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Dr. Tuuli Lappalainen Science Study

The illustration above depicts with an example of four genes, how knowing how variable genes are in the normal population helps to find candidate disease genes in a patient. Above, top: Tuuli Lappalainen, PhD; bottom: Pejman Mohammadi, PhD.

For individuals with rare diseases, getting a diagnosis is often a long and complicated odyssey. Over the past few years, this has been greatly improved by genome sequencing that can pinpoint the mutation that breaks a gene and leads to a severe disease. However, this approach is still unsuccessful in the majority of patients, largely because of our inability to read the genome to identify all mutations that disrupt gene function.

In a new study published on October 10 in Science , researchers from New York Genome Center , Columbia University , and Scripps Research Institute propose a solution to this problem. Building a new computational method for analyzing genomes together with transcriptome data from RNA-sequencing, they can now identify genes where genetic variants disrupt gene expression in patients and improve the diagnosis of rare genetic disease.

The new method introduced in this study, Analysis of Expression Variation or ANEVA, first takes allele-specific expression data from a large reference sample of healthy individuals to understand how much genetic regulatory variation each gene harbors in the normal population. Then, using the ANEVA Dosage Outlier Test, researchers can analyze the transcriptome of any individual – such as a patient – to find a handful of genes where he or she carries a genetic variant with an unusually large effect compared to what healthy individuals have. By applying this test to a cohort of muscle dystrophy and myopathy patients, the researchers demonstrated  the performance of their method and diagnosed additional patients where previous methods of genome and RNA analysis had failed to find the broken genes.

MAGIC - Wang Lab

Illustrated here: (a) In contrast to traditional approaches to cultivate microbes first and then test for genetic accessibility, MAGIC harnesses horizontal gene transfer in the native environment to genetically modify bacteria in situ. (b) MAGIC implementation to transfer replicative or integrative pGT vectors from an engineered donor strain into amenable recipients in a complex microbiome. Replicative vectors feature a broad-host range origin of replication (oriR), while integrative vectors contain a transposable Himar cassette and transposase. The donor E. coli strain contains genomically integrated conjugative transfer genes (tra) and a mCherry gene. Transconjugant bacteria are detectable based on expression of an engineered payload that includes GFP and an antibiotic resistance gene (abr).

A team of researchers, led by Dr. Harris Wang of the Department of Systems Biology , has engineered bacteria to benefit and improve the overall health of our gut microbiome. In a proof-of-concept paper published in Nature Methods , Dr. Wang and his team demonstrate MAGIC, an innovative gene delivery system that ‘hacks’ the gut microbiome to perform any desired function, from harvesting energy from food and protecting against pathogen invasion to bolstering anti-inflammatory properties and regulating immune responses.

“The MAGIC system allows us to insert new gene functions directly into an existing microbiome without permanently altering the composition of the microbiome as a whole,” says Sway Chen , an MD/PhD student in the Wang lab and co-author of the study.

Time lapse of a developing drosophila embryo. (Credit: Carlos Sanchez-Higueras/Hombría lab/CABD)

Every animal, from an ant to a human, contains in their genome pieces of DNA called Hox genes. Architects of the body, these genes are keepers of the body’s blueprints; they dictate how embryos grow into adults, including where a developing animal puts its head, legs and other body parts. Scientists have long searched for ways to decipher how Hox genes create this body map; a key to decoding how we build our bodies.

Now an international group of researchers from Columbia University and the Spanish National Research Council (CSIC) based at the Universidad Pablo de Olavide in Seville, Spain have found one such key: a method that can systematically identify the role each Hox gene plays in a developing fruit fly. Their results, reported recently in Nature Communications , offer a new path forward for researchers hoping to make sense of a process that is equal parts chaotic and precise, and that is critical to understanding not only growth and development but also aging and disease.

“The genome, which contains thousands of genes and millions of letters of DNA, is the most complicated code ever written,” said study co-senior author Richard Mann , PhD, principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and a faculty member in the Department of Systems Biology . “Deciphering this code has proven so difficult because evolution wrote it in fits and starts over hundreds of millions of years. Today’s study offers a key to cracking that code, bringing us closer than ever to understanding how Hox genes build a healthy body, or how this process gets disrupted in disease.”

Read the full article at the Zuckerman Institute

Tal Korem, PhD
Dr. Tal Korem

Tal Korem, PhD, has been named a CIFAR Azrieli Global Scholar, a fellowship that supports leading early-career researchers in science and technology. 

Dr. Korem is an assistant professor of systems biology with a joint appointment in obstetrics and gynecology at Columbia University Vagelos College of Physicians & Surgeons, and a faculty member of the Program for Mathematical Genomics . As a global scholar, he is joining CIFAR’s Humans and the Microbiome research program, where his work will focus on harnessing human microbial communities to identify and develop novel diagnostic and therapeutic tools.

CIFAR’s  Azrieli Global Scholars program supports its fellows through funding and mentorship, emphasizing essential network and professional skills development. The scholars join CIFAR research programs for a two-year period where they collaborate with fellows and brainstorm new approaches to pressing science and technology problems. Research topics are diverse, ranging from bio-solar energy and visual consciousness to engineered proteins and the immune system. 

Dr. Korem is one of 14 researchers out of an applicant pool of 217 selected by the Canadian-based nonprofit organization. This year’s cohort represents citizenship in eight countries and appointments in institutions from Canada, the U.S.,  Israel, Australia, the Netherlands, and Spain.

-Melanie A. Farmer

Sagi Shaipra PHIPSTer Cell Paper
Researchers implement P-HIPSTer, an in silico computational framework that leverages protein structure information to identify approximately 282,000 protein-protein interactions across all fully-sequenced human-infecting viruses (1001 in all). This image highlights that in addition to rediscovering known biology, P-HIPSTer has yielded a series of new findings and enables discovery of a previously unappreciated universe of cellular circuits and biological principles that act on human-infecting viruses. (Image Courtesy of Dr. Sagi Shapira)

Researchers at Columbia University Irving Medical Center have leveraged a computational method to map protein-protein interactions between all known human-infecting viruses and the cells they infect. The method, along with the data that it generated, has spawned a wealth of information toward improving our understanding of how viruses manipulate the cells that they infect and cause disease. Among its findings, the work uncovered a role for estrogen receptor in regulating Zika Virus (ZIKV) infection, as well as links between cancer and the human papillomavirus (HPV).

The research, led by Sagi Shapira , PhD, Assistant Professor in the Department of Systems Biology and the Department of Microbiology & Immunology at Columbia University Vagelos College of Physicians and Surgeons , appears today in the journal, Cell . Dr. Shapira’s collaborators include Professors Barry Honig , PhD, of Systems Biology and of Biochemistry and Molecular Biophysics and Raul Rabadan , PhD, of Systems Biology and of Biomedical Informatics.