Biology subjects

Hoeps, W.

Publications and source records attributed to Hoeps, W..

4 recordsLinked to original sources

bioRxiv2023

Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures

BackgroundThe duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions in cis. Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes. ResultsHere we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the genomic DNA of 24 patients with neurodevelopmental disorders identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted SV haplotypes. Using a combination of short-read genome sequencing (GS), long- read GS, optical genome mapping and StrandSeq the haplotype structure was resolved in 18 samples. This approach refined the point of template switching between inverted LCRs in 4 samples revealing a DNA segment of [~]2.2-5.5 kb of 100% nucleotide similarity. A prediction model was developed to infer the LCR used to mediate the non-allelic homology repair. ConclusionsThese data provide experimental evidence supporting the hypothesis that inverted LCRs act as a recombinant substrate in replication-based repair mechanisms. Such inverted repeats are particularly relevant for formation of copy-number associated inversions, including the DUP-TRP/INV-DUP structures. Moreover, this type of CGR can result in multiple conformers which contributes to generate diverse SV haplotypes in susceptible loci.

genetics↗

bioRxiv2022

Assembly of 43 diverse human Y chromosomes reveals extensive complexity and variation

The prevalence of highly repetitive sequences within the human Y chromosome has led to its incomplete assembly and systematic omission from genomic analyses. Here, we present long-read de novo assemblies of 43 diverse Y chromosomes spanning 180,000 years of human evolution, including two from deep-rooted African Y lineages, and report remarkable complexity and diversity in chromosome size and structure, in contrast with its low level of base substitution variation. The size of the Y chromosome assemblies varies extensively from 45.2 to 84.9 Mbp and include, on average, 81 kbp of novel sequence per Y chromosome. Half of the male-specific euchromatic region is subject to large inversions with a >2-fold higher recurrence rate compared to inversions in the rest of the human genome. Ampliconic sequences associated with these inversions further show differing mutation rates that are sequence context-dependent and some ampliconic genes show evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, the Yq12, is composed of alternating arrays of DYZ1 and DYZ2 repeat units that show extensive variation in the number, size and distribution of these arrays, but retain a 1:1 copy number ratio of the monomer repeats, consistent with the notion that functional or evolutionary forces are acting on this chromosomal region. Finally, our data suggests that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kbp distal to the currently established boundary. The availability of sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of specific traits with Y-chromosomal variants and garnering novel insights into the evolution and function of complex regions of the human genome.

genomics↗

bioRxiv2022

Inversion polymorphism in a complete human genome assembly

The completion of the human genome significantly improved our ability to discover and interpret genome copy number variation. In order to understand its impact on the characterization of inversion polymorphisms, we remapped data from 41 human genomes and 10 new samples against the telomere-to-telomere (T2T) reference genome as compared to the standard GRCh38 reference. Our analysis shows a ~21% increase in sensitivity identifying and improving mapping of 63 inversions. We further identify 26 misorientations within GRCh38, and show that the T2T reference is three times more likely to represent the correct orientation of the major human allele. As a result, we report a significant bias for inversions accumulating within the pericentromeric regions of specific chromosomes and show that functional annotations around inverted regions, such as topological-associated domains, can be better interpreted.

genomics↗

bioRxiv2020

De novo assembly of 64 haplotype-resolved human genomes of diverse ancestry and integrated analysis of structural variation

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation across even complex loci such as the major histocompatibility complex. We focus on 107,590 structural variants (SVs), of which 68% are inaccessible by short-read sequencing. We identify new SV hotspots (spanning megabases of gene-rich sequence), characterize 130 of the most active mobile element source elements, and find that 63% of all SVs arise by homology-mediated mechanisms--a twofold increase from previous studies. Our resource now enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,525 expression quantitative trait loci (SV-eQTLs) as well as SV candidates for adaptive selection within the human population.

genetics↗