Files and links (1)
Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
The Driver of Extreme Human-Specific Olduvai Repeat Expansion Remains Highly Active in the Human Genome
Genetics (Austin), v 214(1), pp 179-191
Jan 2020
PMID: 31754017
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Sequences encoding Olduvai protein domains (formerly DUF1220) show the greatest human lineage-specific increase in copy number of any coding region in the genome and have been associated, in a dosage-dependent manner, with brain size, cognitive aptitude, autism, and schizophrenia. Tandem intragenic duplications of a three-domain block, termed the Olduvai triplet, in four
genes in the chromosomal 1q21.1-0.2 region, are primarily responsible for the striking human-specific copy number increase. Interestingly, most of the Olduvai triplets are adjacent to, and transcriptionally coregulated with, three human-specific
genes that have been shown to promote cortical neurogenesis. Until now, the underlying genomic events that drove the Olduvai hyperamplification in humans have remained unexplained. Here, we show that the presence or absence of an alternative first exon of the Olduvai triplet perfectly discriminates between amplified (58/58) and unamplified (0/12) triplets. We provide sequence and breakpoint analyses that suggest the alternative exon was produced by an nonallelic homologous recombination-based mechanism involving the duplicative transposition of an existing Olduvai exon found in the CON3 domain, which typically occurs at the C-terminal end of
genes. We also provide suggestive
evidence that the alternative exon may promote instability through a putative G-quadraplex (pG4)-based mechanism. Lastly, we use single-molecule optical mapping to characterize the intragenic structural variation observed in
genes in 154 unrelated individuals and 52 related individuals from 16 families and show that the presence of pG4-containing Olduvai triplets is strongly correlated with high levels of Olduvai copy number variation. These results suggest that the same driver of genomic instability that allowed the evolutionarily recent, rapid, and extreme human-specific Olduvai expansion remains highly active in the human genome.
Metrics
Details
- Title
- The Driver of Extreme Human-Specific Olduvai Repeat Expansion Remains Highly Active in the Human Genome
- Creators
- Ilea E Heft - University of Colorado DenverYulia Mostovoy - University of California, San FranciscoMichal Levy-Sakin - University of California, San FranciscoWalfred Ma - University of California, San FranciscoAaron J Stevens - University of OtagoSteven Pastor - Drexel UniversityJennifer McCaffrey - Drexel UniversityDario Boffelli - Children's Hospital Oakland Research InstituteDavid I Martin - Children's Hospital Oakland Research InstituteMing Xiao - Drexel UniversityMartin A Kennedy - University of OtagoPui-Yan Kwok - University of California, San FranciscoJames M Sikela - University of Colorado Denver
- Publication Details
- Genetics (Austin), v 214(1), pp 179-191
- Grant note
- R01 HG005946 / NHGRI NIH HHS R01 MH108684 / NIMH NIH HHS T32 HL007731 / NHLBI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000505807300010
- Scopus ID
- 2-s2.0-85077666460
- Other Identifier
- 991019168095504721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity