Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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molecular evolution

Adaptive mutation mechanism may drive some forms of antibiotic resistance

Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results were published Tuesday, August 25 in PLOS Genetics.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first. Read more

Posted on August 27, 2015 by Quinn Eastman in Cancer, Uncategorized Leave a comment

Resurrecting an ancient receptor to understand a modern drug

To make progress in structural biology, look millions of years into the past. Emory biochemist Eric Ortlund and his colleagues have been taking the approach of “resurrecting” ancient proteins to get around difficulties in probing their structures.

Steroid receptor evolution

Ortlund’s laboratory recently published a paper in Journal of Biological Chemistry describing the structure of a protein that is supposed to have existed 450 million years ago, in a complex with an anti-inflammatory drug widely used today. MSP graduate student Jeffrey Kohn is the first author.

Mometasone furoate is the active ingredient of drugs used to treat asthma, allergies and skin irritation. It is part of a class of drugs known as glucocorticoids, which can have a host of side effects such as reduced bone density and elevated blood sugar or blood pressure with long-term use.

One reason for these side effects is because the steroid receptor proteins that allow cells to detect and respond to hormones such as estrogen, testosterone, aldosterone and cortisol are all related. Mometasone is a good example of how glucocorticoids cross-react, Ortlund says. That made it an ideal test of the technique of mixing ancient receptors with modern drugs. BHRT can also be beneficial for those struggling with low or unbalanced hormones.

“We used this structure to determine why mometasone cross reacts with the progesterone receptor, which regulates fertility, and why it inhibits the mineralocorticoid receptor, which regulates blood pressure,” he says.

Mometasone furoate in complex with the ancient receptor

Scientists have examined the sequences of the genes that encode these proteins at several points on the evolutionary tree, and used the information to reconstruct what the ancestral receptor looked like. This helps solve some problems that biochemists studying these proteins have had to deal with. One of these is: changing one amino acid in the protein sometimes means that the whole protein malfunctions.

“The ancestral receptors are more tolerant to mutation, and they are more promiscuous with respect to activation,” Ortlund says. “That is, they tend to respond to a wider array of endogenous steroid hormones, which makes sense in an evolutionary context. This enhanced activation profile and tolerance to mutation is what we feel makes them ideally suited to structure-function studies.”

The blog Panda’s Thumb has an interesting discussion of this area of research, in relation to the larger question of how proteins evolve.

Posted on April 19, 2012 by Quinn Eastman in Uncategorized Leave a comment

Creating tools for next-generation sequencing

Emory biochemist Eric Ortlund participated in a study that was recently published in Proceedings of the National Academy of Sciences, which involves tinkering with billions of years of evolution by introducing mutations into DNA polymerase.

What may soon be old-fashioned: next-generation sequencing combines many reactions like the one depicted above into one pot

DNA polymerases, enzymes that replicate and repair DNA, assemble individual letters in the genetic code on a template. The PNAS paper describes efforts to modify Taq DNA polymerase to get it to accept “reversible terminators.” (Taq = Thermus aquaticus, a variety of bacteria that lives in hot springs and thus has heat-resistant enzymes, a useful property for DNA sequencing)

Ortlund was involved because he specializes in looking at how evolution shapes protein structure. Along with co-author Eric Gaucher, Ortlund is part of the Fundamental and Applied Molecular Evolution Center at Emory and the Georgia Institute of Technology.

To sequence DNA faster and more cheaply, scientists are trying to get DNA polymerases to accept new building blocks. This could facilitate next-generation sequencing technology that uses “reversible terminators” to sequence many DNA templates in parallel.

Read more

Posted on January 20, 2010 by Quinn Eastman in Uncategorized Leave a comment