DIGGIT identifies mutations upstream of master regulators.

A new algorithm called DIGGIT identifies mutations that lie upstream of crucial bottlenecks within regulatory networks. These bottlenecks, called master regulators, integrate these mutations and become essential functional drivers of diseases such as cancer.

Although genome-wide association studies have made it possible to identify mutations that are linked to diseases such as cancer, determining which mutations actually drive disease and the mechanics of how they do so has been an ongoing challenge. In a paper just published in Cell, researchers in the lab of Andrea Califano describe a new computational approach that may help address this problem.

Dana Pe'er and Kyle Allison

Dana Pe'er has received the Pioneer Award for high-risk, high-reward research, and postdoctoral scientist Kyle Allison has won an Early Independence Award.

Two members of the Columbia University Department of Systems Biology have been named recipients of NIH Director’s Awards from the National Institutes of Health Common Fund.

Associate Professor Dana Pe’er is one of 10 winners of the 2014 NIH Director’s Pioneer Awards. The Pioneer Awards provide up to $2.5 million over 5 years to support exceptionally creative investigators who are pursuing “high risk, high reward” science that holds great potential to transform biomedical or behavioral research. The award will support an ambitious new project to develop the technological and computational methods necessary to create a comprehensive, high-resolution atlas of development for all cell types in the human body.

In addition, Kyle Allison, a postdoctoral scientist in the laboratory of Professor Saeed Tavazoie, has received the NIH Director’s Early Independence Award. (Dr. Tavazoie is also a past winner of the Pioneer Award.) This program enables outstanding young investigators who have recently completed their PhD’s to move rapidly into independent research positions. Dr. Allison is one of just 17 scientists to receive this award this year. In combination with the Department of Systems Biology Fellows program, this five-year, $1.25 million grant will allow him to open his own laboratory at Columbia and pursue independent research to investigate the problem of bacterial persistence. He is the second Department of Systems Biology investigator to receive the Early Independence Award, joining Assistant Professor Harris Wang in being recognized with this honor.

“Having four recipients of NIH Director’s Awards within the Department of Systems Biology — and particularly two in one year — is quite remarkable,” said Department Chair Andrea Califano. “I think it’s a testimony to the timeliness of the perspectives and tools that systems biology offers and to the high quality of research being conducted at Columbia. I look forward to the discoveries that will undoubtedly come from Dana’s and Kyle’s extremely exciting efforts.”

We are pleased to announce that Columbia University Medical Center professors Oliver Hobert, Richard Mann, and Rodney Rothstein have been named to interdisciplinary appointments in the Department of Systems Biology. The addition of this new expertise will expand the breadth of science currently being explored in the Department, enhance educational opportunities for students, facilitate new collaborations, and promote the integration of systems biology perspectives and methods into research being conducted elsewhere in the university.

Harris Wang

As a graduate student in George Church’s lab at Harvard University, Harris Wang developed MAGE, a revolutionary tool for the field of synthetic biology that made it possible to introduce genomic mutations into E. coli cells in a highly specific and targeted way. Now an Assistant Professor in the Columbia University Department of Systems Biology, Dr. Wang recently published a paper in ACS Synthetic Biology that introduces an important advance in the MAGE technology. The new technique, called (MO)-MAGE, uses microarrays to engineer pools of oligonucleotides that, once amplified and integrated into a genome, can generate thousands or even millions of highly controlled mutations simultaneously. This new method offers a cost-effective way for designing and producing large numbers of genomic variants and provides an efficient platform for experimentally exploring genome-wide landscapes of mutations in bacteria and optimizing the organisms’ biochemical capabilities.

In the following interview, Dr. Wang explains the origins of the new technology, and discusses what he sees as the remarkable potential it holds for both basic biological research and industrial applications of synthetic biology.

Ashkenazi Population Bottleneck Model
The consortium’s model of Ashkenazi Jewish ancestry suggests that the population’s history was shaped by three critical bottleneck events. The ancestors of both populations underwent a bottleneck sometime between 85,000 and 91,000 years ago, which was likely coincident with an Out-of-Africa event. The founding European population underwent a bottleneck at approximately 21,000 years ago, beginning a period of interbreeding between individuals of European and Middle Eastern ancestry. A severe bottleneck occurred in the Middle Ages, reducing the population to under 350 individuals. The modern-day Ashkenazi community emerged from this group.

An international research consortium led by Associate Professor Itsik Pe’er has produced a new panel of reference genomes that will significantly improve the study of genetic variation in Ashkenazi Jews. Using deep sequencing to analyze the genomes of 128 healthy individuals of Ashkenazi Jewish origin, The Ashkenazi Genome Consortium (TAGC) has just published a resource that will be much more effective than previously available European reference genomes for identifying disease-causing mutations within this historically isolated population. Their study also provides novel insights into the historical origins and ancestry of the Ashkenazi community. A paper describing their study has just been published online in Nature Communications.

The dataset produced by the consortium provides a high-resolution baseline genomic profile of the Ashkenazi Jewish population, which they revealed to be significantly different from that found in non-Jewish Europeans. In the past, clinicians’ only option for identifying disease-causing mutations in Ashkenazi individuals was to compare their genomes to more heterogeneous European reference sets. This new resource accounts for the historical isolation of this population, and so will make genetic screening much more accurate in identifying disease-causing mutations.

In an article that appears on the website of Columbia University’s Fu Foundation School of Engineering and Computer Science, Dr. Pe’er explains:

“Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes... With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations.”

In addition to offering an important resource for such future translational and clinical research, the paper’s findings also provide new insights that have implications for the much debated question of how European and Ashkenazi Jewish populations emerged historically.