Biology subjects

Höps, W.

Publications and source records attributed to Höps, W..

3 recordsLinked to original sources

bioRxiv2026

Distinct mechanisms of CNV formation at the human 15q13.3 locus

Human chromosome 15q13.3 is a hotspot for recurrent pathogenic copy number variants (CNVs), which remain unresolved at the sequence level. We generated haplotype-resolved assemblies for 10 patient-parent trios and found that both the long ("BP4-BP5") and short ("CHRNA7") forms of 15q13.3 CNVs arise predominantly by non-allelic homologous recombination (NAHR) enabled by inversion polymorphisms. While most BP4-BP5 CNVs are structurally distinct, three breakpoints cluster in a 2 kbp PRDM9-enriched recombination hotspot. CHRNA7 CNVs originate from NAHR between CHRNA7-LCR repeats embedded within locus-spanning inversions and give rise to paired deletion/duplication events. Population analyses of 581 population haplotypes reveal at least 18 distinct structural haplotypes in 15q13.3 and more than 10-fold ancestry-stratification of BP4-BP5 CNV risk, where 68.4% of Europeans but only 5.1% of East Asians are predisposed. Comparison to six ape species indicates that the duplication architecture promoting instability expanded recently and is largely human-specific.

genetics↗

bioRxiv2023

Impact and characterization of serial structural variations across humans and great apes

Modern sequencing technology enables the detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements arising through series of mutations, a phenomenon we term serial SV (sSV), remain understudied since their complexity poses a challenge for SV discovery. Here, we present NAHRwhals (https://github.com/WHops/NAHRwhals), a method to infer repeat-mediated series of SVs in long-read genomic assemblies. Applying NAHRwhals to 58 haplotype-resolved human genomes reveals 37 sSV loci of various length and complexity. These sSVs explain otherwise cryptic variation in medically relevant regions such as the TPSAB1 gene, 8p23.1 and the DiGeorge and Sotos syndrome regions. Comparisons with great ape assemblies indicate that most human sSVs formed recently and involved non-repeat-mediated processes. NAHRwhals reliably discovers and characterizes sSVs at scale and independent of species, uncovering their genomic abundance and revealing broader implications for disease than prior studies suggested.

bioinformatics↗

bioRxiv2021

Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1-retrotransposition; 80% of the larger inversions are balanced and affect twice as many base pairs as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or mobile elements. Since this suggests recurrence due to non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7x10-4 per locus and generation. Recurrent inversions exhibit a sex- chromosomal bias, and significantly co-localize to the critical regions of genomic disorders. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes to disease- causing CNVs.

genomics↗