This application is in response to RFA number RFA-OD-10-005 and addresses thematic area 1: Applying genomics and other high throughput technologies. Retrotransposons are an often-overlooked source of inter-individual genomic variation in mammals. The primary driver of this variation in the human genome is the LINE-1 (L1) retrotransposition, which exists in ~500,000 copies spread across a succession of subfamilies each of which was active at some point in evolutionary history. The currently active subfamily is known as either L1Hs (for Human-specific) or L1-Ta (for Transcribed group a) and consists of some ~1000 members per haploid genome, a small subset of which are actively mobilized. We have developed a technique to locate retrotransposon insertions with good specificity and sensitivity by high-throughput sequencing, and have been using it to find human-specific L1 and SVA (another human retrotransposon) insertions from various individuals. In parallel, the laboratory of Lynn Jorde at the University of Utah has developed a similar next-generation sequencing-based approach to identify Alu insertions on a genome-wide scale. Additionally, we are in the first stages of developing a bead-array platform for the high-throughput detection of known retrotransposon insertion polymorphisms (RIPs) in order to perform an association study using RIPs as an alternate marker to SNPs and CNVs. In our grant application, we will propose to use these technologies to study whether LINE-1 and Alu retrotransposition plays a role in the genetic susceptibility to autism-spectrum disorders (ASDs). This study will follow 3 aims: 1. The association of all (low and high frequency) L1 and Alu polymorphisms with ASDs using our sequencing technique in a limited number of trios consisting of the parents and affected proband, 2. Studying the rate of somatic de novo L1 and Alu insertion in ASD patient genomes, ascertained through the study of discordant monozygotic twins, and 3. The association of moderate- to high-frequency retrotransposon polymorphisms with ASDs using an array-based approach to screen many individuals (RIP-GWAS).

Public Health Relevance

Autism spectrum disorders (ASD) are major neurological conditions affecting a large proportion of the US population of children (1 in 166 live births). To date, the predicted major genetic component of their etiology has been explored using single nucleotide polymorphisms and copy number variations with success in finding the cause of a small minority of ASD cases. Here we propose to add another form of genome variation, retrotransposon-induced polymorphisms (RIPs), to the search for ASD etiology.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
High Impact Research and Research Infrastructure Programs—Multi-Yr Funding (RC4)
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Special Emphasis Panel (ZRG1-BDCN-A (55))
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Koester, Susan E
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Johns Hopkins University
Schools of Medicine
United States
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Mandal, Prabhat K; Ewing, Adam D; Hancks, Dustin C et al. (2013) Enrichment of processed pseudogene transcripts in L1-ribonucleoprotein particles. Hum Mol Genet 22:3730-48
Zhao, Ke; Du, Juan; Han, Xue et al. (2013) Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1. Cell Rep 4:1108-15
Solyom, Szilvia; Ewing, Adam D; Hancks, Dustin C et al. (2012) Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon. Hum Mutat 33:369-71