Biology subjects

Human Genome Structural Variation Consortium (HGSVC),

Publications and source records attributed to Human Genome Structural Variation Consortium (HGSVC),.

4 recordsLinked to original sources

bioRxiv2026

Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures

The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.

genomics↗

bioRxiv2024

Structural polymorphism and diversity of human segmental duplications

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

genomics↗

bioRxiv2023

A comprehensive catalog of 3D genome organization in diverse human genomes facilitates understanding of the impact of structural variation on chromatin structure

The human genome is packaged into the three-dimensional (3D) nucleus and organized into functional units known as topologically associating domains (TADs) and chromatin loops. Recent studies show that the 3D genome can be modified by genome structural variants (SVs) through disrupting higher-order chromatin organizations such as TADs, which play an essential role in insulating genes from aberrant regulation by regulatory elements outside TADs. Here, we have developed an integrative Hi-C analysis pipeline to generate a comprehensive catalog of TADs, TAD boundaries, and loops in human genomes to fill the gap of limited resources. We identified 2,293 TADs and 6,810 sub-TADs missing in the previously released TADs of GM12878. We then quantified the impact of SVs overlapping with TAD boundaries and observed that two SVs could significantly alter chromatin architecture leading to abnormal expression and splicing of genes associated with human diseases.

genomics↗

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↗