Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature
HGV database
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3412.
Related Articles
Enhanced osteogenic potential of iPSC-derived mesenchymal progenitor cells following genome editing of GWAS variants in the RUNX1 gene
Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD), including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1 expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiated into osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lacking these loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containing these loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes and Alizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMD-associated loci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple gene promoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence. Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on the shorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removal removed a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model in mice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMD-associated variants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuable insights into genetic regulation of bone density and potential therapeutic targets.
The Marchantia polymorpha pangenome reveals ancient mechanisms of plant adaptation to the environment
Plant adaptation to terrestrial life started 450 million years ago and has played a major role in the evolution of life on Earth. The genetic mechanisms allowing this adaptation to a diversity of terrestrial constraints have been mostly studied by focusing on flowering plants. Here, we gathered a collection of 133 accessions of the model bryophyte Marchantia polymorpha and studied its intraspecific diversity using selection signature analyses, a genome–environment association study and a pangenome. We identified adaptive features, such as peroxidases or nucleotide-binding and leucine-rich repeats (NLRs), also observed in flowering plants, likely inherited from the first land plants. The M. polymorpha pangenome also harbors lineage-specific accessory genes absent from seed plants. We conclude that different land plant lineages still share many elements from the genetic toolkit evolved by their most recent common ancestor to adapt to the terrestrial habitat, refined by lineage-specific polymorphisms and gene family evolution.
SVLearn: a dual-reference machine learning approach enables accurate cross-species genotyping of structural variants
Structural variations (SVs) are diverse forms of genetic alterations and drive a wide range of human diseases. Accurately genotyping SVs, particularly occurring at repetitive genomic regions, from short-read sequencing data remains challenging. Here, we introduce SVLearn, a machine-learning approach for genotyping bi-allelic SVs. It exploits a dual-reference strategy to engineer a curated set of genomic, alignment, and genotyping features based on a reference genome in concert with an allele-based alternative genome. Using 38,613 human-derived SVs, we show that SVLearn significantly outperforms four state-of-the-art tools, with precision improvements of up to 15.61% for insertions and 13.75% for deletions in repetitive regions. On two additional sets of 121,435 cattle SVs and 113,042 sheep SVs, SVLearn demonstrates a strong generalizability to cross-species genotype SVs with a weighted genotype concordance score of up to 90%. Notably, SVLearn enables accurate genotyping of SVs at low sequencing coverage, which is comparable to the accuracy at 30× coverage. Our studies suggest that SVLearn can accelerate the understanding of associations between the genome-scale, high-quality genotyped SVs and diseases across multiple species.
LolA and LolB are conserved in Bacteroidota and are crucial for gliding motility and Type IX secretion
Lipoproteins are key outer membrane (OM) components in Gram-negative bacteria, essential for functions like membrane biogenesis and virulence. Bacteroidota, a diverse and widespread phylum, produce numerous OM lipoproteins that play vital roles in nutrient acquisition, Type IX secretion system (T9SS), and gliding motility. In Escherichia coli, lipoprotein transport to the OM is mediated by the Lol system, where LolA shuttles lipoproteins to LolB, which anchors them in the OM. However, LolB homologs were previously thought to be limited to γ- and β-proteobacteria. This study uncovers the presence of LolB in Bacteroidota and demonstrates that multiple LolA and LolB proteins co-exist in various species. Specifically, in Flavobacterium johnsoniae, LolA1 and LolB1 transport gliding motility and T9SS lipoproteins to the OM. Notably, these proteins are not interchangeable with their E. coli counterparts, indicating functional specialization. Some lipoproteins still localize to the OM in the absence of LolA and LolB, suggesting the existence of alternative transport pathways in Bacteroidota. This points to a more complex lipoprotein transport system in Bacteroidota compared to other Gram-negative bacteria. These findings reveal previously unrecognized lipoprotein transport mechanisms in Bacteroidota and suggest that this phylum has evolved unique strategies to manage the essential task of lipoprotein localization.
Evolution, genetic diversity, and health
Human genetic diversity in today’s world has been shaped by evolutionary history, demographic shifts and environmental exposures, influencing complex traits, disease susceptibility and drug responses. Capturing this diversity is essential for advancing precision medicine and promoting equitable healthcare. Despite the great progress achieved with initiatives such as the human Pangenome and large biobanks that aim for a better representation of human diversity, important challenges remain. In this Perspective, we discuss the importance of diversity in clinical genomics through an evolutionary lens. We highlight progress and challenges and outline key clinical applications of diverse genetic data. We argue that diversifying both datasets and methodologies—integrating ancestral and environmental factors—is crucial for fully understanding the genetic basis of human health and disease.
Responses