Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B
- Am J Hum Genet. 2024 Aug 8;111(8):1700-1716. doi: 10.1016/j.ajhg.2024.06.007.
- 1. Department 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.
- 2. Institute 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.
- 3. Department 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.
- 4. Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
- 5. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
- 6. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Computational Biology, Cajal Neuroscience Inc, Seattle, WA 98102, USA.
- 7. Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
- 8. Department 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.
- 9. Department 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; Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
- 10. Department 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: [email protected].
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.