Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.
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 de...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-04-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1009112 |
| _version_ | 1811292756531740672 |
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| author | Lucilla Pizzo Micaela Lasser Tanzeen Yusuff Matthew Jensen Phoebe Ingraham Emily Huber Mayanglambam Dhruba Singh Connor Monahan Janani Iyer Inshya Desai Siddharth Karthikeyan Dagny J Gould Sneha Yennawar Alexis T Weiner Vijay Kumar Pounraja Arjun Krishnan Melissa M Rolls Laura Anne Lowery Santhosh Girirajan |
| author_facet | Lucilla Pizzo Micaela Lasser Tanzeen Yusuff Matthew Jensen Phoebe Ingraham Emily Huber Mayanglambam Dhruba Singh Connor Monahan Janani Iyer Inshya Desai Siddharth Karthikeyan Dagny J Gould Sneha Yennawar Alexis T Weiner Vijay Kumar Pounraja Arjun Krishnan Melissa M Rolls Laura Anne Lowery Santhosh Girirajan |
| author_sort | Lucilla Pizzo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T04:51:08Z |
| format | Article |
| id | doaj.art-ea88765e5dca40999d37fc1d27f96ec3 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T04:51:08Z |
| publishDate | 2021-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-ea88765e5dca40999d37fc1d27f96ec32022-12-22T03:01:41ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-04-01174e100911210.1371/journal.pgen.1009112Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.Lucilla PizzoMicaela LasserTanzeen YusuffMatthew JensenPhoebe IngrahamEmily HuberMayanglambam Dhruba SinghConnor MonahanJanani IyerInshya DesaiSiddharth KarthikeyanDagny J GouldSneha YennawarAlexis T WeinerVijay Kumar PounrajaArjun KrishnanMelissa M RollsLaura Anne LowerySanthosh GirirajanWe 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.https://doi.org/10.1371/journal.pgen.1009112 |
| spellingShingle | Lucilla Pizzo Micaela Lasser Tanzeen Yusuff Matthew Jensen Phoebe Ingraham Emily Huber Mayanglambam Dhruba Singh Connor Monahan Janani Iyer Inshya Desai Siddharth Karthikeyan Dagny J Gould Sneha Yennawar Alexis T Weiner Vijay Kumar Pounraja Arjun Krishnan Melissa M Rolls Laura Anne Lowery Santhosh Girirajan Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. PLoS Genetics |
| title | Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. |
| title_full | Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. |
| title_fullStr | Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. |
| title_full_unstemmed | Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. |
| title_short | Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. |
| title_sort | functional assessment of the two hit model for neurodevelopmental defects in drosophila and x laevis |
| url | https://doi.org/10.1371/journal.pgen.1009112 |
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