Biology subjects

Valdmanis, P. N.

Publications and source records attributed to Valdmanis, P. N..

4 recordsLinked to original sources

bioRxiv2026

A family portrait of the genomic factors shaping tandem repeat mutagenesis

Tandem repeats (TRs) are among the most mutable loci in the human genome, but the genomic determinants of TR mutagenesis remain mysterious. We used PacBio HiFi long-read sequencing to profile nearly eight million TR loci in 28 members of a large, four-generation CEPH/Utah family designated K1463. We identified 1,270 de novo TR expansions and contractions across 20 children in the pedigree. De novo mutations (DNMs) were more likely to occur at loci that were longer, composed of uninterrupted motif sequences, and heterozygous in the parental germline. Children born to older fathers also exhibited more de novo mutations at short tandem repeats (STRs). A total of 43 TR loci were hyper-mutable in K1463, expanding or contracting up to twelve times across the pedigree. Among hyper-mutable loci that comprised multiple motifs (i.e., "complex" loci), specific motifs expanded and contracted more often than others; for example, all ten DNMs at a complex, hyper-mutable locus near the non-coding RNA LINC03021 involved the same 19bp motif. The mutability of particular motifs may be attributable to allele length, as 95% of DNMs at complex loci were expansions and contractions of the most abundant motif on a parental haplotype. However, future work will be required to disentangle the effects of nucleotide content and allele length on motif-specific mutability, especially at hyper-mutable TRs. Overall, this study combines long-read sequencing technologies with new software tools to comprehensively investigate the factors that influence TR mutagenesis.

genomics↗

bioRxiv2024

Structural and genetic diversity in the secreted mucins, MUC5AC and MUC5B

The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs 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 (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5249-6325aa) with cysteine-rich domain and VNTR copy number variation. We grouped MUC5AC alleles into three phylogenetic clades: H1 (46%, [~]5654aa), H2 (33%, [~]5742aa), and H3 (7%, [~]6325aa). 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 (LD) and Tajimas D analyses reveal that East Asians carry exceptionally large MUC5AC LD blocks with an excess of rare variation (p<0.05). To validate this result, we used Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observed signatures of positive selection in H1 and H2 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Africans and Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium, consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein coding VNTRs for improved disease associations.

genomics↗

bioRxiv2023

The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection

We study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions. We find diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that the Denisovan-like MUC19 haplotype is under positive selection and carries a higher copy number of a 30 base-pair variable number tandem repeat, and that copy numbers of this repeat are exceedingly high in American populations. Finally, some Neanderthals carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. One-Sentence SummaryModern humans and Neanderthals carry a Denisovan variant of the MUC19 gene, which is under positive selection in populations of Indigenous American ancestry.

evolutionary biology↗

bioRxiv2021

Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

There are over 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in human evolution and genomic variation, they have yet to be studied collectively and in detail, partially due to their large size, variability, and predominant location in non-coding regions. Here, we examine 467 VNTRs that are human-specific expansions, unique to one location in the genome, and not associated with retrotransposons. We leverage publicly available long-read genomes - including from the Human Genome Structural Variant Consortium - to ascertain the exact nucleotide composition of these VNTRs, and compare their composition of alleles. We then confirm repeat unit composition in over 3000 short-read samples from the 1000 Genomes Project. Our analysis reveals that these VNTRs contain remarkably structured repeat motif organization, modified by frequent deletion and duplication events. While overall VNTR compositions tend to remain similar between 1000 Genomes Project super-populations, we describe a notable exception with substantial differences in repeat composition (in PCBP3), as well as several VNTRs that are significantly different in length between super-populations (in ART1, PROP1, WDR60, and LOC102723906). We also observe that most of these VNTRs are expanded in archaic human genomes, yet remain stable in length between single generations. Collectively, our findings indicate that repeat motif variability, repeat composition, and repeat length are all informative modalities to consider when characterizing VNTRs and their contribution to genomic variation.

genomics↗