A shift in the code: New method reveals hidden genetic landscape

The letters in the human genome carry instructions to make proteins, via a three-letter code. Each trio spells out a word, and the words are strung together in a sentence to build a specific protein. Inserting or deleting a letter ('e' in this example) shifts the three-letter code. Known as a frameshift, these mutations cause the remaining words to be misspelled and the protein sentence to become unintelligible. Credit: J. Jansen/ Cold Spring Harbor Laboratory

With three billion letters in the human genome, it seems hard to believe that adding a DNA base here or removing a DNA base there could have much of an effect on our health. In fact, such insertions and deletions can dramatically alter biological function, leading to diseases from autism to cancer. Still, it is has been difficult to detect these mutations. Now, a team of scientists at Cold Spring Harbor Laboratory (CSHL) has devised a new way to analyze genome sequences that pinpoints so-called insertion and deletion mutations (known as "indels") in genomes of people with diseases such as autism, obsessive-compulsive disorder and Tourette syndrome.

The letters in the carry instructions to make proteins, via a three-letter code. Each trio spells out a "word;" the words are then strung together in a sentence to build a specific protein. If a letter is accidentally inserted or deleted from our genome, the three-letter code shifts a notch, causing all of the subsequent words to be misspelled. These "frameshift" mutations cause the protein sentence to become unintelligible. Loss of a single protein can have devastating effects for cells, leading to dysfunction and sometimes to serious diseases.

DNA insertions and deletions vary in length and sequence. Each indel can range in size from one DNA letter to thousands, and they are often highly repetitive. Their variability has made it challenging to identify indels, despite major advancements in genome sequencing technology. They are, in effect, regions of the genome that have remained hidden from view as researchers search for the mutations that cause disease.

A team of CSHL scientists, including Assistant Professors Mike Schatz, Gholson Lyon, and Ivan Iossifov, and Professor Michael Wigler, has devised a way to mine existing genomic datasets for indel mutations. The method, which they call Scalpel, begins by grouping together all of the sequences from a given genomic region. Scalpel – a computer formula, or algorithm – then creates a new sequence alignment for that area, much like piecing together parts of a puzzle.

Each dot represents a short sequence of DNA from the reads mapped to a gene. The red path spells out the normal version of the gene, while the yellow path spells out a truncated path with the indel. The blue 'spikes' show where there are other errors in the reads that have been mapped here. Credit: M. Schatz/ Cold Spring Harbor Laboratory

"These indels are like very fine cuts to the genome – places where DNA is inserted or deleted – and Scalpel provides us with a computational lens to zoom in and see precisely where the cuts occur," says Schatz, a quantitative biologist. Such information is critical to understand the mutations that cause disease. In work published today in Nature Methods, the team used Scalpel to search for indels in patient samples. Lyon, a CSHL researcher who is also a practicing psychiatrist, worked with his team to analyze a patient with severe Tourette syndrome and , identifying and validating more than a thousand indels to demonstrate the accuracy of the method.

The CSHL team performed a similar analysis to search for indels that are associated with autism. They explored a dataset of 593 families from the Simons Simplex Collection, a group composed entirely of families with one affected child but no other family members with the disorder. While the researchers discovered a total of 3.3 million indels across the 593 families, most appeared to be relatively harmless. Still, a few dozen mutations stood out to be specifically associated with autism. "All this adds to our body of knowledge about the spontaneous that cause autism," says Schatz.

But the tool can be applied much more broadly. "We are collaborating with plant scientists, cancer biologists, and others, looking for indels," says Schatz. "This is a powerful tool, and we are looking forward to revealing new pieces of the that make a difference, throughout the tree of life."

More information: "Accurate de novo and transmitted indel detection in exome-capture data using microassembly" appears online in Nature Methods on August 17, 2014. The authors are: Giuseppe Narzisi, Jason O'Rawe, Ivan Iossifov, Han Fang, Yoon-ha Lee, Zihua Wang, Yiyang Wu, Gholson Lyon, Michael Wigler, and Michael Schatz. dx.doi.org/10.1038/nmeth.3069

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JVK
1 / 5 (4) Aug 17, 2014
Excerpt: "...mutations cause the protein sentence to become unintelligible. Loss of a single protein can have devastating effects for cells, leading to dysfunction and sometimes to serious diseases."

