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Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B

Affiliations
  • 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 2Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany; Center for Digital Medicine, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany.
  • 3Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  • 4Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 5Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 6Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Computational Biology, Cajal Neuroscience Inc, Seattle, WA 98102, USA.
  • 7Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
  • 8Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 9Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: ee3@uw.edu.

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July 11, 2024

Abstract

The 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 (5,761-5,762 amino acids [aa]); however, seven haplotypes have expanded VNTRs (6,291-7,019 aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5,249-6,325 aa) with cysteine-rich domain and VNTR copy-number variation. We group MUC5AC alleles into three phylogenetic clades: H1 (46%, ∼5,654 aa), H2 (33%, ∼5,742 aa), and H3 (7%, ∼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’s D analyses reveal that East Asians carry exceptionally large blocks with an excess of rare variation (p < 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 < 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.

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