Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(8), P. 1700 - 1716

Published: July 10, 2024

The secreted mucins MUC5AC and MUC5B are large glycoproteins that play critical defensive roles in pathogen entrapment mucociliary clearance. Their respective genes contain polymorphic degenerate protein-coding variable number tandem repeats (VNTRs) make the loci difficult to investigate with short reads. We characterize structural diversity of by long-read sequencing assembly 206 human 20 nonhuman primate (NHP) haplotypes. find 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 encode 16 distinct proteins (5,249–6,325 aa) cysteine-rich domain VNTR copy-number variation. group alleles into three phylogenetic clades: H1 (46%, ∼5,654 aa), H2 (33%, ∼5,742 H3 (7%, ∼6,325 two most common smaller than NHP gene models, suggesting a reduction protein length during recent evolution. Linkage disequilibrium Tajima's D analyses reveal East Asians carry exceptionally blocks an excess rare variation (p < 0.05) at MUC5AC. To validate this result, we use Locityper for genotyping haplogroups 2,600 unrelated samples from 1000 Genomes Project. observe signature positive selection among depletion likely ancestral haplogroup (H3). Europeans, show deviate Hardy-Weinberg equilibrium 0.05), consistent heterozygote advantage balancing selection. This study provides generalizable strategy complex improved disease associations.

Language: Английский

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Small polymorphisms are a source of ancestral bias in structural variant breakpoint placement

Genome Research, Journal Year: 2024, Volume and Issue: 34(1), P. 7 - 19

Published: Jan. 1, 2024

High-quality genome assemblies and sophisticated algorithms have increased sensitivity for a wide range of variant types, breakpoint accuracy structural variants (SVs, ≥50 bp) has improved to near base pair precision. Despite these advances, many SV locations are subject systematic bias affecting representation. To understand why breakpoints inconsistent across samples, we reanalyzed 64 phased haplotypes constructed from long-read released by the Human Genome Structural Variation Consortium (HGSVC). We identify 882 insertions 180 deletions with variable not anchored in tandem repeats (TRs) or segmental duplications (SDs). SVs called aligned sequencing reads increase disagreements 2×–16×. Sequence had minimal impact on breakpoints, but observe strong effect ancestry. confirm that SNP indel polymorphisms enriched at shifted also absent callsets. Breakpoint homology increases likelihood imprecise calls distance they shifted, most heavily affected SVs. Because graph methods normalize investigated graphs generated two different find resulting other technical biases accuracy. The inconsistencies characterize affect ∼5% human can interpretation annotation. These limitations underscore need algorithm development improve databases, mitigate ancestry value callsets investigating features.

Language: Английский

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Comparative genomics of macaques and integrated insights into genetic variation and population history

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 8, 2024

ABSTRACT The crab-eating macaques ( Macaca fascicularis ) and rhesus M. mulatta are widely studied nonhuman primates in biomedical evolutionary research. Despite their significance, the current understanding of complex genomic structure differences between species requires substantial improvement. Here, we present a complete genome assembly macaque 20 haplotype-resolved assemblies to investigate regions major species. Segmental duplication is ∼42% lower, while centromeres ∼3.7 times longer than those humans. characterization ∼2 Mbp fixed genetic variants ∼240 loci highlights potential associations with metabolic two (e.g., CYP2C76 EHBP1L1 ). Additionally, hundreds alternative splicing show post-transcriptional regulation divergence these PNPO We also characterize 91 large-scale humans at single-base-pair resolution highlight impact on gene primate evolution FOLH1 PIEZO2 Finally, population genetics recapitulates speciation selective sweeps, highlighting basis reproduction tail phenotype STAB1 , SEMA3F HOXD13 In summary, integrated analysis variation greatly enhances our comprehension lineage-specific phenotypes, adaptation, evolution, thereby improving applications human diseases.

Language: Английский

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Structural polymorphism and diversity of human segmental duplications

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 genome assemblies where majority are fully resolved using long-read assembly. Excluding acrocentric short arms, we identify 173.2 Mbp duplicated (47.4 not in telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. find that intrachromosomal among most variable with rare events mapping near their progenitor sequences. African genomes harbor more likely recently gene families higher copy number when compared non-African samples. A comparison resource 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding these SDs.

