Erica Davis

Overview:

Two key questions thematically underscore my research in the Center for Human Disease Modeling at Duke University: First of all, how can variation at the DNA level be functionally interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered with functional information about genetic variants, how can pathogenic alleles be mapped back to disease phenotypes? Using the ciliary disease module as a model system of investigation, we are using multidisciplinary tactics to address these questions and continue to harness these approaches toward the further dissection of the architecture of human genetic disease. Moreover, we have applied the in vivo tools and lessons learned from ciliary phenotypes affecting the renal, craniofacial, and central nervous systems to interrogate rare pediatric disorders characterized by these phenotypic hallmarks.


Positions:

Associate Professor of Pediatrics

Pediatrics, Neonatology
School of Medicine

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Associate Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2005

University of Liege (Belgium)

Postdoctoral Research Fellow, Institute Of Genetic Medicine

Johns Hopkins University

Postdoctoral Research Fellow, Cell Biology

Duke University

Grants:

Bridge Funding Plan with Ann & Robert H Lurie Children's Hospital of Chicago

Administered By
Institutes and Centers
Awarded By
Ann & Robert H. Lurie Children's Hospital of Chicago
Role
Principal Investigator
Start Date
End Date

Genetic and Functional Dissection of Congenital Anomalies of the Brain

Administered By
Institutes and Centers
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Functional Dissection of CNVs in Neurodevelopmental Traits

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

RPB: 2014 Nelson Trust Award

Administered By
Ophthalmology
Role
Collaborator
Start Date
End Date

The Genetic Architecture of Neurodegenerative Disorders

Administered By
Institutes and Centers
Role
Principal Investigator
Start Date
End Date

Publications:

Oligogenic Effects of 16p11.2 Copy Number Variation on Craniofacial Development

Authors
Qiu, Y; Arbogast, T; Lorenzo, SM; Li, H; Tang, SC; Richardson, E; Hong, O; Cho, S; Shanta, O; Pang, T; Corsello, C; Chevalier, C; Davis, EE; Iakoucheva, LM; Herault, Y; Katsanis, N; Messer, K; Sebat, J
URI
https://scholars.duke.edu/individual/pub1368311
Source
ssrn
Published Date

Zebrafish: A Model System to Study the Architecture of Human Genetic Disease

© 2017 Elsevier Inc. All rights reserved. The current ability to sequence whole exomes and genomes has reached an unprecedented pace. Variant data have been cataloged for >1 M individuals representative of Mendelian disease cohorts, complex trait consortia, and healthy populations. This flood of information, expected to grow hyperexponentially in the coming years, has already fuelled the development of animal models to assign physiological relevance of genotype to phenotype; to inform variant pathogenicity; and to dissect multilocus interactions. Here, we discuss zebrafish as a robust model system that offers similar genomic and anatomical orthology to humans, with the added advantages of experimental tractability and a refined set of molecular tools that enable scalable throughput analyses. We will compare and contrast zebrafish to other animal model systems; provide a historical perspective on zebrafish forward and reverse genetics; and we will overlay the relative strengths and weaknesses of the model to interpret pathomechanism of germline mutations in humans.
Authors
Davis, EE; Katsanis, N
MLA Citation
Davis, E. E., and N. Katsanis. “Zebrafish: A Model System to Study the Architecture of Human Genetic Disease.” Animal Models for the Study of Human Disease: Second Edition, 2017, pp. 651–70. Scopus, doi:10.1016/B978-0-12-809468-6.00025-5.
URI
https://scholars.duke.edu/individual/pub1284566
Source
scopus
Published Date
Start Page
651
End Page
670
DOI
10.1016/B978-0-12-809468-6.00025-5

Identification of cis-suppression of human disease mutations by comparative genomics.

Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.
Authors
Jordan, DM; Frangakis, SG; Golzio, C; Cassa, CA; Kurtzberg, J; Task Force for Neonatal Genomics,; Davis, EE; Sunyaev, SR; Katsanis, N
MLA Citation
Jordan, Daniel M., et al. “Identification of cis-suppression of human disease mutations by comparative genomics.Nature, vol. 524, no. 7564, Aug. 2015, pp. 225–29. Pubmed, doi:10.1038/nature14497.
URI
https://scholars.duke.edu/individual/pub1075538
PMID
26123021
Source
pubmed
Published In
Nature
Volume
524
Published Date
Start Page
225
End Page
229
DOI
10.1038/nature14497

Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.

Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.
Authors
Lindstrand, A; Davis, EE; Carvalho, CMB; Pehlivan, D; Willer, JR; Tsai, I-C; Ramanathan, S; Zuppan, C; Sabo, A; Muzny, D; Gibbs, R; Liu, P; Lewis, RA; Banin, E; Lupski, JR; Clark, R; Katsanis, N
MLA Citation
Lindstrand, Anna, et al. “Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome..” Am J Hum Genet, vol. 94, no. 5, May 2014, pp. 745–54. Pubmed, doi:10.1016/j.ajhg.2014.03.017.
URI
https://scholars.duke.edu/individual/pub1028235
PMID
24746959
Source
pubmed
Published In
Am J Hum Genet
Volume
94
Published Date
Start Page
745
End Page
754
DOI
10.1016/j.ajhg.2014.03.017

Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel-Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting.
Authors
Ashkinadze, E; Rosen, T; Brooks, SS; Katsanis, N; Davis, EE
MLA Citation
Ashkinadze, E., et al. “Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome..” Clin Genet, vol. 83, no. 6, June 2013, pp. 553–59. Pubmed, doi:10.1111/cge.12022.
URI
https://scholars.duke.edu/individual/pub779439
PMID
22998390
Source
pubmed
Published In
Clin Genet
Volume
83
Published Date
Start Page
553
End Page
559
DOI
10.1111/cge.12022

Research Areas:

Abnormalities, Multiple
Adolescent
Alleles
Animals
Animals, Genetically Modified
Antigens, Neoplasm
Axoneme
Bardet-Biedl Syndrome
Base Sequence
Body Patterning
Bone and Bones
Brain
Caenorhabditis elegans
Cardiomyopathies
Cell Line
Cell Polarity
Cells, Cultured
Cerebellar Ataxia
Cerebellar Diseases
Cerebellum
Chaperonins
Child
Chromatography, High Pressure Liquid
Cilia
Ciliary Motility Disorders
Cohort Studies
Conserved Sequence
Craniosynostoses
Cytoskeletal Proteins
DNA Copy Number Variations
DNA Mutational Analysis
DNA, Intergenic
Diagnosis
Disease
Disease Models, Animal
Early Diagnosis
Embryo, Mammalian
Embryo, Nonmammalian
Encephalocele
Epistasis, Genetic
Eukaryota
Evolution, Molecular
Eye Abnormalities
Family Health
Fibroblasts
Gastrulation
Gene Deletion
Gene Duplication
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Developmental
Gene Frequency
Gene Knockdown Techniques
Genes, Dominant
Genes, Helminth
Genes, Recessive
Genes, X-Linked
Genetic Association Studies
Genetic Diseases, Inborn
Genetic Heterogeneity
Genetic Load
Genetic Loci
Genetic Markers
Genetic Predisposition to Disease
Genetic Testing
Genetic Therapy
Genetic Variation
Genetic Vectors
Genetics, Medical
Genome, Human
Genotype
Green Fluorescent Proteins
HEK293 Cells
Hand Deformities, Congenital
Heart Defects, Congenital
Hedgehog Proteins
Hirschsprung Disease
Homozygote
Human genetics
Humans
Immediate-Early Proteins
Immunohistochemistry
Infant
Inheritance Patterns
Intracellular Signaling Peptides and Proteins
Jaw Abnormalities
Kartagener Syndrome
Kidney
Kidney Diseases, Cystic
Leukoencephalopathies
Mice
Microinjections
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Models, Animal
Molecular Sequence Data
Molecular genetics
Morphogenesis
Multiprotein Complexes
Muscle, Skeletal
Muscular Diseases
Mutation
Mutation, Missense
Myocardium
Neurons, Afferent
Oligonucleotide Array Sequence Analysis
Oligonucleotides, Antisense
Otx Transcription Factors
Pedigree
Penetrance
Phenotype
Photoreceptor Cells
Polymorphism, Single Nucleotide
Proteins
Proteome
Proteomics
RNA
Respiratory System
Retina
Retinal Degeneration
Retinitis Pigmentosa
Ribosomal Proteins
Sequence Alignment
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Signal Transduction
Situs Inversus
Syndrome
Systems Biology
Transcription Factors
Transcription, Genetic
Vertebrates
Wnt Proteins
Zebrafish