Monday, January 25, 2016

Autistic Monkeys via gene editing

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See also De novo mutations and autism and Disruptive mutations and the genetic architecture of autism.
Nature News: The laboratory monkeys run obsessively in circles, largely ignore their peers and grunt anxiously when stared at. Engineered to have a gene that is related to autism spectrum disorder in people, the monkeys are the most realistic animal model of the condition yet, say their creators. Researchers hope that the animals will open up new ways to test treatments and investigate the biology of autism. But the jury is still out on how well the monkeys’ condition matches that of people with autism. 
Autism has a vast array of symptoms and types, but researchers think that at least 100 genes play a part. The scientists who led the latest work, which is published on 25 January in Nature (Z. Liu et al. Nature; 2016), turned to the autism-related gene MECP2: both people who have extra copies of the gene (MECP2-duplication syndrome) and people who have certain mutations in this gene (Rett’s syndrome) share many of the symptoms of autism. Previously researchers have engineered monkeys to have autism-related genes (H. Liu et al. Cell Stem Cell 14, 323–328; 2014), but this is the first published demonstration of a link between those genes and the animals’ behaviour. 
... Qiu, meanwhile, is excited by the prospect of using the model to identify exactly where in the brain the MECP2 overexpression causes trouble. His team is already using brain-imaging technology on the monkeys to pinpoint such areas. Next, the researchers plan to use the CRISPR gene-editing technique to knock out the extra MECP2 copies in cells in those regions and then check whether the autisim-like symptoms stop.
Here's the paper:
Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2 
Nature (2016) doi:10.1038/nature16533 
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing1, 2, 3, 4. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes5. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders6. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression7, 8. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test9. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.

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