Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis


Autoři: Lucilla Pizzo aff001;  Micaela Lasser aff002;  Tanzeen Yusuff aff001;  Matthew Jensen aff001;  Phoebe Ingraham aff001;  Emily Huber aff001;  Mayanglambam Dhruba Singh aff001;  Connor Monahan aff002;  Janani Iyer aff001;  Inshya Desai aff001;  Siddharth Karthikeyan aff001;  Dagny J. Gould aff001;  Sneha Yennawar aff001;  Alexis T. Weiner aff001;  Vijay Kumar Pounraja aff001;  Arjun Krishnan aff003;  Melissa M. Rolls aff001;  Laura Anne Lowery aff005;  Santhosh Girirajan aff001
Působiště autorů: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States of America aff001;  Department of Biology, Boston College, Chestnut Hill, MA, United States of America aff002;  Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, United States of America aff003;  Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States of America aff004;  Department of Medicine, Boston University Medical Center, Boston, MA, United States of America aff005;  Department of Anthropology, The Pennsylvania State University, University Park, PA, United States of America aff006
Vyšlo v časopise: Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis. PLoS Genet 17(4): e1009112. doi:10.1371/journal.pgen.1009112
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009112

Souhrn

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second-hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second-hit” genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with “second-hit” genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific “second-hits” enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation.

Klíčová slova:

Drosophila melanogaster – Eyes – Genetic interactions – Larvae – Phenotypes – RNA interference – Xenopus – Morpholino


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