Using Multi-level Genomic Approaches to Tackle Regional Issues

NYUAD CGSB uses modern genomics and systems biology techniques to focus on model species and non-model organisms of regional interest.

"Among the most fundamental questions in the life sciences are those of how molecular systems are built from the interaction of molecular genetic elements," said NYU New York Silver Professor of Biology Claude Desplan. "How such networks adapt to new conditions, when and how they break down — as in diseases — and how natural selection works at the network level to enable living systems to adapt to very different environments," added Michael Purugganan, dean of science and Dorothy Schiff Professor of Genomics at NYU New York's Faculty of Arts and Science (FAS). These are the questions that lie at the heart of NYU Abu Dhabi's Center for Genomics and Systems Biology (CGSB), said Fabio Piano, NYUAD's provost and founding director of the New York CGSB. Established in 2012 to investigate and address such broadly and regionally based biological matters, the Center's team includes Piano, Desplan, and Purugganan.

Deciphering the Link from Genotype to Phenotype

As Kourosh Salehi-Ashtiani, NYUAD associate professor of Biology and the Center's co-director, explained, "Over the last decade, the complete genome sequences for thousands of organisms, including humans, have been elucidated, opening new horizons for biological research." For scientists at the Center, this development has enabled them to focus on the next phase of biological research: to identify the mechanisms that underlie the evolution of these genomes and that transform genetic information into cellular and organismal behaviors using a global or systems-level view. While genomics provides the necessary tools for the generation and interpretation of large-scale datasets, systems biology investigates multiple facets of molecular complexity across the entire genome of an organism. According to Piano, by bringing together both data production and data analysis, the Center will not only be able to focus on a wide range of research, but also allow researchers to connect disparate data to decipher the link from genotype — the genetic constitution of an individual organism — to phenotype — the set of observable characteristics of an individual, including the interaction of genotype with the environment.

Created as a sister center to NYU New York's CGSB — and to which several NYU New York faculty, graduate students, and researchers continue to establish connections — the NYUAD CGSB will use modern genomics and systems biology techniques, such as next-generation sequencing, proteomics, imaging, and computational science. Using these methods, it will focus on model species (Chlamydomonas reinhardtii, Caenorhabditis elegans, Drosophila, and mice), as well as non-model organisms of regional interest (date palms, marine algae, and environmental microbes), and examine living processes across different biological levels, from cells to organisms to populations/species to ecosystems. By doing so, it will help tackle regional issues in human health, energy, agriculture, and the environment.

The Center is working on three research programs with an emphasis on key areas of renewable resources and regional biodiversity, cancer cell systems and disease-related chemical genomics, and neuronal systems. Each uses genomics, or, as Desplan, also, the director of the Center for Developmental Genetics at NYU New York's FAS and an affiliate of the NYU New York CGSB, explained, "high-throughput sequencing to analyze the entire set of genes expressed in different situations."

Over the last decade, the complete genome sequences for thousands of organisms, including humans, have been elucidated, opening new horizons for biological research.

Kourosh Salehi-Ashtiani, NYUAD associate professor of Biology and co-director of NYUAD's CGSB
Renewable Resources and Regional Biodiversity

The first program focuses on environmental genomics, algal systems biology, and renewable resources and includes four research projects that study genomic variation at the within- and between-species level. One of the four projects, the date palm project, spearheaded by Purugganan — who was also the associate director of NYU New York's CGSB from 2010 to 2012 — seeks to understand the evolution of domesticated plant species. By studying genomic variation in species and strains that are of regional importance, such as the date palm (Phoenix dactylifera), researchers are able to trace the origin and spread of crop species and to develop new ways of identifying agriculturally important genes. As Purugganan explained, despite the abundance of date palms in the region, "there is very little known about their genetics, preventing concerted efforts at breeding and also leaving unanswered several questions on the origin and spread of the species. Moreover, breeding efforts in date palms are hampered by their relatively long generation times and large sizes, which make it difficult to perform conventional genetic crosses."

