Complex mosaic structural variations in human fetal brains
- Shobana Sekar1,
- Livia Tomasini2,
- Christos Proukakis3,
- Taejeong Bae1,
- Logan Manlove1,
- Yeongjun Jang1,
- Soraya Scuderi2,
- Bo Zhou4,
- Maria Kalyva3,
- Anahita Amiri2,
- Jessica Mariani2,
- Fritz J. Sedlazeck5,
- Alexander E. Urban4,
- Flora M. Vaccarino2 and
- Alexej Abyzov1
- 1Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA;
- 2Child Study Center and Department of Neuroscience, Yale University, New Haven, Connecticut 06520, USA;
- 3Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London NW3 2PF, United Kingdom;
- 4Departments of Psychiatry and Genetics, Stanford University, Palo Alto, California 94305, USA;
- 5Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA
Abstract
Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200–400 mosaic SNVs per cell in three human fetal brains (15–21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to ∼14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in ∼10% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (∼6200 vs. ∼4000 bp), implying that they may have similar functional consequences.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.262667.120.
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Freely available online through the Genome Research Open Access option.
- Received February 23, 2020.
- Accepted September 12, 2020.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
