Independent expansion, selection, and hypervariability of the TBC1D3 gene family in humans
Open accessPublished version of a preprint
Abstract
TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 nonhuman primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy-number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ∼1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Last, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL . These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.
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Cites
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“To better understand the evolution of the clusters, we investigated the organization of TBC1D3 in 10 different NHP lineages (Supplemental Table S4).”
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“New World monkeys, owl monkeys, and marmosets do not have TBC1D3 organized into clusters.”
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Human-specific genetic hallmarks in neocortical development: focus on neural progenitors
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- Authors
- Guitart, X., Porubsky, D., Yoo, D., Dougherty, M. L., Dishuck, P. C., Munson, K. M., Lewis, A. P., Hoekzema, K., Knuth, J., Chang, S., Pastinen, T., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Tisch Cancer Institute (US)
- Stanford Medicine (US)
- Children's Mercy Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eichler, Evan E.
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2024-08-06
- Volume
- 34
- Issue
- 11
- Pages
- 1798-1810
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC11610581
- OpenAlex
- W4401363300
- Cited by
- 14
- References
- 8
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Genome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Institutes of Health (HG002385, HG010169, HG007497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- gene family expansion, segmental duplication, copy number variation, chromosome 17q12, positive selection, haplotype variation, paralogs, primate-specific genes, cortical development, neuronal progenitor proliferation
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