Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B.
Am J Hum Genet
; 111(8): 1700-1716, 2024 Aug 08.
Article
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| MEDLINE
| ID: mdl-38991590
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%, â¼5,654 aa), H2 (33%, â¼5,742 aa), and H3 (7%, â¼6,325 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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Banco de datos:
MEDLINE
Asunto principal:
Filogenia
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Variación Genética
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Haplotipos
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Repeticiones de Minisatélite
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Alelos
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Mucina 5B
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Mucina 5AC
Límite:
Animals
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article