. During the last phase of this project, we developed new tools to discover mobile element insertions (MEIs) in human genomes on a population-scale and then used these tools to generate the final MEI call sets for the 1000 Genomes Project. During the next phase of this competitive renewal, we now propose to build upon these initial successes to perform MEI discovery on an even larger scale.
In Aim 1 we propose to perform population-scale MEI discovery and analysis in collaboration with several large consortia. Through collaborations with the Simons Foundation Autism Consortium, the TOPMed project, and other projects, we will perform MEI discovery in ~94,000 genomes and exomes. These studies will allow us to examine the impact of MEIs on human traits and diseases on a much larger scale than has been examined previously.
In Aim 2 we will study the full-length L1 (FL-L1) source elements that generate MEIs in humans. We will develop a comprehensive resource of FL-L1 elements using PacBio-based sequencing approaches. We will then use this resource to study how MEI genesis varies in diverse human genomes and populations. Finally, in Aim 3 we will leverage the unique resources that we will generate in Aims 1 and 2 of this project to study the rates of de novo MEI formation in families and extended pedigrees. These studies involve large resources of diverse families and pedigrees (including European, African American, East Asian, and Hispanic families and pedigrees), which also provides us with a unique opportunity to compare the relative rates of de novo MEI production across diverse populations. We hypothesize that MEI production rates will vary among diverse populations due to differences in FL-L1 source content. We will continue to test this hypothesis in Aim 3. This project will potentially have a sustained and significant impact on the human genetics community by facilitating MEI detection on a broad scale for the first time.

Public Health Relevance

. We are studying natural genetic changes in human genomes that are caused by mobile element insertions (MEI?s). This type of genome variation contributes to a wide range of human diseases, and thus is relevant to the broad mission of the National Institutes of Health. Our project will facilitate efforts to understand how genetic variation affects human traits and diseases.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
2R01HG002898-09A1
Application #
9312059
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Brooks, Lisa
Project Start
2004-09-24
Project End
2020-05-31
Budget Start
2017-07-17
Budget End
2018-05-31
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Connolly, Nina P; Shetty, Amol C; Stokum, Jesse A et al. (2018) Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma. Sci Rep 8:1180
Gardner, Eugene J; Lam, Vincent K; Harris, Daniel N et al. (2017) The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. Genome Res 27:1916-1929
Scott, Emma C; Devine, Scott E (2017) The Role of Somatic L1 Retrotransposition in Human Cancers. Viruses 9:
Scott, Emma C; Gardner, Eugene J; Masood, Ashiq et al. (2016) A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res 26:745-55
Sudmant, Peter H; Rausch, Tobias; Gardner, Eugene J et al. (2015) An integrated map of structural variation in 2,504 human genomes. Nature 526:75-81
Nugent, Bridget M; Wright, Christopher L; Shetty, Amol C et al. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690-7
1000 Genomes Project Consortium; Auton, Adam; Brooks, Lisa D et al. (2015) A global reference for human genetic variation. Nature 526:68-74
Delaneau, Olivier; Marchini, Jonathan; 1000 Genomes Project Consortium et al. (2014) Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel. Nat Commun 5:3934
Colonna, Vincenza; Ayub, Qasim; Chen, Yuan et al. (2014) Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences. Genome Biol 15:R88
Khurana, Ekta; Fu, Yao; Colonna, Vincenza et al. (2013) Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 342:1235587

Showing the most recent 10 out of 23 publications