My comment: Mutations that cause the protein sentence to become unintelligible do not lead from ecological variation to nutrient-dependent ecological adaptations controlled by the physiology of reproduction in the context of cell type differentiation of all cells in all individuals of all species by amino acid substitutions in my model.

I think that's why the pseudoscientific nonsense about mutation-initiated natural selection and the evolution of biodiversity attributed to constraint-breaking mutations is no longer considered by serious scientists who understand how the epigenetic landscape becomes the physical landscape of DNA in the organized genomes of species from microbes to man. See for examples: http://www.ncbi.n...24693353
anonymous_9001
5 / 5 (3) Aug 17, 2014
I think that's why the pseudoscientific nonsense about mutation-initiated natural selection and the evolution of biodiversity attributed to constraint-breaking mutations is no longer considered by serious scientists


It is most certainly still considered by most everyone but you. You have yet to demonstrate otherwise. All the "serious scientists" I've contacted disagree with you and you refuse to contact them yourself. Instead, you misinterpret their writings and force me to contact them to clear up your misrepresentation. Then, when I post the evidence, you essentially say "well, I guess they're not serious scientists in that case. They're idiot minions."
JVK
1 / 5 (2) Aug 17, 2014
http://medicalxpr...ife.html

This report links ecological variation from a nutrient-dependent base pair change to changes in the microRNA/messenger RNA balance and amino acid substitutions that differentiate the cell types of species from microbes to man via stabilization of biophysically-constrained thermodynamic cycles of protein biosynthesis and degradation, which enables organism-level thermoregulation. It reveals how much pseudoscientific nonsense is incorporated into the claim that an 8,000 year-old mutation somehow led to the ecological adaptation manifested in this modern human population.

For comparison, a base pair change and single amino acid substitution in another modern human population in what is now central China linked nutrient-dependent pheromone-controlled ecological adaptations in the mouse-to-human model of cell type differentiation manifested in hair, teeth, sweat glands, and mammary tissue in ~ 30K years.
JVK
1 / 5 (2) Aug 17, 2014
http://medicalxpr...ase.html

Excerpt:
"...these CpG associations revealed nearby genes whose RNA expression was altered in brain samples..."

My comment: This suggests a clear link from ecological variation to nutrient-dependent changes in the microRNA/messenger RNA balance, which lead from alternative splicings of pre-mRNA to amino acid substitutions that differentiate the cell types of all individuals of all species from microbes to man via conserved molecular mechanisms.

The model that details the chain of events was first offered in the context of cell type differentiation and sex differences in cell types, which was before I realized that cell type differentiation must occur via conserved molecular mechanisms in all cells, of all tissues, of all organs, in all organ systems with the increasing organismal complexity manifested in nutrient-dependent pheromone-controlled morphological and behavioral phenotypes.
animah
5 / 5 (1) Aug 18, 2014
Keep going scammer James V Kohl. Your SEO profile is slowly changing, and it won't stop until you stop spamming this board:

https://www.googl...+scammer
c0y0te
5 / 5 (2) Aug 18, 2014
"With three billion letters in the human genome, it seems hard to believe that adding a DNA base here or removing a DNA base there could have much of an effect on our health."

Let me guess... You've never done any meaningful programming work in your life, am I right?

Let's be serious. DNA is sort of a low level programming language, and even in higher computer programming languages sometimes even a single character change can lead to unnoticed bugs that change the program's behavior, or even crush it altogether. Inserting or deleting a DNA base would be something like inserting or deleting a byte from machine code which (if done within the code and not the data) will almost certainly totally break any assembly program.

I'd say that it's much, much harder to believe how resilient DNA is to changes! (at least to old school coders...)
animah
5 / 5 (1) Aug 18, 2014
Coyote, you might be interested in googling DNA Chemical Reaction Networks, a programming language for designing synthetic DNA :-)

That said the analogy has limits I think. First, a biological organism is not a finite state machine in the classical computing sense because of quantum effects. Also even assuming we develop quantum computation languages in future (which is definitely happening), DNA is not sufficient to achieve any outcome or end state in an organism.
JVK
1 / 5 (1) Aug 18, 2014

Non‐coding RNAs as the bridge between epigenetic mechanisms, lineages and domains of life
http://jp.physoc....abstract

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