This is a new proposal submitted in response to a funding opportunity focused on comparative genomics research (PAR-17-482). The FOA states that NHGRI invites applications for the ?development of new comparative genomics research approaches using genomic data types to understand biological systems, networks, and pathways.? And that ?high priority will be given to applications that propose innovative and promising approaches to genome-wide and multi-species comparisons.? Differences in gene regulation between humans and other primates may ultimately be used to explain the molecular basis for human-specific traits. While current comparative studies in primates have provided valuable insight into the genetic architecture of gene regulation, they do not provide a flexible framework to study inter-species variation in gene regulation in multiple cell types from the same individuals. In particular, frozen post-mortem tissues are not optimal templates for many functional genomic assays; as a result, we lack data sets that survey multiple dimensions of gene regulatory mechanisms and phenotypes from the same samples. Moreover, because it is rare to collect a large number of tissue samples from the same donor, we have never had the opportunity to study population-level patterns of gene regulation in multiple tissues or cell types derived from the same non-human ape genotype (same donor), and we have not been able to study population-level dynamics of gene regulation, for example, during perturbation. We propose to explore an alternative promising way to move forward. Recent extraordinary advances in molecular biology suggest a way forward. It has now become possible to reprogram somatic cells, such as fibroblasts and several types of blood cells, into a pluripotent state, in which the cells have the capability to both self-replicate indefinitely and to differentiate into any cell type in the body. These reprogrammed (or induced) pluripotent stem cells (iPSCs) can then be directed to differentiate into specific cell types, which can then be studied in detail. The availability of iPSC lines from multiple species could therefore change comparative primate genetics and genomics in a profound way, by allowing us to sidestep traditional limitations on research in primates.

Public Health Relevance

We propose to develop, and freely share with the community, panels of matched induced pluripotent stem cell (iPSCs) from humans, chimpanzees, and rhesus macaques as a new transformative model system for comparative functional genomic studies in primates.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG010772-02
Application #
10005952
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Troyer, Jennifer L
Project Start
2019-09-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637