentially expressed genes demonstrated extensive activation of the innate immune response, particularly the interferon signaling network. There was a significant downregulation of transcripts corresponding to antigen presentation.
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http://dx.doi.org/10.1097/INF.0b013e318278b4b3DOI Listing
February 2013

Prior infections with seasonal influenza A/H1N1 virus reduced the illness severity and epidemic intensity of pandemic H1N1 influenza in healthy adults.

Clin Infect Dis 2012 Feb 10;54(3):311-7. Epub 2011 Nov 10.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.

Background: A new influenza A/H1N1 (pH1N1) virus emerged in April 2009, proceeded to spread worldwide, and was designated as an influenza pandemic. A/H1N1 viruses had circulated in 1918-1957 and 1977-2009 and were in the annual vaccine during 1977-2009.

Methods: Serum antibody to the pH1N1 and seasonal A/H1N1 viruses was measured in 579 healthy adults at enrollment (fall 2009) and after surveillance for illness (spring 2010). Subjects reporting with moderate to severe acute respiratory illness had illness and virus quantitation for 1 week; evaluations for missed illnesses were conducted over holiday periods and at the spring 2010 visit.

Results: After excluding 66 subjects who received pH1N1 vaccine, 513 remained. Seventy-seven had reported with moderate to severe illnesses; 31 were infected with pH1N1 virus, and 30 with a rhinovirus. Determining etiology from clinical findings was not possible, but fever and prominent myalgias favored influenza and prominent rhinorrhea favored rhinovirus. Tests of fall and spring antibody indicated pH1N1 infection of 23% had occurred, with the rate decreasing with increasing anti-pH1N1 antibody; a similar pattern was seen for influenza-associated illness. A reducing frequency of pH1N1 infections was also seen with increasing antibody to the recent seasonal A/H1N1 virus (A/Brisbane/59/07). Preexisting antibody to pH1N1 virus, responses to a single vaccine dose, a low infection-to-illness ratio, and a short duration of illness and virus shedding among those with influenza indicated presence of considerable preexisting immunity to pH1N1 in the population.

Conclusions: The 2009 A/H1N1 epidemic among healthy adults was relatively mild, most likely because of immunity from prior infections with A/H1N1 viruses.
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http://dx.doi.org/10.1093/cid/cir809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258274PMC
February 2012

Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.

Nat Genet 2011 Oct 2;43(11):1074-81. Epub 2011 Oct 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat-mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.
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http://dx.doi.org/10.1038/ng.944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235474PMC
October 2011
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