Biology subjects

Paylakhi, S.

Publications and source records attributed to Paylakhi, S..

3 recordsLinked to original sources

bioRxiv2026

Cellular morphology emerges from polygenic, distributed transcriptional variation

Height and disease risk are canonical polygenic traits, but whether an analogous architecture governs cellular phenotypes remains unclear. Here, we show that cellular morphology behaves as a polygenic systems phenotype by integrating cross-modal modeling, perturbation profiling, and human genetic variation. An adversarially aligned autoencoder trained on four perturbation datasets predicted morphology from gene expression and generalized without retraining to matched RNA-seq and Cell Painting profiles from 100 genetically diverse iPSC donors. Seventeen morphological features were strongly predicted, particularly those capturing organelle distribution and cytoskeletal architecture. Predictive signal was broadly distributed across genes, with weak individual gene-morphology correlations. Independent CRISPR perturbations supported model-prioritized genes including TIAM1, RAB31, and ABCC5, while genetic analyses identified variant-gene-morphology associations involving PDHX, SLC11A2, and MAPKAPK5. These findings extend polygenic models of complex traits to cellular architecture and provide a framework for interpreting cross-modal prediction in functional genomics.

genetics↗

bioRxiv2020

Identification of ADAMTS19 as a novel retinal factor involved in ocular growth regulation

Refractive errors are the most common ocular disorders and are a leading cause of visual impairment worldwide. Although ocular axial length is well established to be a major determinant of refractive errors, the molecular and cellular processes regulating ocular axial growth are poorly understood. Mutations in genes encoding the PRSS56 and MFRP are a major cause of nanophthalmos. Accordingly, mouse models with mutations in the genes encoding the retinal factor PRSS56 or MFRP, a gene predominantly localized in the retinal pigment epithelial (RPE) exhibit ocular axial length reduction and extreme hyperopia. However, the precise mechanisms underlying PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in retina of mice lacking either Prss56 or Mfrp. Using a combination of genetic approaches and mouse models, we show that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in both Prss56 or Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 expression is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach. We further demonstrate that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of developmental myopia caused by a null mutation in Irpb, demonstrating that ocular axial elongation in Irbp-/- mice is fully dependent on PRSS56 and MFRP functions. Collectively, our findings provide insight into the molecular network involved in ocular axial growth regulation and refractive development and support the notion that relay of the signal between the retina and RPE could be critical for promoting ocular axial elongation.

genetics↗

bioRxiv2018

PRSS56 is required for the developmental positioning of ocular angle structures

Angle-closure glaucoma (ACG) is a severe form of glaucoma affecting up to 16 million people worldwide. In ACG, physical blockage of the ocular drainage tissue by the peripheral iris impedes the drainage of aqueous humor resulting in elevated intraocular pressure (IOP) and subsequent optic nerve damage. Despite the high prevalence of ACG, the precise mechanism(s) underlying pathogenesis are only partially understood. We have previously demonstrated that a mutation in the gene encoding the serine protease PRSS56 causes an ACG phenotype in mice. Notably, Prss56 mutant mice exhibit a reduced ocular axial length and a lens occupying a larger ocular volume compared to WT mice, recapitulating characteristic features of human AGC. Our findings utilizing mouse genetic models demonstrate that loss of PRSS56 function results in altered configuration of ocular angle structures characterized by a posterior shift in the positioning of the ocular drainage tissue relative to the ciliary body and iris during development, leading to a physical blockage of drainage structure (angle closure) and high IOP. Utilizing a previously employed genetic strategy of rescuing mutant Prss56 mediated reduction in ocular size by inactivation of EGR1 (Egr1;Prss56 double mutants) we determined the influence of ocular size on developmental positioning of the ocular angle tissues. Our findings suggest that abnormal positioning of the drainage structure as a result of loss of PRSS56 function is uncoupled from its effect on ocular axial length reduction. Furthermore, we demonstrate that the IOP elevation observed in Prss56 mutant mice is genetic context-dependent and identify a dominant modifier locus on Chromosome 2 of the C3H/HeJ genome conferring susceptibility to high IOP. Overall, our findings reveal a novel role for PRSS56 in the proper configuration of the iridocorneal angle and provide new insight into the developmental pathways implicated in glaucoma pathogenesis.

genetics↗