An ~140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival
John C. Fyfe,Marilyn Menotti-Raymond,Victor A. David,Lars Brichta,Alejandro A. Schäffer,Richa Agarwala,William J. Murphy,William J. Wedemeyer,Brittany L. Gregory,Bethany G. Buzzell,Meghan C. Drummond,Brunhilde Wirth,Stephen J. O'Brien +12 more
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TLDR
A novel SMA gene candidate, LIX1, is identified in an approximately140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15, where the predicted secondary structure is compatible with a role in RNA metabolism.Abstract:
The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an approximately140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found.read more
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The evolution of gene expression levels in mammalian organs
David Brawand,Magali Soumillon,Magali Soumillon,Anamaria Necsulea,Anamaria Necsulea,Philippe Julien,Philippe Julien,Gábor Csárdi,Gábor Csárdi,Patrick Harrigan,Manuela Weier,Angélica Liechti,Ayinuer Aximu-Petri,Martin Kircher,Frank W. Albert,Ulrich Zeller,Philipp Khaitovich,Frank Grützner,Sven Bergmann,Sven Bergmann,Rasmus Nielsen,Rasmus Nielsen,Svante Pääbo,Henrik Kaessmann +23 more
TL;DR: It is shown that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation.
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Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons
S. Duque,Béatrice Joussemet,Christel Rivière,Thibaut Marais,Thibaut Marais,Laurence Dubreil,Anne Douar,John C. Fyfe,Philippe Moullier,Philippe Moullier,Marie Anne Colle,Martine Barkats,Martine Barkats +12 more
TL;DR: This is the first successful study of MN transduction in adult animals following intravenous (i.v.) delivery of self-complementary (sc) AAV9 vectors and this finding was successfully translated to large animals, with the demonstration of an efficient systemic scAAV9 gene delivery to the neonate and adult cat spinal cord.
Journal ArticleDOI
Initial sequence and comparative analysis of the cat genome
Joan Pontius,James C. Mullikin,Douglas Smith,Agencourt Sequencing Team,Kerstin Lindblad-Toh,Sante Gnerre,Michele Clamp,Jean Chang,Robert M. Stephens,Beena Neelam,Natalia Volfovsky,Alejandro A. Schäffer,Richa Agarwala,Kristina Narfström,William J. Murphy,Urs Giger,Alfred L. Roca,Agostinho Antunes,Agostinho Antunes,Marilyn Menotti-Raymond,Naoya Yuhki,Jill Pecon-Slattery,Warren E. Johnson,Guillaume Bourque,Glenn Tesler,Nisc Comparative Sequencing Program,Stephen J. O'Brien +26 more
TL;DR: The genome sequence of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals, shedding new light on the tempo and mode of gene/genome evolution in mammals and promising several research applications for the cat.
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Every genome sequence needs a good map
TL;DR: This work has shown that high-resolution physical maps of vertebrate species’ chromosomes empower comparative genomics discovery and are indispensable for sequence assembly precision.
Journal ArticleDOI
A homozygous single-base deletion in MLPH causes the dilute coat color phenotype in the domestic cat.
Yasuko Ishida,Victor A. David,Eduardo Eizirik,Alejandro A. Schäffer,Beena Neelam,Melody E. Roelke,Steven S. Hannah,Stephen J. O'Brien,Marilyn Menotti-Raymond +8 more
TL;DR: In this article, the authors performed linkage mapping with microsatellites in a large multigeneration pedigree of domestic cats and detected tight linkage for dilute on cat chromosome C1 (θ=0.08, LOD=10.81).
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