During the project, the team will re-sequence 100 date palm varieties (including 30 from the UAE and the rest from the Middle East and North Africa) to perform a comprehensive study of their evolution and develop a whole-genome haplotype map for use in genome-wide association studies in date palms. The team will also develop a single nucleotide polymorphism (SNP) — the variation in a single base pair in a DNA sequence — mapping chip for deeper genotyping of a larger pool of date palm germplasm and use the SNP data to examine the origin and spread of date palms. To further their research, the team hopes to collaborate with private nurseries and breeders in the UAE. A second project in this program is the development of a model biofuel organism for systems-level studies and the exploration of local marine algal species for their biofuel potential. Directed by Salehi-Ashtiani, also a co-principal investigator on the team, researchers use C. reinhardtii as a model algal species to identify, isolate, and optimize species native to the UAE for biofuel applications. "C. reinhardtii can produce hydrogen gas as a by-product of photosynthesis under oxygen and sulfur deprivation," said Salehi-Ashtiani, "which makes it an attractive model system for biofuel production." The team will also examine the genomic diversity of the algae by sequencing the genomes of approximately 30 natural strains of the species found worldwide in order to, among other things, associate the biofuel production capacity of the strains with specific genes, their natural allelic variants (genetic variants that arise by mutation, found at the same place
on a chromosome), and epigenetic modifications (those resulting from external rather than genetic influences). 

Using Genetic Blueprints to Fight Disease

The second program will use nematode model organisms — namely C. elegans, or roundworm, the first animal to have its genome completely sequenced, and of which scientists at the center recently created the first genetic blueprint — to identify small molecules that are relevant to mechanisms of human disease, such as cancer and diabetes, or potential anti-helminthic (anti-nematode) agents. "While C. elegans is a free-living, non-pathogenic nematode, related pathogenic species are estimated to infect a staggering 2 billion people worldwide, leading to diseases including ascariasis, trichuriasis, filariasis (elephantiasis), and onchocerciasis (river blindness)," explained Kristin Gunsalus, NYUAD CGSB co-principal investigator, NYU New York associate professor of Biology, and researcher at NYU New York's CGSB. According to Gunsalus, nematodes that parasitize livestock and plant crops cause billions of dollars in economic damage each year. Thus, in this project, researchers will use C. elegans — ideal due to its small size, rapid lifecycle, and ease of propagation and manipulation — to identify bioactive compounds and their molecular targets in vivo using high-throughput screening (HTP) to examine new drugs affecting pathological processes.

These will provide the basis for unbiased screens aimed at discovering drugs that activate or suppress activity in specific interneuron populations and may lead to the development of treatments for currently intractable diseases such as autism.

Claude Desplan, NYU New York Silver Professor of Biology

Last but certainly not least, Desplan will direct a team of scientists in the Center's third program: mapping the complexity of neurons in the vertebrate and invertebrate brain with the goal of understanding how each neuron acquires its specific properties and connects with its correct targets. "The huge diversity of cell types and the numbers of neuronal connections in the brain are a daunting problem that must be understood in order to comprehend neural circuit function," Desplan, a developmental neurobiologist, said. By charting the complete transcriptional profile of neurons in different parts of the vertebrate and invertebrate and using this molecular characterization to manipulate neuronal function in vivo, researchers will open a path to assessing their role in brain function, as well as be able to create models of neurological disease. As Desplan explained, "These will provide the basis for unbiased screens aimed at discovering drugs that activate or suppress activity in specific interneuron populations and may lead to the development of treatments for currently intractable diseases such as autism."

All of these projects require a robust and state-of-the-art bioinformatic infrastructure. Gunsalus and Richard Bonneau, NYU New York associate professor of Biology and Computer Science and faculty director of Bioinformatics, are leading the development of that effort.

Involving NYUAD Students in the Research

Looking to the future, the Center hopes to commence large-scale chemical genetic screening and plans to have an environmental sample collection, assays, and sequencing from multiple terrestrial and aquatic Gulf-region habitats well under way. It is also the Center's goal to initiate an undergraduate research program and involve NYUAD students in the projects well before the Campus moves to Saadiyat Island. "They are all anxious to start Capstone projects at the NYUAD Institute," Desplan said. Additionally, collaborations between the Center and other NYUAD faculty, as well as local and regional scientists and organizations, are already in the works.

With these collaborations, the Center will be poised to address biological, behavioral, environmental, and even conceptually complex cultural questions. "The research we propose will not only enable NYUAD to advance the general understanding of biological systems, but the Center will provide a focal point for leading biological research in the Emirates," said Piano. "It will serve to transform a locationally constrained research enterprise into an open organizational structure that will foster research projects around the world."