About

What We Do

Modern genetics involves the decoding of biological information encoded in organismal genomes and how this DNA code specifies phenotypes, be they biochemical or organismal. Genetics is also concerned with elucidating how various biological processes maintain or alter this code, its mechanism of transmission across generations and its evolution. Human genetics is the specific study of these questions in humans, studies that raise new challenges both because we cannot design genetic crosses as we do in model organisms but also because we can study phenotypes unique to humans, such as mental illness. A particular focus of human genetics is to understand the molecular basis of human disease and, thus, disease pathophysiology.

Our laboratory focuses on the formulation, development and application of genetic, genomic, and computational technologies and perspectives for discovery of genes and mechanisms in a variety of complex (non-Mendelian) human diseases. Specifically, we use a variety of human patients, their families and animal models of these disorders to infer the genetic characteristics of two developmental disorders of neuronal function (Hirschsprung disease, autism) and two late age-at-onset cardiovascular disorders (hypertension, sudden cardiac death). These disorders represent the extremes of genetic action, provide us with different models of non-Mendelian inheritance and articulate the importance of gene regulatory networks in human disease.

Common human diseases, be they birth defects, diabetes, cardiovascular disease, infectious disease, psychiatric illness or neurodegenerative disease, are familial and arise from a combination of genetic and environmental factors. The familial nature of most diseases suggests an underlying genetic susceptibility, but environmental, stochastic and epigenetic factors are also critical. Additional genetic hallmarks of complex disorders are that the underlying mutations are neither necessary nor sufficient for the development of disease, and that these mutations are common in the general population. Current genomic technologies, using the human genomic sequence, comparative sequence from many other vertebrates, a genome-wide map of polymorphic sites and emerging genome-wide maps of functional elements are all critical elements of this genetic dissection and the tools of our trade.

Our overall goals are to develop a paradigm for the genetics of common disease and to assess how genomic information can be used in modern clinical medicine in the era of personalized medicine.

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News

March 27, 2020

The Chakarvarti lab welcomes new post-doc Teesta Naskar.

June 13, 2019

The Chakravarti Lab welcomes new post-docs Ryan Fine and Or Yaacov!

April 4, 2019

Congratulations to Joseph Tilghman et al. on the new lab publication “Molecular Genetic Anatomy and Risk Profile of Hirchsprung’s Disease” in The New England Journal of Medicine!

October 28, 2018

New Publication: Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants. Genome Research.

March 7, 2017

New lab publication: Testing the Ret and Sema3d genetic interaction in mouse enteric nervous system development. Human Molecular Genetics. [Epub ahead of print]

Lab Members

Dr. Aravinda Chakravarti

Principal Investigator

Sumantra Chatterjee

Senior Research Scientist

Georg Ehret

Research Associate

Dongwon Lee

Biomedical Engineer

Nan Hu

Assistant Research Scientist

Hanna Berk-Rauch

Program Supervisor

Ryan Fine

Postdoctoral Fellow

Or Yaacov

Post Doctoral Fellow

Lauren Fries

Associate Research Technician

Monica Erazo

Sr Research Coordinator/ Genetic Counseling

Mingzhou Fu

Graduate Student

Hilda Rebecca Chubaryov

Graduate Student

Lab Gallery

Lab Alumni

Postdoc Alumni

PhD/MD Alumni

Undergraduate Students

MS Students

High School Students

Research

Research in my laboratory focuses on the human genetics of complex traits and disease and the use of computational and animal models of human disease. Our studies cover three broad areas, as outlined below. Specifically, we are developing the principles and methods to do genetics ‘by sequence not breeding.’ The combination of whole genome studies (using genetic markers, sequencing or expression) and phenotypic analyses of patients, their family members and controls, can now allow the detailed dissection of both rare and common complex disorders into their component genes. Hypotheses of transmission and disease mechanism can then be studied using animal models (zebrafish and mouse). We are specifically interested in developing gene regulatory networks by cell types, that is groups of functionally interacting genes and their encoded proteins, as a basis for the multigenic action and interactions in complex traits.

