@article {330078,
	title = {Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B},
	journal = {American Journal of Human Genetics},
	year = {2024},
	month = {2024/07/10/},
	abstract = {<p>SummaryThe secreted mucins MUC5AC and MUC5B are large glycoproteins that play critical defensive roles in pathogen entrapment and mucociliary clearance. Their respective genes contain polymorphic and degenerate protein-coding variable number tandem repeats (VNTRs) that make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5,761\&ndash;5,762 amino acids [aa]); however, seven haplotypes have expanded VNTRs (6,291\&ndash;7,019 aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5,249\&ndash;6,325 aa) with cysteine-rich domain and VNTR copy-number variation. We group MUC5AC alleles into three phylogenetic clades: H1 (46\%, \&sim;5,654 aa), H2 (33\%, \&sim;5,742 aa), and H3 (7\%, \&sim;6,325 aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium and Tajima\&rsquo;s D analyses reveal that East Asians carry exceptionally large blocks with an excess of rare variation (p\&nbsp;\&lt;\&nbsp;0.05) at MUC5AC. To validate this result, we use Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observe a signature of positive selection in H1 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium (p\&nbsp;\&lt;\&nbsp;0.05), consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein-coding VNTRs for improved disease associations.</p>
},
	isbn = {0002-9297},
	doi = {https://doi.org/10.1016/j.ajhg.2024.06.007},
	url = {https://www.sciencedirect.com/science/article/pii/S0002929724002131},
	author = {Plender, Elizabeth G. and Prodanov, Timofey and Hsieh, Pinghsun and Nizamis, Evangelos and Harvey, William T. and Sulovari, Arvis and Munson, Katherine M. and Kaufman, Eli J. and O{\textquoteright}Neal, Wanda K. and Valdmanis, Paul N. and Marschall, Tobias and Bloom, Jesse D. and Eichler, Evan E.}
}
