Harendra Guturu

Stanford University | SU · Division of Medical Genetics

Sense organs acquire their distinctive shapes concomitantly with the differentiation of sensory cells and neurons necessary for their function. While our understanding of the mechanisms controlling morphogenesis and neurogenesis in these structures has grown, how these processes are coordinated remains largely unexplored. Neurogenesis in the zebraf...

The diagnosis of Mendelian disorders requires labor-intensive literature research. Trained clinicians can spend hours looking for the right publication(s) supporting a single gene that best explains a patient’s disease. AMELIE (Automatic Mendelian Literature Evaluation) greatly accelerates this process. AMELIE parses all 29 million PubMed abstracts...

The diagnosis of Mendelian disorders requires labor-intensive literature research. Trained clinicians can spend hours looking for the right publication/s supporting a single gene that best explains a patient's disease. AMELIE (Automatic Mendelian Literature Evaluation) greatly accelerates this process. AMELIE parses all 29 million PubMed abstracts,...

Sense organs acquire their distinctive shapes concomitantly with the differentiation of sensory cells and neurons necessary for their function. While our understanding of the mechanisms controlling morphogenesis and neurogenesis in these structures has grown, how these processes are coordinated remains largely unexplored. Neurogenesis in the zebraf...

Genetic variation in cis-regulatory elements is thought to be a major driving force in morphological and physiological changes. However, identifying transcription factor binding events that code for complex traits remains a challenge, motivating novel means of detecting putatively important binding events. Using a curated set of 1154 high-quality t...

Approximately 2% of the human genome accounts for protein-coding genes, yet most known Mendelian disease-causing variants lie in exons or splice sites. Individuals who symptomatically present with monogenic disorders but do not possess function-altering variants in the protein-coding regions of causative genes may harbor variants in the surrounding...

Purpose: Exome sequencing and diagnosis is beginning to spread across the medical establishment. The most time-consuming part of genome-based diagnosis is the manual step of matching the potentially long list of patient candidate genes to patient phenotypes to identify the causative disease. Methods: We introduce Phrank (for phenotype ranking),...

Purpose Exome sequencing and diagnosis is beginning to spread across the medical establishment. The most time-consuming part of genome based diagnosis is the manual step of matching the potentially long list of patient candidate genes to patient phenotypes to identify the causative disease. Methods We introduce Phrank (for phenotype ranking), an i...

Robinow syndrome (RS) is a well-recognized Mendelian disorder known to demonstrate both autosomal dominant and autosomal recessive inheritance. Typical manifestations include short stature, characteristic facies, and skeletal anomalies. Recessive inheritance has been associated with mutations in ROR2 while dominant inheritance has been observed for...

Genetic variation in cis -regulatory elements is thought to be a major driving force in morphological and physiological change. However, identifying transcription factor binding events which code for complex traits remains a challenge, motivating novel means of detecting putatively important binding events. Using a curated set of 1,154 high-quality...

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations,...

The diagnosis of Mendelian disorders requires labor-intensive literature research. Our software system AMELIE ( A utomatic M endelian L iterature E valuation) greatly automates this process. AMELIE parses hundreds of thousands of full text articles to find an underlying diagnosis to explain a patient’s phenotypes given the patient’s exome. AMELIE p...

Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the cl...

Purpose: Clinical exome sequencing is nondiagnostic for about 75% of patients evaluated for a possible Mendelian disorder. We examined the ability of systematic reevaluation of exome data to establish additional diagnoses. Methods: The exome and phenotypic data of 40 individuals with previously nondiagnostic clinical exomes were reanalyzed with...

Author A central goal of personal genomics is to interpret an individual’s genome to identify variants that confer disease risk, an aim that has far-reaching implications for personalized, precision medicine. Here, we leverage next generation sequencing, health records, and functional genome annotations to develop statistical methods that predict...

The set of binding loci and predicted upstream factors for the Quake “abnormal cardiac output” prediction in Table 1. (XLSX)

The full set of CoBELs for the Quake genome. (XLSX)

The full set of CoBELs for the Lupski genome. (XLSX)

The set of binding loci and predicted upstream factors for the Angrist “epithelial cell morphogenesis” prediction in Table 1. (XLSX)

The set of binding loci and predicted upstream factors for the Gill “decreased circulating sodium level” prediction in Table 1. (XLSX)

The set of binding loci and predicted upstream factors for the Lupski “regulation of oligodendrocyte differentiation” prediction in Table 1. (XLSX)

The medical histories of each individual and the top enrichments for their CoBELs. These histories represent the most relevant disease phenotypes for each of individuals analyzed. The histories were obtained either from the original publications of their genomes and/or from the public database from which their genomes were downloaded. (XLSX)

Narcolepsy associated SNPs. Narcolepsy associated GWAS SNPs are tallied for the five analyzed genomes, indicating Church, who has narcolepsy and two GWAS variants, is not unlike the other genomes in having 2–3 common narcolepsy variants. As such, our CoBEL based narcolepsy-associated prediction for Church comes from orthogonal means–namely ensemble...

