Publications by authors named "Bradley Killingsworth"

2 Publications

  • Page 1 of 1

Nanolattice-Forming Hybrid Collagens in Protective Shark Egg Cases.

Biomacromolecules 2022 07 24;23(7):2878-2890. Epub 2022 Jun 24.

Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, United States.

Nanoscopic structural control with long-range ordering remains a profound challenge in nanomaterial fabrication. The nanoarchitectured egg cases of elasmobranchs rely on a hierarchically ordered latticework for their protective function─serving as an exemplary system for nanoscale self-assembly. Although the proteinaceous precursors are known to undergo intermediate liquid crystalline phase transitions before being structurally arrested in the final nanolattice architecture, their sequences have so far remained unknown. By leveraging RNA-seq and proteomic techniques, we identified a cohort of nanolattice-forming proteins comprising a collagenous midblock flanked by domains typically associated with innate immunity and network-forming collagens. Structurally homologous proteins were found in the genomes of other egg-case-producing cartilaginous fishes, suggesting a conserved molecular self-assembly strategy. The identity and stabilizing role of cross-links were subsequently elucidated using mass spectrometry and small-angle X-ray scattering. Our findings provide a new design approach for protein-based liquid crystalline elastomers and the self-assembly of nanolattices.
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http://dx.doi.org/10.1021/acs.biomac.2c00341DOI Listing
July 2022

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

Genome Med 2022 03 8;14(1):27. Epub 2022 Mar 8.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries.

Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes.

Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent.

Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.
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http://dx.doi.org/10.1186/s13073-022-01035-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902761PMC
March 2022
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