Limits...
Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Zhang S, Ross KD, Seidner GA, Gorman MR, Poon TH, Wang X, Keithley EM, Lee PN, Martindale MQ, Joiner WJ, Hamilton BA - PLoS Genet. (2015)

Bottom Line: Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9.Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes.These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.

ABSTRACT
Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

No MeSH data available.


Nmf9 protein is highly conserved in Metazoans.(A) Nmf9 homologs exist for all branches of Metazoa (except Urochordates) and several non-animal Holozoa. A single example in fungi (Mortierella verticillata) may represent horizontal gene transfer. (B) Sliding window analysis of 14 approximately full-length metazoan homologs highlights known motifs and predicts three novel domains where the most highly conserved individual residues tend to cluster. Threshold line (red) indicates 25% percentile of values. Aligned schematic shows motif annotations (rectangles) and constrained intervals (ovals) in relation to the sliding window plot. (C) The most highly conserved amino acid sequence (red box) was in domain 2 and encoded by the exon skipped in nmf9 mRNA.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4488434&req=5

pgen.1005344.g006: Nmf9 protein is highly conserved in Metazoans.(A) Nmf9 homologs exist for all branches of Metazoa (except Urochordates) and several non-animal Holozoa. A single example in fungi (Mortierella verticillata) may represent horizontal gene transfer. (B) Sliding window analysis of 14 approximately full-length metazoan homologs highlights known motifs and predicts three novel domains where the most highly conserved individual residues tend to cluster. Threshold line (red) indicates 25% percentile of values. Aligned schematic shows motif annotations (rectangles) and constrained intervals (ovals) in relation to the sliding window plot. (C) The most highly conserved amino acid sequence (red box) was in domain 2 and encoded by the exon skipped in nmf9 mRNA.

Mentions: Homologs of Nmf9 across wide taxonomic boundaries showed strong patterns of conservation that highlight select domains, as well as lineage-restricted modulation of domain architecture (Figs 6A and S4). Homologs were identified by reciprocal BLAST/BLAT searches in sequenced genomes of nearly all metazoan lineages, including placozoa and porifera, and in at least some choanoflagellates and filasterea, sister groups to animals that diverged from the lineage leading to animals after the split between animals and fungi. Choanoflagellate (M. brevicollis, S. rosetta) and filasterea (C. owczarzaki) homologs included an N-terminal CRIB domain (associated with binding to Cdc42/Rac subfamily small GTPases), a C-terminal Ras-association (RA) domain, or neither. A single instance in fungi–comprising only a choanoflagellate-like copy of the conserved, non-motif domains–was found in Mortierella verticillata, but not in basal or sister lineages, and might therefore represent a horizontal gene transfer event rather than an earlier origin of the gene genealogy. Sequenced invertebrate animal genomes had a single Nmf9 homolog, except for an apparent loss in the urochordate lineage (0/4 species). Invertebrate homologs included an RA domain, except for the single placozoa sequence and a few genomes with incomplete assembly, but none included a CRIB domain. Jawed vertebrates basal to mammals contained two homologs: an ancestral copy with the RA domain and a derived copy without it. Mammalian genomes had only the derived copy. Most animal homologs occur in poorly annotated regions of their respective genome assemblies, limiting the number of complete sequences available among homologs we examined.


Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Zhang S, Ross KD, Seidner GA, Gorman MR, Poon TH, Wang X, Keithley EM, Lee PN, Martindale MQ, Joiner WJ, Hamilton BA - PLoS Genet. (2015)

Nmf9 protein is highly conserved in Metazoans.(A) Nmf9 homologs exist for all branches of Metazoa (except Urochordates) and several non-animal Holozoa. A single example in fungi (Mortierella verticillata) may represent horizontal gene transfer. (B) Sliding window analysis of 14 approximately full-length metazoan homologs highlights known motifs and predicts three novel domains where the most highly conserved individual residues tend to cluster. Threshold line (red) indicates 25% percentile of values. Aligned schematic shows motif annotations (rectangles) and constrained intervals (ovals) in relation to the sliding window plot. (C) The most highly conserved amino acid sequence (red box) was in domain 2 and encoded by the exon skipped in nmf9 mRNA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488434&req=5

pgen.1005344.g006: Nmf9 protein is highly conserved in Metazoans.(A) Nmf9 homologs exist for all branches of Metazoa (except Urochordates) and several non-animal Holozoa. A single example in fungi (Mortierella verticillata) may represent horizontal gene transfer. (B) Sliding window analysis of 14 approximately full-length metazoan homologs highlights known motifs and predicts three novel domains where the most highly conserved individual residues tend to cluster. Threshold line (red) indicates 25% percentile of values. Aligned schematic shows motif annotations (rectangles) and constrained intervals (ovals) in relation to the sliding window plot. (C) The most highly conserved amino acid sequence (red box) was in domain 2 and encoded by the exon skipped in nmf9 mRNA.
Mentions: Homologs of Nmf9 across wide taxonomic boundaries showed strong patterns of conservation that highlight select domains, as well as lineage-restricted modulation of domain architecture (Figs 6A and S4). Homologs were identified by reciprocal BLAST/BLAT searches in sequenced genomes of nearly all metazoan lineages, including placozoa and porifera, and in at least some choanoflagellates and filasterea, sister groups to animals that diverged from the lineage leading to animals after the split between animals and fungi. Choanoflagellate (M. brevicollis, S. rosetta) and filasterea (C. owczarzaki) homologs included an N-terminal CRIB domain (associated with binding to Cdc42/Rac subfamily small GTPases), a C-terminal Ras-association (RA) domain, or neither. A single instance in fungi–comprising only a choanoflagellate-like copy of the conserved, non-motif domains–was found in Mortierella verticillata, but not in basal or sister lineages, and might therefore represent a horizontal gene transfer event rather than an earlier origin of the gene genealogy. Sequenced invertebrate animal genomes had a single Nmf9 homolog, except for an apparent loss in the urochordate lineage (0/4 species). Invertebrate homologs included an RA domain, except for the single placozoa sequence and a few genomes with incomplete assembly, but none included a CRIB domain. Jawed vertebrates basal to mammals contained two homologs: an ancestral copy with the RA domain and a derived copy without it. Mammalian genomes had only the derived copy. Most animal homologs occur in poorly annotated regions of their respective genome assemblies, limiting the number of complete sequences available among homologs we examined.

Bottom Line: Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9.Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes.These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, California, United States of America.

ABSTRACT
Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

No MeSH data available.