{"id":10992,"date":"2016-09-09T13:28:55","date_gmt":"2016-09-09T20:28:55","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=10992"},"modified":"2024-01-30T15:14:02","modified_gmt":"2024-01-30T23:14:02","slug":"brains-stunning-genomic-diversity-revealed","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/brains-stunning-genomic-diversity-revealed\/","title":{"rendered":"The brain\u2019s stunning genomic diversity revealed"},"content":{"rendered":"
\"overlay-neurons\"<\/a>
Using postmortem human brains and human embryonic stem cell models of brain development, Salk Institute researchers discover a new mechanism to generate DNA variation in human neurons. Here, human embryonic cell- derived neurons stained for a neurons specific marker (Tuj1, green, DNA show in red) show remarkable diversity. <\/p>\n

Click here<\/a> for a high-resolution image<\/figcaption><\/figure>\n

LA JOLLA\u2014Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different.<\/p>\n

Now researchers at the Salk Institute and their collaborators have shown that one source of this variation\u2014called long interspersed nuclear elements or L1s\u2014are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called \u201cjumping genes\u201d that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What\u2019s more, such variations can influence the expression of genes that are crucial for the developing brain.<\/p>\n

The findings, published September 12, 2016 in the journal Nature Neuroscience<\/a><\/em>, may help explain what makes us each unique\u2014why even identical twins can be so different from one other, for example\u2014and how jumping genes can go awry and cause disease.<\/p>\n

\u201cIn 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person,\u201d says the study\u2019s senior investigator \u9c81\u65af\u8482\u00b7\u76d6\u5947<\/a>, a professor in Salk\u2019s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. \u201cThis recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism<\/a>.\u201d<\/p>\n

In 2005, Gage\u2019s team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 \u79d1\u5b66<\/em> paper, Gage\u2019s group showed that large chunks of DNA were inserted\u2014or deleted\u2014into the genomes of the cells.<\/p>\n

\"lre_53_2_maximum-intensity-projection\"
The \u201cjumping gene\u201d L1 cuts DNA in human cells to generate neuronal genomic diversity. Cells expressing L1 (genomic DNA shown in red) have high levels of DNA breaks as visualized by 53BP1 staining (green) which repairs broken DNA.<\/p>\n

Click here<\/a> for a high-resolution image<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions.<\/p>\n

In the new study, Gage, co-first authors Jennifer Erwin and Apu\u00e3 Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before.<\/p>\n

Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That\u2019s because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found.<\/p>\n

\u201cThe surprising part was that we thought all L1s could do was insert into new places. But the fact that they\u2019re causing deletions means that they\u2019re affecting the genome in a more significant way,\u201d says Erwin, a staff scientist in Gage\u2019s group.<\/p>\n

\"apua-paquola_rusty-gage_jennifer-erwin_0x8c4669e\"<\/a>
Apua Paquola, Rusty Gage and Jennifer Erwin<\/p>\n

Click here<\/a> for a high-resolution image<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

Gage believes that diversity can be good for the brain\u2014after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone\u2014but that too much of it can cause disease.<\/p>\n

Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amounts of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene\u2019s expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.<\/p>\n

Other authors on the study are Tatjana Singer, Iryna Gallina, Carolina Quayle, Tracy Bedrosian, Cheyenne Butcher, Joseph Herdy and Anindita Sarkar of Salk; Mark Novotny and Roger Lasken of the J. Craig Venter Institute<\/a>; Francisco Alves of the University of S\u00e3o Paulo<\/a> in Brazil; and Alysson Muotri of the University of California, San Diego<\/a>.<\/p>\n

The research was supported by George E. Hewitt Foundation for Medical Research, the California Institute for Regenerative Medicine<\/a>, the National Institutes of Health<\/a> (MH095741, MH088485), the G. Harold & Leila Y. Mathers Foundation<\/a>, the Engman Foundation, the Leona M. and Harry B. Helmsley Charitable Trust<\/a>, the Paul G. Allen Family Foundation<\/a>, the Glenn Center for Aging Research<\/a> at the Salk Institute, and JPB Foundation<\/a>.<\/p>","protected":false},"featured_media":10993,"template":"","faculty":[76],"disease-research":[169,124,167],"class_list":["post-10992","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-rusty-gage","disease-research-autism","disease-research-neuroscience-and-neurological-disorders","disease-research-schizophrenia"],"acf":[],"yoast_head":"\nThe brain\u2019s stunning genomic diversity revealed - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/brains-stunning-genomic-diversity-revealed\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The brain\u2019s stunning genomic diversity revealed - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"Using postmortem human brains and human embryonic stem cell models of brain development, Salk Institute researchers discover a new mechanism to generate DNA variation in human neurons. 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