Genomic basis of human disease

We are actively involved in computational and experimental studies of genetic dissection, that is identification of the underlying genes and their effects on disease, and also is known as the genetic ‘architecture,’ of human disease. Here the goal is to identify the different ways in which the complexity of genetic disorders emerge. To identify potentially different architectures, we have chosen for study rare and common, congenital, childhood and adult-onset, and neurogenetic and cardiovascular phenotypes with vastly different environmental effects.

Hirschsprung Disease: Hirschsprung Disease is a congenital anomaly (birth defect) of the bowel in which there is an absence of ganglia (nerves) in the wall of the bowel. We are trying to understand how normal ganglionosis develops and which perturbations interrupt these processes. To date we have identified >34 genes and loci that affect development of the enteric nervous system (ENS) but largely with coordinated action through a single, large RET gene regulatory network that explains ~67% of the total disease risk. We are performing focused genetic studies of the ENS to identify additional disease genes and are using single cell transcriptional analyses of enteric neurons to understand the disease mechanisms using mouse models.

Autism: Autism is a spectrum of neuropsychiatric disorders characterized by deficits in social interaction, language and communication, with unusual and repetitive behavior. Most of the genetic defects here are presumed to be at the level of neuronal circuits. Here also, we are trying to understand how normal circuitry develops and which perturbations interrupt these processes. The autism research community has identified >50 genes, of the ~800 estimated to exist, that contribute to this disorder. We are studying rare families with autism, specifically those with multiple and severely affected girls, to identify which of these numerous genes confer the greatest disease risk. We expect that these studies will lead to identification of rate-limiting steps in CNS development, such as the delta catenin CTNND2 gene we identified, thereby clarifying critical biochemical steps disrupted in autism.

Essential Hypertension: High blood pressure, defined as a repeatedly elevated systolic and diastolic blood pressure exceeding 140 mmHg and 90 mmHg, respectively, is a modestly heritable physiological trait. How is this phenotype genetically controlled and how is this control disrupted in hypertension? We have made major genetic contributions to studies showing that over 150 genes and loci are specifically involved in blood pressure control. This genetic control is not through variation or mutation in the coding sequence of genes but rather in a gene’s regulatory sequences. We are now actively involved in elucidating the regulatory sequences in the human genome, in specific tissues such as the heart, so that their broad effect on the genetic control of blood pressure can be quantified. We are also attempting to assess whether the many genes identified are functionally united through gene regulatory networks. Our recent studies, beyond these experimental investigations, involve large (~100,000 individuals) human cohort studies using electronic health records (EHR) to study whether the genes we identify can predict the target organ damage in the heart, kidney, etc. observed in untreated hypertensives.

Sudden Cardiac Death: Sudden cardiac death (SCD) is an unexpected death due to cardiac causes occurring in a short time period in a person with known or unknown cardiac disease. Many of such cases arise from genetic defects in heart rhythm. We are using genetic analysis of the QT interval to understand this physiological process. Once again, this common trait arises from genetic control in a gene’s regulatory sequences, effects that we have shown are specifically enriched in a cardiac tissue component called the intercalated disk. We are now actively involved in elucidating the regulatory sequences in the human genome, in the heart, so that their broad effect on the genetic control of blood pressure can be quantified. Our studies can also be used to answer how much of this variation can explain other EKG features routinely measured in patients. The identified genes will then be specifically studied for variants associated with sudden cardiac death.

