Biology subjects

Izquierdo, D.

Publications and source records attributed to Izquierdo, D..

3 recordsLinked to original sources

bioRxiv2025

Centriole biogenesis is seeded by CEP152-CEP63-PCNT aggregates propagating outside the centriole through the Alstrom syndrome protein ALMS1

Biogenesis of subcellular structures like centrioles is viewed as a physical transformation wherein elementary constituents form order without preexisting templates. Centrioles grow with precision from a composite scaffold known as the cartwheel, which is thought to self-assemble without templates and disassemble following centriole growth; however, the mechanism governing cartwheel assembly-disassembly dynamics remains obscure. Here, we identify ALMS1, a disease-linked, intrinsically disordered protein (IDP), as an external mediator of cartwheel dynamics that causes a seed for cartwheel--and thus centriole--formation without itself incorporating into the seed structure. The cartwheel seed (CS), characterized as a dense composite of CEP152/CEP63 protein complexes, forms in interphase and adopts a nanoscale, concentric ring from which the cartwheel grows. Upon mitotic entry, CSs recruit ALMS1 while disassembling into constituents associating with ALMS1 in proximity, correlating with cartwheel assembly-disassembly cycles. Hypomorph, disease-linked ALMS1 mutations trigger cartwheel expansion and shedding by its own grown procentriole, in turn forming ectopic centrioles, leading to perpetual reciprocal amplification. Without ALMS1, CS formation fails, negating centriole biogenesis, whereas reintroducing ALMS1 initializes biogenesis anew, creating diverse yet heritable architectures that evolve through selection, instead of generating a single canonical form. These results suggest that centriole biogenesis is grounded on adaptable transformation cues extrinsic to its constituents, propagating via IDP-mediated CS assembly-disassembly cycles, a process we conjecture involves memory.

cell biology↗

bioRxiv2019

Determining the impact of uncharacterized inversions in the human genome by droplet digital PCR

Despite the interest in characterizing all genomic variation, the presence of large repeats at the breakpoints of many structural variants hinders their analysis. This is especially problematic in the case of inversions, since they are balanced changes without gain or loss of DNA. Here we tested novel linkage-based droplet digital PCR (ddPCR) assays on 20 inversions ranging from 3.1 to 742 kb and flanked by long inverted repeats (IRs) of up to 134 kb. Among these, we validated 13 inversions predicted by different genome-wide techniques. In addition, we have generated new experimental human population information across 95 African, European and East-Asian individuals for 16 of them, including four already known inversions for which there were no high-throughput methods to determine directly the orientation, like the well-characterized 17q21 inversion. Through comparison with previous data, independent replicates and both inversion breakpoints, we have demonstrated that the technique is highly accurate and reproducible. Most of the studied inversions are frequent and widespread across continents, showing a negative correlation with genetic length. Moreover, all except two show clear signs of being recurrent, and the new data allowed us to define more clearly the factors affecting recurrence levels and estimate the inversion rate across the genome. Finally, thanks to the generated genotypes, we have been able to check inversion functional effects in multiple tissues, validating gene expression differences reported before for two inversions and finding new candidate associations. Our work therefore provides a tool to screen these and other complex genomic variants quickly in a large number of samples for the first time, highlighting the importance of direct genotyping to assess their potential consequences and clinical implications.

genomics↗

bioRxiv2018

Functional and evolutionary impact of polymorphic inversions in the human genome

Inversions are one type of structural variants linked to phenotypic differences and adaptation in multiple organisms. However, there is still very little information about inversions in the human genome due to the difficulty of their detection. Here, thanks to the development of a new high-throughput genotyping method, we have performed a complete study of a representative set of 45 common human polymorphic inversions. Most inversions promoted by homologous recombination occur recurrently both in humans and great apes and, since they are not tagged by SNPs, they are missed by genome-wide association studies. Furthermore, there is an enrichment of inversions showing signatures of positive or balancing selection, diverse functional effects, such as gene disruption and gene-expression changes, or association with phenotypic traits. Therefore, our results indicate that the genome is more dynamic than previously thought and that human inversions have important functional and evolutionary consequences, making possible to determine for the first time their contribution to complex traits.

genomics↗