RT Journal
A1 Guitart, Xavi
A1 Porubsky, David
A1 Yoo, DongAhn
A1 Dougherty, Max L.
A1 Dishuck, Philip C.
A1 Munson, Katherine M.
A1 Lewis, Alexandra P.
A1 Hoekzema, Kendra
A1 Knuth, Jordan
A1 Chang, Stephen
A1 Pastinen, Tomi
A1 Eichler, Evan E.
T1 Independent expansion, selection, and hypervariability of the TBC1D3 gene family in humans
JF Genome Research 
JO Genome Research 
YR 2024 
FD November 01 
VO 34 
IS 11 
SP 1798 
OP 1810 
DO 10.1101/gr.279299.124 
UL http://genome.cshlp.org/content/34/11/1798.abstract 
AB 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.