Computational biology and statistical genetics

Our studies are intensely computational in a variety of ways. First, gene discovery depends on the analysis of genotype and sequence data in patient families and cohorts. We are now entering a phase of extracting phenotype data from electronic health records (EHR) which allow the study of phenotypes across time (longitudinally), thereby allowing better phenotypic characterization than a single cross-sectional measure. However, these time-series data bring new challenges of adjusting for time-dependent short-term and long-term confounders. Second, we are developing new technologies for constructing genome-wide, cell-type/tissue-relevant enhancer maps using computational methods that rely on the sequence features of these enhancers. Such sequence-dependent methods are new but have the advantages of predicting unobserved yet active enhancers, which appear to be more cell-type-specific, and explaining why they are not so frequently observed. The enhancer sequence features also allows predictions of the TFs binding these elements. Finally, sequence variants within these enhancers can be used to identify the genes they regulate. Tying TFs with their enhancers and the genes they regulate brings a new genome-level view to complex disease analyses and identification of the levels at which sequence variation alters phenotype variation. Finally, we are also developing methods that will allow prediction of the effects of sequence variation within the enhancers on gene expression and, thereby, trait variation.

Our final computational program of research involves the construction of gene regulatory networks. This involves identifying the TFs that bind enhancers of a gene and the genes that are subsequently affected. We are using single cell RNA-seq of mouse tissues, and siRNA-based knockdown of individual genes in cell lines, to identify GRNs. These studies are now geared to constructing a detailed GRN for RET in the ENS, and, subsequently, a broader GRN for the ENS.

Genome function

Almost all complex disorders involve multiple genes but that is not the inherent basis of their genetic differences. Our recent research suggests that the majority of the effects at these many genes are not from sequence differences within their coding regions but rather from sequence differences within their regulatory regions. Our hypothesis is that the number and identity of the regulators (transcription factors, TF), the number, identity and nature (sequence and the effects of sequence variation) of the enhancers binding these TFs, and their cumulative effects on the many target genes determine the effects on the phenotype. Additionally, the many genes involved are not unrelated to one another, although they are location-wise genetically independent, but they become functionally united through one or more gene regulatory networks (GRN). Therefore, the functions disrupted in a complex trait or disease are encoded largely in these enhancers which are genomically dispersed. Further, understanding disease mechanisms involves understanding which enhancers regulate which genes, which genes exist within which GRN and how variants disrupt entire GRN functions.

Our current studies are deeply involved in identifying cell-type/tissue-relevant enhancers, the TFs that bind these cis elements, the genes they regulate and the composition of GRNs. These studies are being performed in the mouse heart and gut, relevant to the many disorders we are already studying. More specifically, we will focus on cardiomyocytes and enteric neurons. These studies depend on the production of maps of open chromatin, using DNAseI hypersensitivity and ATAC-seq assays, computational analyses of these data to identify enhancers, computational analyses of the enhancer sequences to identify the relevant TFs, and gene co-expression in wildtype and mutant tissue/cell types to generate the GRNs. The emerging GRNs show widespread genetic feedback interactions and suggest that GRN function is the relevant unit in disease (and normal physiology) rather than gene function.

Hirschsprung Disease Study

An Overview

What is Hirschsprung disease?

Hirschsprung disease (abbreviated as HSCR) is a problem with the way the gut develops and is present from birth. About 1 in 5000 babies is born with HSCR, though this rate varies two-fold across different ethnic groups for reasons still not fully understood.

What causes Hirschsprung disease?

The gut or gastrointestinal tract is lined by nerve cells (100 million of them). Some of these nerve cells sense food in the gut and others work to move food through the gut by causing the wave-like contraction (squeezing) and relaxation (expanding) necessary for passing stool.

HSCR arises when certain nerve cells in the gut (called ganglion cells) fail to develop and mature correctly. This occurs during the first trimester of pregnancy while the embryo is developing in the womb. Ganglion cells arise from a group of cells called neural crest cells, which migrate to the gut and then develop into nerve cells. In Hirschsprung disease, the cells may fail to migrate to the gut, or once in the gut they may fail to survive, multiply, or develop correctly. This results in an ‘aganglionic’ segment (a segment lacking ganglion cells), in which contraction and relaxation is absent, making it difficult for stool to pass through. This leads to chronic constipation and the other symptoms of HSCR.