The full set of CoBELs for the Church genome. (XLSX)

The association matrix between all medical histories and enrichments as defined by a literature survey. Each column represents an enriched biological process or phenotype. Each row represents a disease phenotype. A value is placed only where the primary literature offers potential support for a causal connection between the two entities. Where the...

CoBELs shared across the five analyzed individuals. The number and distribution of CoBEL (conserved binding site eroding loci) SNPs for the enrichments listed in Table 1 for (A) Quake, (B) Church, (C) Angrist, (D) Gill, and (E) Lupski across the five personal genomes. Individual variants, colored red, make the largest contribution (17%-34%) across...

GREAT enrichments for GWAS SNPs are congruent with GWAS phenotype. For GWAS phenotypes ranging from metabolic traits to cancer and Crohn’s disease, the set of non-exonic GWAS SNPs, from the NHGRI catalog, associated with the trait is most highly enriched for a GREAT annotation closely associated to the trait, suggesting gene regulatory mutations of...

False Discovery Rate (FDR) of Enrichments using 1,000 Genomes Data. (A) CoBELs from control individuals from the 1,000 Genomes project were submitted to GREAT and the fraction of individuals with the same or (B) a related top enrichment to the top enrichment of the five analyzed genomes was computed. In all cases, less than 10% of control people, r...

The full set of CoBELs for the Angrist genome. (XLSX)

The full set of CoBELs for the Gill genome. (XLSX)

The set of binding loci and predicted upstream factors for the Church “preganglionic parasympathetic nervous system development” prediction in Table 1. (XLSX)

The association matrix between all medical histories and enrichments as defined by a medical doctor. Each column represents an enriched biological process or phenotype. Each row represents a disease phenotype. An ‘X’ is placed only where the physician considers that biological process or phenotype can be linked with that disease phenotype. (XLSX)

High-throughput technologies such as flow and mass cytometry have the potential to illuminate cellular networks. However, analyzing the data produced by these technologies is challenging. Visualization is needed to help researchers explore this data. We developed a web-based software program, NetworkPainter, to enable researchers to analyze dynamic...

Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis-regulatory regions (CRRs) characterized by nucleosome-depleted accessible chroma...

Mapping the DNA-binding preferences of transcription factor (TF) complexes is critical for deciphering the functions of cis-regulatory elements. Here, we developed a computational method that compares co-occurring motif spacings in conserved versus unconserved regions of the human genome to detect evolutionarily constrained binding sites of rigid T...

All whole mounts of transgenic embryos for enhancer elt5 (Figure 2E), near Auts2. (TIFF)

All whole mounts of transgenic embryos for enhancer elt6 (Figure 2F), near Id4. (TIFF)

PCR primers used to clone candidate enhancer elements from mouse genomic DNA. 5′-CACC” was added to each left primer for cloning into pENTR/D. (DOCX)

All whole mounts of transgenic embryos for enhancer elt7 (Figure 2G), near Bhlhb5. (TIFF)

All whole mounts of transgenic embryos for enhancer elt8 (Figure 2H), near Auts2. (TIFF)

Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions...

Many important model organisms for biomedical and evolutionary research have sequenced genomes, but occupy a phylogenetically isolated position, evolutionarily distant from other sequenced genomes. This phylogenetic isolation is exemplified for zebrafish, a vertebrate model for cis-regulation, development and human disease, whose evolutionary dista...

The human genome encodes 1,500-2,000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context relevant target genes, that most binding is distal, and that binding i...

Early patterning in the Drosophila melanogaster embryo occurs through a complicated network of interactions involving transcription factor proteins and the mRNA of their target genes. One such system is the pattern of hunchback mRNA and its regulation by Bicoid and Kru¿ppel proteins. This system is well-studied, but there is disagreement amongst b...

The BioText Search Engine is a freely available Web-based application that provides biologists with new ways to access the scientific literature. One novel feature is the ability to search and browse article figures and their captions. A grid view juxtaposes many different figures associated with the same keywords, providing new insight into the li...