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 이성욱 ( 2016-04-22 05:37:16 , Hit : 975
 CRISPR Aids Identification of Sporadic Parkinson’s Mutation in GWAS


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Apr 21, 2016

The overwhelming majority of Parkinson’s disease (PD) and Alzheimer’s disease cases that occur are sporadic—caused by a complex mix of environmental and shared genetic factors. These types of interactions are notoriously difficult for scientists to study, which is why most research has focused on familial cases that have much clearer genetic origins.

Now, investigators at the Whitehead Institute have determined how a noncoding mutation identified in genome-wide association studies (GWAS) can contribute to sporadic PD. The researchers are hopeful that their novel approach will be helpful in analyzing future GWAS results for other sporadic diseases with genetic causes, such as Alzheimer’s, multiple sclerosis, diabetes, and cancer.  

"This is really the first time we've gone from risk variants highlighted by GWAS to a mechanistic and molecular understanding—right down to the nucleotide—of how a mutation can contribute to the risk of developing disease," explained senior study author Rudolf Jaenisch, M.D., Whitehead Institute founding member and professor of biology at MIT.

Scientists often view GWAS as a treasure trove of genomic information marking the general locations of mutations that could be risk factors for a given condition. Yet, GWAS do not reveal the precise locations of potentially pathogenic mutations, nor do they indicate how a particular locus on a genomic map contributes, if at all, to a disease. For instance, in sporadic PD, multiple GWAS have pointed to the α-synuclein gene (SNCA) as one of the strongest risk loci in patients' genomes. However, the GWAS contain little information regarding the mechanism of how this gene is dysregulated in sporadic PD patients.

To determine if distant gene regulatory elements on the same chromosome carrying SNCA affected cellular levels of α-synuclein, the Whitehead team investigated two GWAS-flagged risk variants located in a putative SNCA enhancer.

The researchers then used the CRISPR/Cas9 genome editing system to modify the mutations into isogenic human pluripotent stem cells. By altering the genetic variant on only one chromosome, the other chromosome remains unchanged and acts as an internal control. This method allows the scientists to measure very subtle effects with very high confidence while eliminating the effect of any genetic or epigenetic modifications and cell culture related variations that could occur during the experiment.

“Here we describe a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells,” the authors wrote. “By generating a genetically precisely controlled experimental system, we identify a common Parkinson’s disease associated risk variant in a non-coding distal enhancer element that regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson’s disease.”

The findings from this study were published recently in Nature in an article entitled "Parkinson-Associated Risk Variant in Distal Enhancer of α-Synuclein Modulates Target Gene Expression."

"Our method addresses an essential shortcoming of GWAS—using the correlations produced by GWAS, you cannot distinguish the effect between two variants that are very close together in the genome," noted lead study author Frank Soldner, M.D., senior research scientist in Dr. Jaenisch’s laboratory. "Such physical proximity means that they will always co-segregate during inheritance, which is why we had to do what we did—modify and analyze each variant independently while keeping the rest of the genome completely constant."

Once the Whitehead team differentiated the stem cells into neurons, they took careful note of the changes in SNCA expression. While one of the mutations had no effect, the other, which switches one nucleotide from an A to a G, slightly but significantly, boosts SNCA production. When compared to the enhanced SCNA production in the familial form of the disease, the modest effect created by the A-to-G mutation would be sufficient over a lifetime to increase the risk of PD, the researcher postulated.

To see how the mutation affects α-synuclein production, the researchers identified two transcription factors that bind to the enhancer carrying this mutation. When the enhancer was not mutated, the transcription factors bind to it normally and suppress SNCA production. If the enhancer had the G mutation, the transcription factors were unable to bind to the enhancer, and SNCA production is activated.

The research team was excited by their findings and looking to apply their novel technique used to pinpoint additional pathogenic genes for sporadic PD and sift through the GWAS hits for other diseases.







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  CRISPR Aids Identification of Sporadic Parkinson’s Mutation in GWAS  이성욱 2016/04/22 975

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