In HSCR the ganglion cells are missing along varying lengths of the gut from the rectum to the small intestine (See diagram of the gut below). The anus (the farthest end of the gut) is almost always affected when someone has HSCR. About 80% of individuals with Hirschsprung disease have “short-segment” disease, affecting only the rectum, sigmoid colon, and sometimes the descending colon. The other 20% have “long segment” which can include part of the transverse and ascending colons, the total colon, or even extend to parts of the small intestine. (Note: There are different definitions of long segment Hirschsprung disease. Some define it as lack of ganglion cells in the intestine past the sigmoid region, and others say it means beyond the descending colon/splenic flexure.)

Photo courtesy of: Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. – Own work, CC BY 3.0.

What are the symptoms of Hirschsprung disease?

Hirschsprung disease is most often diagnosed within the first week after birth. However, some people are diagnosed later in childhood and as adults, though they have had digestive system problems their whole lives. Symptoms of Hirschsprung disease include constipation, abdominal distension (swelling of the belly), vomiting, decreased appetite, cramping, and failure to gain weight, grow or develop at the expected rate. One of the first signs in a newborn may be not passing meconium (the first bowel movement) within 24-48 hours after birth. Some people with HSCR also develop enterocolitis, an infection of the bowel requiring immediate medical care. Signs of enterocolitis are diarrhea, abdominal distention and fever.

How is Hirschsprung disease diagnosed?

There are several tools used to find out if someone has Hirschsprung disease:

Barium enema x-ray: Barium, a chalky liquid, is put into the colon through the anus and coats the inside of the colon. When an x-ray of the gut is taken, doctors can see the colon. If Hirschsprung disease is present, a funnel-like “transition zone” may be seen. In the part without nerve cells, the colon will appear to be of normal size or somewhat narrowed. In the area above this, the colon may look expanded. The stool that cannot be passed backs up and the colon is stretched and enlarged around it. Seeing the transition zone is a clue that a person may have Hirschsprung disease.

Rectal manometry: The doctor inflates a small balloon inside the rectum. Normally, the anal muscle will relax. If it doesn’t, HSCR may be the problem.

Rectal biopsy: The definitive diagnosis of Hirschsprung disease is made by a rectal biopsy. During the biopsy a small piece of tissue is removed from the rectum. Doctors view the tissue sample under a microscope and look for ganglion cells (nerve cells). If no nerve cells are seen, Hirschsprung disease is diagnosed.

How is Hirschsprung disease treated?

Treatment for Hirschsprung disease consists of surgery to remove the part of the gut without nerve cells and re-connect the remaining intestine to the anus so stool can pass out of the body. This is called a “pull-through” surgery. There are various surgical techniques and methods used. Some patients may need a temporary or permanent ostomy (opening of the intestines to the outside of the body by a hole in the abdomen, through which stool passes), as part of surgical treatment.

The long-term outcome of surgery for Hirschsprung disease is generally good, with most patients having normal or almost normal bowel habits. Some people do have continuing problems with frequency of bowel movements, constipation/diarrhea, leakage of stool from the anus, and recurrent episodes of enterocolitis.

**Because we are a lab of genetic researchers, not medical doctors, we are not experts in the diagnosis and treatment of Hirschsprung disease. Below are two websites that focus more on these aspects of the disease. You should always talk with your doctor about any personal medical concerns.**

National Digestive Diseases Information Clearinghouse

American Pediatric Surgical Association

More information about Hirschsprung disease.

Publications

All trainees are highlighted.
Dr. Chakravarti’s full publication list can be found here.

