DUF1220 protein domains have undergone the largest human lineage-specific increase in copy numberof any protein coding region in the genome (~290 copies in human haploid genome), and map primarily to1q21, a region where copy number variations containing many DUF1220 copies have been repeatedly linkedto autism, schizophrenia, micro- and macrocephaly. DUF1220 copy number exhibits a broad Gaussiandistribution in human populations, and is a rich source of unexamined functional allelic variation. Previously wehave implicated DUF1220 copy number (dosage) in human brain expansion and normal and pathologicalchanges in brain size. Over the past year we have demonstrated that DUF1220 (CON1 subtype) dosage islinearly associated with increasing symptom severity of autism (now confirmed by a replication study) and alsoinversely with schizophrenia severity and risk. These findings are remarkable in that they imply that dosagevariations within the same protein domain family (DUF1220) may be involved in human brain evolution, autismand schizophrenia, and that these processes may be genetically and mechanistically interrelated. Building on these significant findings, we will expand our study of DUF1220 copy number in autism andschizophrenia severity (Aim 1) and risk (Aim 2) and in micro-/macrocephaly (Aim 3) using methods we haveused successfully (ddPCR, 1q21-targeted arrayCGH) as well as through application of novel methods thathave the potential to significantly improve DUF1220 copy number analysis (Aim 4). For example, we haverecently optimized and validated our sequence read-depth method for measuring DUF1220 copy number athigh resolution and precision from whole genome sequence (WGS) data. We will apply this approach to WGSdata from 1) the Autism 10K project in collaboration with Dr. Stephen Scherer, and 2) to several additionallarge WGS datasets that are emerging for autism and schizophrenia. In addition, we have established asubcontract with our collaborator, Dr. Pui Kwok, to apply Irys, an optical mapping method for automatedgenome mapping of long (>150kb) single DNA molecules, to assess DUF1220 copy number variation in thesedisorders. The Irys approach should be aided by our development of a CRISPR-Cas9 method which allowsDUF1220-specific labeling of genomic DNA. These approaches, including our exploration of long-readsequencing technologies, will be facilitated by utilization of a new, more accurate and gap-free 1q21 assemblywe recently helped generate. Finally, we will build on our recent progress linking DUF1220 function toincreases in neuron number by testing whether DUF1220 promotes neural stem cell (H9-derived) proliferationin a dosage-dependent manner and identifying cellular pathways affected by progressively increasingDUF1220 dosage.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