Language: Английский

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Structural variation in humans and our primate kin in the era of telomere-to-telomere genomes and pangenomics

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 87, P. 102233 - 102233

Published: July 23, 2024

Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding inter- intra-species SV has been historically hampered by quality draft genomes absence genome resources key taxa. Recently, advances in long-read sequencing assembly have begun to radically reshape SVs. Two landmark achievements include publication a human telomere-to-telomere (T2T) as well development first pangenome reference. In this review, we look back major works laying foundation these projects. We then examine ways which T2T assemblies pangenomes are transforming approach SV. Finally, discuss what future research may like era pangenomics.

Language: Английский

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Cryptic variation fuels plant phenotypic change through hierarchical epistasis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Cryptic genetic variants exert minimal or no phenotypic effects alone but have long been hypothesized to form a vast, hidden reservoir of diversity that drives trait evolvability through epistatic interactions. This classical theory has reinvigorated by pan-genome sequencing, which revealed pervasive variation within gene families and regulatory networks, including extensive cis-regulatory changes, duplication, divergence between paralogs. Nevertheless, empirical testing cryptic variation's capacity fuel diversification hindered intractable genetics, limited allelic diversity, inadequate resolution. Here, guided natural engineered in recently evolved paralogous pair, we identified an additional pair redundant trans regulators, establishing network controls tomato inflorescence architecture. By combining coding mutations with series populations segregating for all four genes, systematically constructed collection 216 genotypes spanning the full spectrum complexity quantified branching over 27,000 inflorescences. Analysis resulting high-resolution genotype-phenotype map layer dose-dependent interactions paralog pairs enhances branching, culminating strong, synergistic effects. However, also uncovered unexpected antagonism pairs, where accumulating one progressively diminished other. Our results demonstrate how architecture complex dosage from converge shape space under hierarchical model Given prevalence evolution genomes, propose networks elicits hierarchies interactions, catalyzing bursts change. Keyword: mutations, paralogs, redundancy, cis-regulatory, tomato, inflorescence, network, modeling, epistasis.

Language: Английский

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The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution

Published: Jan. 13, 2025

Gene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution is the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across ∼60 million year history primates, some MHC genes have turned over completely, changed function, converged others remained essentially unchanged. Past work typically focused on identifying alleles within particular species or comparing content, but more needed to understand overall across species. Thus, despite immunologic importance its peculiar evolutionary history, we lack a complete picture primates. We readdress this question using sequences from dozens pseudogenes spanning entire primate order, building comprehensive set allele trees with modern methods. Overall, find Class I subfamily evolving much quickly than II subfamily, exception MHC-DRB also pay special attention often-ignored pseudogenes, which use reconstruct different events region. shared function species, employ genes, haplotypes, patterns variation achieve successful immune response. Our extensive literature review represent most look into date.

Language: Английский

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The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution

Published: Jan. 13, 2025

Gene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution is the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across ∼60 million year history primates, some MHC genes have turned over completely, changed function, converged others remained essentially unchanged. Past work typically focused on identifying alleles within particular species or comparing content, but more needed to understand overall across species. Thus, despite immunologic importance its peculiar evolutionary history, we lack a complete picture primates. We readdress this question using sequences from dozens pseudogenes spanning entire primate order, building comprehensive set allele trees with modern methods. Overall, find Class I subfamily evolving much quickly than II subfamily, exception MHC-DRB also pay special attention often-ignored pseudogenes, which use reconstruct different events region. shared function species, employ genes, haplotypes, patterns variation achieve successful immune response. Our extensive literature review represent most look into date.

Language: Английский

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Genomic basis of non-human-primate diversity and adaptation

Published: March 31, 2025

Language: Английский

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Decoding human brain evolution: Insights from genomics

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 103033 - 103033

Published: May 6, 2025

The human brain has undergone remarkable structural and functional specializations compared to that of nonhuman primates (NHPs), underlying the advanced cognitive abilities unique humans. However, cellular genetic basis driving these remains largely unknown. Comparing humans our closest living relatives, chimpanzee other great apes, is essential for identifying truly human-specific features. Recent comparative studies with closely related NHPs at single-cell resolution using multimodal genomic profiling, assisted high-throughput screening have provided unprecedented insights into features their underpinnings. In this review, we synthesize current knowledge evolution molecular levels, emphasizing how changes shaped adaptations. We also discuss emerging opportunities presented by new technologies comprehensive atlases advancing understanding evolution.

Language: Английский

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