2020

2019

Wang, H, Nandakumar, P, Tekola-Ayele, F, Tayo, BO, Ware, EB, Gu, CC, Lu, Y, Yao, J, Zhao, W, Smith, JA, Hellwege, JN, Guo, X, Edwards, TL, Loos, RJF, Arnett, DK, Fornage, M, Rotimi, C, Kardia, SLR, Cooper, RS, Rao, DC, Ehret, G, Chakravarti, A & Zhu, X 2018, ‘Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31’, European Journal of Human Genetics. PMID:30262922
Chatterjee S, Chakravarti A: A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease. Hum Mol Genet. 2019 Sep 15;28(18):3137-3147. PMID 31313802
Kapoor A, Lee D, Zhu L, Soliman EZ, Grove ML, Boerwinkle E, Arking DE, Chakravarti A. Multiple SCN5A variant enhancers modulate its cardiac gene expression and the QT interval. Proceedings of the National Academy of Sciences. 2019 May 8:201808734. PMID: 31068470
Tilghman JM, Ling AY, Turner TN, Sosa MX, Krumm N, Chatterjee S, Kapoor A, Coe BP, Nguyen KD, Gupta N, Gabriel S. Molecular Genetic Anatomy and Risk Profile of Hirschsprung’s Disease. New England Journal of Medicine. 2019 Apr 11;380(15):1421-32. PMID: 30970187
He, K., Li, X., Kelly, T., Liang, J., Cade, B., Assimes, T., Becker, L., Beitelshees, A., Bress, A., Chang, Y., Chen, Y., de Vries, P., Fox, E., Franceschini, N., Furniss, A., Gao, Y., Guo, X., Haessler, J., Hwang, S., Irvin, M., Kalyani, R., Liu, C., Liu, C., Martin, L., Montasser, M., Muntner, P., Mwasongwe, S., Palmas, W., Reiner, A., Shimbo, D., Smith, J., Snively, B., Yanek, L., Boerwinkle, E., Correa, A., Cupples, L., He, J., Kardia, S., Kooperberg, C., Mathias, R., Mitchell, B., Psaty, B., Vasan, R., Rao, D., Rich, S., Rotter, J., Wilson, J., Chakravarti, A., Morrison, A., Levy, D., Arnett, D., Redline, S., & Zhu, X. (2019). Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.. Human genetics, (). PMID:30671673

2018

2017

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

Lin S, Chakravarti A, Cutler DJ: Exhaustive allelic disequilibrium tests are a new approach to genome-wide association studies. Nat Genet 36:1181-1188, 2004. PMID 15502828.
Lin S, Chakravarti A, Cutler DJ: Haplotype and Missing Data Inference in Nuclear Families. Genome Res 14:1624-32, 2004. PMID 15256514. PMC509272.
The International HapMap Consortium: Integrating Ethics and Science in the International HapMap Project. Nat Rev Genet 5:467-475, 2004. PMID 15153999. PMC2271136.
Maitra A, Cohen Y, Gillespie SED, Shah N, Sidransky D, Chakravarti A: The Human MitoChip: A high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res 14:812-819, 2004. PMID 15123581. PMC479107.
Mitchell AA, Zwick ME, Chakravarti A, Cutler DJ: Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns. Bioinformatics 20:1022-1032, 2004. PMID 14764571.
Arking DE, Chugh SS, Chakravarti A, Spooner PM: Genomics in Sudden Cardiac Death. Circ Rev 94:712-723, 2004. PMID 15059941.
Hong HK, Chakravarti A, Takahashi J: The gene for soluble NSF attachment protein α (α-SNAP) is mutated in hydrocephalus with hop gait mice. Proc Natl Acad Sci (USA) 101:1748-1753, 2004. PMID 14755058. PMC341847.
Xu Z, Kerstann KF, Sherman SL, Chakravarti A, Feingold E: A Trisomic Transmission Disequilibrium Test. Genet Epid 26:125-131, 2004. PMID 14748012.
Barkley RA, Chakravarti A, Cooper RS, Ellison RC, Hunt SC, Province MA, Turner ST, Weder AB, Boerwinkle E; Family Blood Pressure Program: Positional identification of hypertension susceptibility genes on chromosome 2. Hypertension 43:477-482, 2004. PMID 14732741.

