Improving research mentor training requires new approaches.

Mentoring is essential for the success of researchers at all career stages, but not all mentor-mentee relationships are created equal. Students from historically underrepresented backgrounds often receive less mentoring than their peers, and many mentors are not trained in how to mentor effectively. To address some of these needs, Entering Mentoring, an evidence-based program for research mentor training, was developed and shown to be effective in improving mentoring. 

Of course, such programs are only useful if people have access to them. In CBE—Life Sciences Education, Spencer et al. report on the infrastructure they have created to facilitate more widespread research mentor training.

The first hurdle that must be cleared for more mentors to receive training is to have more people capable of giving the training. Therefore, the authors took a train-the-trainer approach and recruited and trained master facilitators to instruct others in how to implement research mentor training, termed facilitator training. This approach has resulted in nearly 600 people being trained as facilitators, with over 4,000 mentors receiving research mentor training.

In order to be broadly useful, training for mentors needs to be applicable in a variety of settings, including at different institutions and for researchers at multiple career stages. The original Entering Mentoring program was designed as a summer seminar for graduate students mentoring undergraduates, but it has been expanded for different research areas and for those mentoring everyone from undergraduates to junior faculty. Modules to address specific concerns, like culturally aware mentoring, have also been developed, and there are resources available for structuring the programs in a variety of formats.

Even though a person might be trained in facilitating research mentor training, actually running such workshops requires time, resources, and support, which are not always available. To help address these concerns, facilitator training workshops were restructured to include resources and strategies for overcoming obstacles to implementation, such as encouraging facilitators at the same or similar institutions to cooperatively plan.

As mentorship programs expand, quality control is necessary to ensure that workshops are productive and that resources are accessible. Therefore, assessment tools were developed for facilitators to evaluate workshops they run, and a centralized evaluation system was developed to more effectively make use of feedback.

By developing this infrastructure, better training will become more accessible for more mentors. Early results of self-reported surveys suggest that research mentor training is already being effectively implemented—ultimately helping make science more accessible and productive. 

CITATION:

Building a Sustainable National Infrastructure to Expand Research Mentor Training

Kimberly C. Spencer, Melissa McDaniels, Emily Utzerath, Jenna Griebel Rogers, Christine A. Sorkness, Pamela Asquith, Christine Pfund

CBE—Life Sciences Education Published Online: 28 Aug 2018

DOI: https://doi.org/10.1187/cbe.18-03-0034

Improved duplex sequencing identifies spontaneous mutations in bacteria without long-term culturing.

Spontaneous mutations are the driving force of evolution, yet, our ability to detect and study them can be limited to mutations that accumulate clonally. Sequencing technology often cannot identify very rare variants or discriminate between bona fide mutations and errors introduced during sample preparation. In GENETICS, Zhang et al. created an improved sequencing method to study low-abundance spontaneous mutations in the bacterium Escherichia coli.

To develop their method, the authors began with duplex sequencing, in which fragmented DNA molecules are tagged with an adaptor sequence for sequencing. This method is powerful, but at high read depths, it can erroneously call true mutations as PCR duplicates, making it ill-suited for finding rare mutations.

The authors first determined the error rate of the PCR step of duplex sequencing, where most experimental artifacts would be expected to occur. Because duplex sequencing can identify reads that came from the same parental DNA molecules (based on the adaptor sequences), the authors assumed that any such reads that had mismatches must have come from base changes during the PCR. By identifying these discrepancies, they determined the rates of different kinds of errors in the sequencing process.

The authors then sequenced E. coli genomes using a new method, which they termed improved duplex sequencing (IDS). IDS is similar to duplex sequencing, but it uses adaptor sequences of multiple different lengths. The use of more and different adaptor sequences minimizes the chance that two different DNA molecules that happen to break at the same place will be erroneously called as PCR replicates. By employing this method and accounting for the error rate of the PCRs, which they had already determined, the authors were able to confidently identify rare, random mutations in E. coli.

Having identified such mutations, the authors looked for patterns. They found that clusters of mutations occurred in regions of the genome that are known to be replication fork stopping regions. This is suggestive of transcriptional errors, as would be expected for spontaneous mutations. Interestingly, mutations in these hotspots were almost entirely in relatively unimportant regions of the genome—for instance, in the non-functional parts of tRNA genes. These vulnerable areas of the genome hint at mechanisms in E. coli that may protect more critical regions from damage.

CITATION:

Spatial Vulnerabilities of the Escherichia coli Genome to Spontaneous Mutations Revealed with Improved Duplex Sequencing

Xiaolong Zhang, Xuehong Zhang, Xia Zhang, Yuwei Liao, Luyao Song, Qingzheng Zhang, Peiying Li, Jichao Tian, Yanyan Shao, Aisha Mohammed AI-Dherasi, Yulong Li, Ruimei Liu, Tao Chen, Xiaodi Deng, Yu Zhang, Dekang Lv, Jie Zhao, Jun Chen, Zhiguang Li

Genetics October 2018 210: 547-558; https://doi.org/10.1534/genetics.118.301345

https://www.genetics.org/content/210/2/547

Analysis of insulin-like signaling in C. elegans reveals extensive positive and negative feedback regulation.

