Larger set of human tissues to be analyzed to contribute to a database and tissue bank that researchers can use to study how genomic variants influence gene activity
The National Institutes of Health has awarded eight grants as part of the Genotype-Tissue Expression (GTEx) project to explore how human genes are expressed and regulated in different tissues, and the role that genomic variation plays in modulating that expression. The GTEx awards will contribute to a resource database and tissue bank that researchers can use to study how inherited genomic variants – inherited spelling changes in the DNA code – may influence gene activity and lead to disease. The grants will add data from analyses of tissue samples whose collection began in 2010, as well as expand the resource database and tissue bank.
The research groups will receive approximately $9 million in the first year, and nearly $15 million over three years pending the availability of funds. The project is funded by the NIH Common Fund, the National Institute of Mental Health (NIMH) and the National Heart, Lung, and Blood Institute (NHLBI).
“The new studies complement the current GTEx project in assessing genomic variation and gene expression,” explained Simona Volpi, Pharm.D., Ph.D., GTEx program director in the Division of Genomic Medicine at the National Human Genome Research Institute (NHGRI), which helps administer the program. “They delve deeper into what is happening in tissues on a molecular basis to explain how genomic variation affects how genes work. Ultimately, GTEx will provide an atlas of human gene expression.”
The groups plan to further characterize gene activity in tissues by analyzing several molecular phenotypes, or properties of cells – such as which genes are turned on and off, the various ways genes are regulated and the proteins that cells produce based on such regulation. To do this, scientists will examine part of the more than 30 tissue types available, which were collected through autopsies or organ and tissue transplant programs. The project will eventually include samples from about 900 deceased donors. Researchers will analyze DNA and RNA from the samples to identify and catalog genomic variants and gene expression.
For the last decade, scientists have used genome-wide association studies (GWAS) to study the role that genomic variation plays in complex diseases and traits. In GWAS, researchers compare thousands of genomic variants in individuals with a disease with those without the disease, establishing associations with particular variants and the disease being studied. But understanding what specific genomic variants do and how they influence the development of disease has been much more difficult to pinpoint.
By detailing certain features of cells and tissues, such as methylation patterns, protein levels and other characteristics, Dr. Volpi said that the new studies will “help paint a clearer picture of how genomic variation leads to particular diseases.” In methylation, one way that cells control gene expression is by adding chemicals, such as methyl groups.
“A scientist who is studying asthma or kidney cancer might be particularly interested in studying how genomic variants influence gene expression in the lungs or the kidneys, and the GTEx resource will provide this opportunity,” said Jeffery Struewing, M.D., GTEx program director in the NHGRI Division of Genomic Medicine.
The following research groups have been awarded grants (pending available funds)
University of Washington, Seattle, $1.85 million Principal Investigator: Joshua Michael Akey, Ph.D.
Somatic mutations – genetic mutations that are not inherited, but instead occur randomly or are caused by environmental factors – can play important roles in many diseases and conditions, especially in cancer. But how these mutations contribute to genetic variability and disease susceptibility is not well understood.
To find out, Dr. Akey and his coworkers plan to sequence the protein-coding genome regions of more than 15 tissue types and look for variations in DNA sequences and structures. Proteins are the working elements within a cell. They are vital for cellular growth, differentiation and repair. They catalyze chemical reactions and provide defense against disease, among myriad other housekeeping functions. The researchers will develop a comprehensive catalog of somatic mutations, which they hope will aid in identifying and interpreting mutations that cause human disease.
Johns Hopkins University, Baltimore, $3.24 million (including co-funding from NIMH)
Principal Investigator: Andrew Feinberg, M.D., M.P.H. The investigators plan to analyze DNA methylation patterns across the entire genome, though their main focus is on brain regions that are important in schizophrenia, depression and addiction. Methylation is a process by which cells add chemicals – methyl groups – to genes to control their expression. The work will help researchers understand the relationship between DNA methylation, gene expression and gene sequences in human health and disease.