2003

2002

2001

Green ED, Chakravarti A: The Human Genome Sequence Expedition: Views from the “Base Camp”. Genome Res 11:645-651, 2001. PMID 11337462.
Cutler DJ, Zwick ME, Carrasquillo MM, Yohn CT, Tobin KP, Kashuk C, Mathews DJ, Shah NA, Eichler EE, Warrington JA, Chakravarti A: High-throughput variation detection and genotyping using microarrays. Genome Res 11:1913-1925, 2001. PMID 11691856. PMC311146.
Wiesner GL, Platzer P, Buxbaum S, Lewis S, MacMillen M, Olechnowicz J, Willis J, Chakravarti A, Elston RC, Markowitz SD: Absence of colon neoplasia susceptibility variants at the human COX2 locus. J Natl Cancer Inst 18:635-639, 2001. PMID 11309440.
Mathews DJ, Kashuk C, Brightwell G, Eichler EE, Chakravarti A: Sequence variation within the fragile X locus. Genome Res 11:1382-1391, 2001. PMID 11483579. PMC311115.
Hong H-K, Noveroske JK, Headon DJ, Liu T, Sy M-S, Justice MJ, Chakravarti A: The winged helix/forkhead transcription factor Foxq1 regulates differentiation of hair in satin mice. Genesis 29:163-171, 2001. PMID 11309849.

2000

How to apply

FOR PROSPECTIVE GRADUATE STUDENTS, POSTDOCTORAL FELLOWS AND OTHER TRAINEES….

I am always in the search for scientifically enthusiastic graduate students and postdoctoral fellows to join my laboratory. I find my laboratory exciting precisely because of my trainees who bring new perspectives, questions and ideas…and, of course, new interests and new personalities! Over the past 37 years, and ever since I have been a preceptor in one or more graduate and post-graduate training programs, I have been fortunate to recruit a large number (~70) of talented trainees who have taught me just as much as we have been able to teach them.

My laboratory is focused on the fundamentals of human genetics, particularly as it relates to the understanding of human disease. Our current research is focused on two disorders of the nervous system where disease onset is early (Hirschsprung disease, autism) and two disorders of the cardiovascular system where disease onset is late (sudden cardiac death, hypertension). This breadth emphasizes the gamut of human genetic mechanisms. I expect that human genetic diseases are the photographic ‘negatives’ from which the ‘positives’ of normal physiology will emerge. To do so, we successfully use both experimental and computational approaches in human genetics and genomics, as well as use model organisms to test mechanistic hypotheses emerging from gene discovery.

My philosophy has been to let trainees choose what they want to study within the confines of the broad interests and grant support of the laboratory. I do not force any of them, graduate students or postdoctoral fellows, to focus on a particular question, but do help and guide them to the major scientific questions of the day; rather, I expect my trainees to learn to think independently but to work collaboratively because this is what they will need to do when they start their careers. Nevertheless, I work with all of my trainees very closely and expect them to gain expertise in both experimental and computational approaches, and contribute to the scientific life of the lab.

Mine is not a very large lab nor one where high-throughput technologies dominate but one where genetic arguments and genetic perspectives are central: we use the tools, both small and large, necessary for answering the question at hand. For any potential PhD trainee interested in our research please apply to the Sackler Institute of Biomedical Sciences at NYU and directly to my email; postdoctoral fellows should write to me directly at least 9 months prior to an expected start. For any trainee, a visit to the lab is always a good idea.

My lab also hosts visiting international undergraduate students in the summer, and any NYU undergraduate throughout the year through a practicum. For all such students, research work in my lab can be taken for academic credit. We also host exceptional high school students who have a deep interest in human genetics.

Aravinda Chakravarti

Principal Investigator

Email

CONTACT

Center for Human Genetics and Genomics
NYU School of Medicine
Science Building
435 E 30th Street
New York, NY 10016 USA

Tel: (212)-263-8029 Fax:(646)-501-4526

For administrative questions, contact: Veronika Worosz

For study participation questions, contact: Monica Erazo

For laboratory questions, contact: Hanna Berk-Rauch

LOCATION

CAMPUS MAP