The haplolethality paradox of the wupA gene in Drosophila
Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth stud...
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| Published in | PLoS genetics Vol. 17; no. 3; p. e1009108 |
|---|---|
| Main Authors | , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
19.03.2021
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1553-7404 1553-7390 1553-7404 |
| DOI | 10.1371/journal.pgen.1009108 |
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| Abstract | Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene
wings up A
(
wupA
). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes
CDK2
,
CDK4
,
Rap
and
Rab5
. The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3’ end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of
wupA
products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the
wupA
associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the
wupA
genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These
wupA
features are comparable to those of
dpp
, the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting. |
|---|---|
| AbstractList | Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene wings up A (wupA). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes CDK2, CDK4, Rap and Rab5. The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3' end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of wupA products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the wupA associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the wupA genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These wupA features are comparable to those of dpp, the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting. Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene wings up A (wupA). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes CDK2, CDK4, Rap and Rab5. The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3' end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of wupA products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the wupA associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the wupA genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These wupA features are comparable to those of dpp, the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting.Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene wings up A (wupA). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes CDK2, CDK4, Rap and Rab5. The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3' end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of wupA products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the wupA associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the wupA genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These wupA features are comparable to those of dpp, the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting. In Drosophila, the seminal work by the groups of Lindsley and Sandler in 1972 [20], based on segmental aneuploidies covering 85% of its genome, provided the first estimation of HL regions, up to 20, one of them being haplo-, as well as, triplo-lethal (Tpl). Since organism survival is inversely proportional to the extent of the genetic material deleted, the HL condition could result from the additive insufficiency of several adjacent genes. [...]the estimated number of HL regions in flies has been reduced when smaller deletions have become available. Interestingly, the two 13 kb hobo inserts in the Hin region of dpp that had been reported, one of them landed in an intron, and the other did it in the 3’ untranslated region of exon 3 [23]. [...]the dpp associated haplolethality is currently understood as a dosage insufficiency of the single encoded protein, the morphogen DPP a.k.a. BMP in vertebrates. Remarkably, the Tpl region has proven also refractory to point mutations and only rearrangements were obtained [28]. Since the duplication required to isolate DL mutants in the 16F7 region, Dp(1;3R)JC153, also contains genes adjacent to wupA, the HL function could result from the combined insufficiency of several genes under the control of regulatory sequences located inside the wupA gene or, alternatively, from the haploinsufficiency of the wupA encoded protein, Troponin I (TnI). Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene wings up A ( wupA ). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes CDK2 , CDK4 , Rap and Rab5 . The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3’ end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of wupA products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the wupA associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the wupA genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These wupA features are comparable to those of dpp , the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting. Most species contain two copies of their genetic endowment, each received from each progenitor. If one of the duplicated genes is non-functional, the remaining copy may supply enough product as to cover the requirements for normal function or, alternatively, may reflect the insufficiency through a visible phenotype. In rare occasions, however, having one copy is so deleterious that causes lethality. These so called “haplolethal regions”, exist across species and represent an evolutionary paradox since they should have been subject to intense negative selection. The inherent difficulties to study haplolethals have precluded their study so far. Here, we analyzed the case of one of the five haplolethal regions of Drosophila , the one associated to the Troponin I encoding gene wupA , by measuring the transcriptional effects of mutations and chromosomal rearrangements affecting this gene. The data show that this haplolethality results from the combined insufficiency of a large number of Troponin I isoforms, which are functionally specialized, show interference and require the integrity of the native chromatin structure for their quantitatively regulated expression. These features unveil novel aspects of gene expression and, possibly, on evolutionary gene splitting. Also, haplolethals underscore the biological significance of protein dosage, in particular for functionally related products. Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous loss-of-function mutations result in dominant lethality (DL) and, consequently, should be under strong negative selection. We report an in depth study of the HL associated to the gene wings up A ( wupA ). It encodes 13 transcripts (A-M) that yield 11 protein isoforms (A-K) of Troponin I (TnI). They are functionally diverse in their control of muscle contraction, cell polarity and cell proliferation. Isoform K transfers to the nucleus where it increases transcription of the cell proliferation related genes CDK2 , CDK4 , Rap and Rab5 . The nuclear translocation of isoform K is prevented by the co-expression of A or B isoforms, which illustrates isoform interactions. The corresponding DL mutations are, either DNA rearrangements clustered towards the gene 3’ end, thus affecting the genomic organization of all transcripts, or CRISPR-induced mutations in one of the two ATG sites which eliminate a subset of wupA products. The joint elimination of isoforms C, F, G and H, however, do not cause DL phenotypes. Genetically driven expression of single isoforms rescue neither DL nor any of the mutants known in the gene, suggesting that normal function requires properly regulated expression of specific combinations, rather than single, TnI isoforms. We conclude that the wupA associated HL results from the combined haploinsufficiency of a large set of TnI isoforms. The qualitative and quantitative normal expression of which, requires the chromosomal integrity of the wupA genomic region. Since all fly TnI isoforms are encoded in the same gene, its HL condition becomes unavoidable. These wupA features are comparable to those of dpp , the only other HL studied to some extent, and reveal a scenario of strict dosage dependence with implications for gene expression regulation and splitting. In Drosophila, the seminal work by the groups of Lindsley and Sandler in 1972 [20], based on segmental aneuploidies covering 85% of its genome, provided the first estimation of HL regions, up to 20, one of them being haplo-, as well as, triplo-lethal (Tpl). Since organism survival is inversely proportional to the extent of the genetic material deleted, the HL condition could result from the additive insufficiency of several adjacent genes. [...]the estimated number of HL regions in flies has been reduced when smaller deletions have become available. Interestingly, the two 13 kb hobo inserts in the Hin region of dpp that had been reported, one of them landed in an intron, and the other did it in the 3’ untranslated region of exon 3 [23]. [...]the dpp associated haplolethality is currently understood as a dosage insufficiency of the single encoded protein, the morphogen DPP a.k.a. BMP in vertebrates. Remarkably, the Tpl region has proven also refractory to point mutations and only rearrangements were obtained [28]. Since the duplication required to isolate DL mutants in the 16F7 region, Dp(1;3R)JC153, also contains genes adjacent to wupA, the HL function could result from the combined insufficiency of several genes under the control of regulatory sequences located inside the wupA gene or, alternatively, from the haploinsufficiency of the wupA encoded protein, Troponin I (TnI). |
| Audience | Academic |
| Author | Ferrús, Alberto Casas-Tintó, Sergio |
| AuthorAffiliation | Stowers Institute for Medical Research, UNITED STATES Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33739971$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1111_1744_7917_13403 crossref_primary_10_1038_s41467_024_55391_8 crossref_primary_10_1016_j_tplants_2023_07_009 crossref_primary_10_1186_s12864_024_10934_7 crossref_primary_10_1093_g3journal_jkae025 |
| Cites_doi | 10.1091/mbc.e03-09-0663 10.1016/j.devcel.2019.12.007 10.1093/genetics/79.4.589 10.1242/jcs.050880 10.1007/s00335-005-0045-8 |
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| Copyright | COPYRIGHT 2021 Public Library of Science 2021 Casas-Tintó, Ferrús. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2021 Casas-Tintó, Ferrús 2021 Casas-Tintó, Ferrús |
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| Snippet | Haplolethals (HL) are regions of diploid genomes that in one dose are fatal for the organism. Their biological meaning is obscure because heterozygous... In Drosophila, the seminal work by the groups of Lindsley and Sandler in 1972 [20], based on segmental aneuploidies covering 85% of its genome, provided the... |
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| SubjectTerms | 3' Untranslated regions Analysis Biology and Life Sciences Bone morphogenetic proteins Calcium-binding protein Dosage Drosophila Ethanol Genes Genetic aspects Genetic engineering Genomes Genotype & phenotype Haploidy Haploinsufficiency Insects Lethal mutation Mutation Proteins Regulatory sequences Research and Analysis Methods Troponin Troponin I Wings (Animal) |
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| Title | The haplolethality paradox of the wupA gene in Drosophila |
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