# Investigation of DUF1220 domains in human brain function and disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $385,918

## Abstract

SUMMARY
 DUF1220 protein domains have undergone the largest human lineage-specific increase in copy number
of any protein coding region in the genome (~290 copies in human haploid genome), and map primarily to
1q21, a region where copy number variations containing many DUF1220 copies have been repeatedly linked
to autism, schizophrenia, micro- and macrocephaly. DUF1220 copy number exhibits a broad Gaussian
distribution in human populations, and is a rich source of unexamined functional allelic variation. Previously we
have implicated DUF1220 copy number (dosage) in human brain expansion and normal and pathological
changes in brain size. Over the past year we have demonstrated that DUF1220 (CON1 subtype) dosage is
linearly associated with increasing symptom severity of autism (now confirmed by a replication study) and also
inversely with schizophrenia severity and risk. These findings are remarkable in that they imply that dosage
variations within the same protein domain family (DUF1220) may be involved in human brain evolution, autism
and 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 and
schizophrenia severity (Aim 1) and risk (Aim 2) and in micro-/macrocephaly (Aim 3) using methods we have
used successfully (ddPCR, 1q21-targeted arrayCGH) as well as through application of novel methods that
have the potential to significantly improve DUF1220 copy number analysis (Aim 4). For example, we have
recently optimized and validated our sequence read-depth method for measuring DUF1220 copy number at
high resolution and precision from whole genome sequence (WGS) data. We will apply this approach to WGS
data from 1) the Autism 10K project in collaboration with Dr. Stephen Scherer, and 2) to several additional
large WGS datasets that are emerging for autism and schizophrenia. In addition, we have established a
subcontract with our collaborator, Dr. Pui Kwok, to apply Irys, an optical mapping method for automated
genome mapping of long (>150kb) single DNA molecules, to assess DUF1220 copy number variation in these
disorders. The Irys approach should be aided by our development of a CRISPR-Cas9 method which allows
DUF1220-specific labeling of genomic DNA. These approaches, including our exploration of long-read
sequencing technologies, will be facilitated by utilization of a new, more accurate and gap-free 1q21 assembly
we recently helped generate. Finally, we will build on our recent progress linking DUF1220 function to
increases in neuron number by testing whether DUF1220 promotes neural stem cell (H9-derived) proliferation
in a dosage-dependent manner and identifying cellular pathways affected by progressively increasing
DUF1220 dosage.

## Key facts

- **NIH application ID:** 9956723
- **Project number:** 5R01MH108684-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** JAMES M SIKELA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,918
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956723

## Citation

> US National Institutes of Health, RePORTER application 9956723, Investigation of DUF1220 domains in human brain function and disease (5R01MH108684-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9956723. Licensed CC0.

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