Massachusetts Institute of Technology, Cambridge, $1.25 million
Principal Investigator: Manolis Kellis, Ph.D. Most genetic variants linked to disease don’t code for proteins, but instead have subtle gene regulatory roles, such as altering gene activity levels, or affecting the chemical modifications — epigenomic marks — made to DNA that influence which genes are active in which cells. To better understand the effects of these regulatory variants, researchers plan to characterize the epigenomic effects of genetic variation in nine peripheral tissues with roles in diabetes, heart disease, and cancer. The research will help explain how genetic variation leads to changes in gene expression across tissues, and ultimately how these differences affect a person’s predisposition to disease.
Stanford University, Palo Alto, California, $1.22 million
Principal Investigator: Jin Billy Li, Ph.D.
To gauge the influence of genetic variation on gene regulation and expression in different cells and tissues, researchers can attempt to correlate gene expression with the degree to which a gene is turned on or off. One way to do this is to measure allele-specific expression (ASE). Genes come in pairs, or alleles, and sometimes one allele is expressed to a different degree than the other gene allele.
Dr. Li, co-investigator Stephen Montgomery, Ph.D., and their colleagues plan to examine ASE in different tissue types to try to better understand the interaction between genetic variants that regulate gene expression and potential disease-causing variants.
University of Washington, Seattle, $2.24 million
Principal Investigator: John Stamatoyannopoulos, Ph.D.
Dr. Stamatoyannopoulos and his group plan to study genetic variants in non-protein coding regions of the genome, where most variants reside. They hope to explore how genetic variation in different types of tissues affects regulatory regions in the genome that control gene activity patterns. To do this, they will use a technique called DNase I-sequencing to examine certain areas in the genome and gauge gene regulation within tissue samples from various ethnic groups.
Stanford University, Palo Alto, California, $2.475 million (including co-funding from NHLBI)
Principal Investigators: Michael P. Snyder, Ph.D., and Hua Tang, Ph.D. The large-scale project aims to characterize the many different ways in which proteins normally vary, across more than nine tissue types. Scientists will catalog protein variants by mass spectroscopy (a technique to identify chemicals by mass and charge), which will help them understand the genetic basis for protein variation. This will be a valuable resource for researchers to understand the genetic basis of complex traits, and ultimately, in predicting individual disease susceptibility. These research results may also help clinicians design individual prevention and treatment strategies.
University of Chicago, $1 million
Principal Investigator: Barbara Stranger, Ph.D.
Investigators plan to characterize the proteome — the entire set of proteins produced by a genome — in several tissue types to determine the genetic basis of variation in protein expression. They will measure the levels of certain types of proteins that are responsible for sending signals in cells, and another group of proteins that act as switches, affecting which genes are turned on. The researchers will then look for variation associated with differences in protein levels to see if variants associated with protein expression have been previously linked to complex diseases. This may enable them to pinpoint specific proteins or protein networks that may underlie such disease.
University of Chicago, $1.375 million
Principal Investigator: Brandon L. Pierce, Ph.D.
Telomeres are DNA caps at the end of chromosomes that are thought to protect cells from aging. The length of telomeres plays an important role in cell division, growth and genome stability, and evidence suggests that telomere shortening over a lifetime may be involved in disease, including heart disease, dementia and cancer. Interestingly, new research suggests that two common gene variants that lead to longer telomeres may actually increase the risk for deadly brain cancers called gliomas. To better determine the role of telomere length in disease development, Dr. Pierce and his colleagues will ask if telomere length in blood reflects its length in tissues usually associated with cancer, and whether telomere length in specific tissues indicates DNA damage and chromosomes that are unstable. They also will try to gauge the role of variants in genes known to affect telomere length and cancer risk in specific tissues.
The awards are supported by the following NIH grants: U01HG007591-01; U01MH104393-01; U01HG007610-01; U01HG007593-01; U01HG007599-01; U01HG007611-01; U01HG007598-01; and U01HG007601-01.
The GTEx project is funded through the Common Fund, and managed by the NIH Office of the Director in partnership with NHGRI, NIMH, NHLBI, the National Cancer Institute, the National Center for Biotechnology Information at the National Library of Medicine, the National Institute on Drug Abuse, and the National Institute of Neurological Diseases and Stroke, all part of NIH.
The NIH Common Fund encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.
NHGRI is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research and training and career development at sites nationwide. Additional information about NHGRI can be found at www.genome.gov
The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit http://www.nimh.nih.gov/index.shtml.
Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.