A Revolution in Mapping Complex Genetic Traits

 :: Posted by American Biotechnologist on 09-18-2014

Life is rarely simple. From crop yields to disease risks, the biological characteristics people care most about are usually those considered “complex traits.” Just as for height—the textbook example of a complex trait—attributes like risk for a particular human disease are shaped by multiple genetic and environmental influences, making it challenging to find the genes involved. To track down such genes, geneticists typically mate two individuals that differ in key ways—for example, a large mouse and a small mouse—and then study their descendents, looking for genes that tend to be inherited with the trait value of interest. But this method only implicates a broad genomic region, and the identities of the crucial gene/s often remain a mystery.

Now, geneticists are embracing a powerful approach that pinpoints more precise areas of the genome by founding the breeding population with multiple, genetically diverse parents. To encourage innovations in this rapidly developing field, the Genetics Society of America journals GENETICS and G3: Genes|Genomes|Genetics today published the first articles in an ongoing special collection on mapping complex trait genes in multiparental populations.

The 18 articles describe methods and applications in a wide range of organisms, including mice, fruit flies, and maize. Among the advances reported are the creation of a multiparental population of wheat, methods for use with the Diversity Outbred and Collaborative Cross mouse populations, and the identification of nicotine resistance genes in fruit flies. The power of the approach for disease genetics is highlighted in an article describing how a multiparental rat population was used to find a human gene variant that affects insulin levels.

“These collections of multiparental strains are extremely powerful and greatly accelerate discovery. For example, in one of the articles, researchers report using a multiparental population to rapidly identify fruit fly genome regions associated with the toxicity of chemotherapy drugs. The authors could then examine these regions to find several candidate causative genes,” said Dirk-Jan de Koning, Professor at the Swedish University of Agricultural Sciences, Deputy Editor-in-Chief, Complex Traits, at G3, and an editor of the new collection. “Using standard two-parent crosses, they would have been stuck with unmanageably large regions each containing hundreds or even thousands of candidate genes.”

Because the field is so new, geneticists are still developing the best methods for creating and analyzing multiparental populations. “This collection will move the field forward by stimulating discussion between different disciplines and research communities,” said Lauren McIntyre, Professor at the University of Florida, and an editor of the collection. “To help foster this ongoing exchange, the collection will continue to publish new articles, and all associated data will be freely available.”

In an editorial, McIntyre and de Koning describe how the idea for the multiparental populations collection was born and how scientific society journals like GENETICS and G3 can advance new research fields.

Thanks to Genetics Society of America for contributing this story.

Extinguishing the Flames of Scientific Creativity

 :: Posted by American Biotechnologist on 09-17-2014

Like most of my friends, I fell in love with science at a very early age and decided to live my dream by becoming a scientist. If you are reading this post, chances are that you too share this feeling and are passionate about science. Unfortunately, there are many passion-killers out there and the reality of living life as a scientists is too much to bear for many seasoned researchers. In a very interesting article published in NPR last week, author Richard Harris describes the struggle of two men who had successful science careers and the reasons they left the lab behind to pursue other interests.

I urge you to read the original article on NPR. You will be introduced to former Professor, Ian Glomski who had a well funded lab at the University of Virginia. Dr. Glomski’s was funded to do predictable and somewhat boring research. Like the rest of us, he too entered science to fulfill his passion and his line of research was not answering that call. So Ian asked the NIH to fund a revolutionary idea that he hoped would rock his world of research. Unfortunately, his ideas were never funded and with his loss of funding, down went his science career.

You will also read about Dr. Randen Patterson who also tried, unsuccessfully, to receive funding for unconventional, yet potentially ground breaking research. When his idea was shot down, he too left the university, never to set foot in an academic lab again.

The article laments a funding system that fits scientists safely into a standardized square box and penalizes those who dare propose to do something different. Every scientist dreams about conducting Nobel-Prize-worthy research. Every scientist is desperately seeking that Eureka! moment. We all entered science to fulfill that spark. Shouldn’t our funding systems be geared towards fanning the flames of creativity rather than extinguishing the flames in a drought of funding?

Droplet Digital™ PCR Tips & Tricks: ddPCR™ Assay Design

 :: Posted by American Biotechnologist on 09-16-2014

Admitting My Darkest Secret

 :: Posted by American Biotechnologist on 09-15-2014

OK…this might sound a little childish, but I bet that many of you have felt the same way at one time or another. Sometimes, when I’m alone in the lab, I pretend that my pipette is a weapon and I wield my pipette like John Wayne at the OK Corral. Am I alone? I think not!

Stressed Out Cells Shut Off Protein Production

 :: Posted by American Biotechnologist on 09-12-2014

Living cells are like miniature factories, responsible for the production of more than 25,000 different proteins with very specific 3-D shapes. And just as an overwhelmed assembly line can begin making mistakes, a stressed cell can end up producing misshapen proteins that are unfolded or misfolded.

Now Duke University researchers in North Carolina and Singapore have shown that the cell recognizes the buildup of these misfolded proteins and responds by reshuffling its workload, much like a stressed out employee might temporarily move papers from an overflowing inbox into a junk drawer.

The study, which appears Sept. 11, 2014 in Cell, could lend insight into diseases that result from misfolded proteins piling up, such as Alzheimer’s disease, ALS, Huntington’s disease, Parkinson’s disease, and type 2 diabetes.

“We have identified an entirely new mechanism for how the cell responds to stress,” said Christopher V. Nicchitta, Ph.D., a professor of cell biology at Duke University School of Medicine. “Essentially, the cell remodels the organization of its protein production machinery in order to compartmentalize the tasks at hand.”

The general architecture and workflow of these cellular factories has been understood for decades. First, DNA’s master blueprint, which is locked tightly in the nucleus of each cell, is transcribed into messenger RNA or mRNA. Then this working copy travels to the ribosomes standing on the surface of a larger accordion-shaped structure called the endoplasmic reticulum (ER). The ribosomes on the ER are tiny assembly lines that translate the mRNAs into proteins.

When a cell gets stressed, either by overheating or starvation, its proteins no longer fold properly. These unfolded proteins can set off an alarm — called the unfolded protein response or UPR – to slow down the assembly line and clean up the improperly folded products. Nicchitta wondered if the stress response might also employ other tactics to deal with the problem.

In this study, Nicchitta and his colleagues treated tissue culture cells with a stress-inducing agent called thapsigargin. They then separated the cells into two groups — those containing mRNAs associated with ribosomes on the endoplasmic reticulum, and those containing mRNAs associated with free-floating ribosomes in the neighboring fluid-filled space known as the cytosol.

The researchers found that when the cells were stressed, they quickly moved mRNAs from the endoplasmic reticulum to the cytosol. Once the stress was resolved, the mRNAs went back to their spots on the production floor of the endoplasmic reticulum.

“You can slow down protein production, but sometimes slowing down the workflow is not enough,” Nicchitta said. “You can activate genes to help chew up the misfolded proteins, but sometimes they are accumulating too quickly. Here we have discovered a mechanism that does one better — it effectively puts everything on hold. Once things get back to normal, the mRNAs are released from the holding pattern.”

Interestingly, the researchers found that shuttling ribosomes between the ER and the cytoplasm during stress only affected the subset of mRNAs that would give rise to secreted proteins like hormones or membrane proteins like growth factor receptors — the types of proteins that set off the stress response if they’re misfolded. They aren’t sure yet what this means.

Nicchitta is currently searching for the factors that ultimately determine which mechanisms cells employ during the stress response. He has already pinpointed one promising candidate, and is looking to see how cells respond to stress when that factor is manipulated.

Thanks to Duke University for contributing this story.