Document Type

Article

Publication Date

11-20-2024

Identifier

DOI: 10.1101/gr.279299.124

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.

Journal Title

Genome research

Volume

34

Issue

11

First Page

1798

Last Page

1810

MeSH Keywords

Humans; GTPase-Activating Proteins; Animals; Selection, Genetic; Multigene Family; DNA Copy Number Variations; Evolution, Molecular; Chromosomes, Human, Pair 17; Primates; Nerve Tissue Proteins; Gene Duplication; Proto-Oncogene Proteins

Keywords

GTPase-Activating Proteins; Genetic Selection; Multigene Family; DNA Copy Number Variations; Molecular Evolution; Human Chromosomes, Pair 17; Primates; Nerve Tissue Proteins; Gene Duplication; Proto-Oncogene Proteins

Comments

Grants and funding

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/.

Publisher's Link: https://genome.cshlp.org/content/34/11/1798.long

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