The insulin-like signaling system of nematode worms is comparable to that of more complex organisms; it helps regulate a wide range of the animal’s biology, including metabolism, growth, and development. This system is remarkably flexible, with the ability to maintain a physiological steady-state (homeostasis) while also controlling switches between quite different developmental fates (developmental plasticity). A report published in GENETICS reveals the pervasive involvement of both positive and negative feedback in regulating this master pathway in the model nematode Caenorhabditis elegans.

The C. elegans genome encodes one insulin-like receptor and 40 insulin-like signaling proteins. The activity of insulin-like peptides can, in turn, affect the expression of these peptides themselves, yet exactly how this signaling network is regulated remains ambiguous. Kaplan et al. explored the extent of the feedback mechanisms of insulin-like signaling, along with their dependence on nutrient availability.

The worm insulin-like receptor, DAF-2, signals through antagonizing the activity of the transcription factor DAF-16, the nematode ortholog of mammalian FoxO. Because of these opposing functions, daf-2– and daf-16-mutant nematodes were employed to observe how changes in insulin-like signaling affect the expression of insulin-like genes.

Using these mutants under multiple conditions, such as fed vs. starved larval worms, the authors analyzed the expression of insulin-like genes, along with other genes involved in insulin-like signaling, like those in the PI3K pathway.

The authors found extensive feedback regulations within insulin-like signaling; the expression of nearly all detectable insulin-like genes was affected by altering insulin-like signaling, as were some components of the PI3K pathway. These feedback mechanisms were extensive and complex; for example, the well-studied insulin-like protein DAF-28, an agonist of DAF-2, seems to be repressed by DAF-16—thus, DAF-28 is a positive regulator of its own transcription, since activating DAF-2 represses DAF-16.

Overall, considerable evidence for both negative and positive feedback of insulin-like signaling was found; the authors write that this is likely to allow for rapid response to stimuli—like food availability—while still maintaining homeostasis. Further studies will be needed to delve into the precise molecular mechanisms of such feedback systems and to explore similar regulation in other organisms.

CITATION:

Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans

Rebecca E. W. Kaplan, Colin S. Maxwell, Nicole Kurhanewicz Codd, L. Ryan Baugh

GENETICS  January 2019 211: 349-361; https://doi.org/10.1534/genetics.118.301702

https://www.genetics.org/content/211/1/349

Apoptotic pathway promotes asymmetric cell division during C. elegans development.

Cell division doesn’t always produce identical daughter cells; often, the demands of multicellular development require cells to split into two quite different daughters with quite different fates. These “asymmetric” divisions are needed so that cells can differentiate and specialize, and some cells are even programmed to die shortly after their creation to ensure the proper function of the organism as a whole. In GENETICS, Mishra et al. found that the apoptotic cell death pathway regulates asymmetric division in the nematode worm Caenorhabditis elegans.

C. elegans is an exceptionally useful model organism for studying development because the fate of each of its relatively few cells can be precisely mapped. Many of the cells destined for death in the worm are actually the product of unequal division into a larger cell that differentiates and a smaller cell that undergoes apoptosis. The authors of the new report had previously studied the parent of one such uneven division, a cell known as the embryonic neurosecretory motor neuron neuroblast. They found that in the parental neuroblast, there is a gradient of activated CED-3 caspase, an executioner of apoptosis. This gradient leads to more active CED-3 caspase in the smaller daughter cell, which helps facilitate its death.

The authors wondered whether this CED-3 caspase gradient might be a general phenomenon in asymmetric divisions, so in the GENETICS report they studied another cell that divides into a large cell that survives and a smaller cell that dies: the QL.p neuroblast. The authors identified a similar CED-3 caspase gradient in these cells, showing that the phenomenon is indeed somewhat general.

Then, the authors used loss-of-function mutants to explore the role of the CED-3 caspase and its related pathways in the asymmetric division of QL.p. They found that disrupting the cell death pathway impaired the ability of QL.p to divide asymmetrically and could impact the fate of the daughter cells—often giving rise to two living cells, rather than one that lives and one that dies. Mutations in other genes associated with asymmetric division, like pig-1, also affected the fate of the daughter cells but did not change the CED-3 caspase gradient.

The authors explain that, in QL.p, two molecular gradients are simultaneously created: one of “mitotic potential,” which is normally passed on to the larger daughter to facilitate its differentiation, and one of “apoptotic potential,” which is passed on to the smaller daughter and promotes its death. Although the details of these “potentials” are not yet understood, this separation within the parental cell seems crucial for ensuring that each cell reaches its proper endpoint.

Although caspases are well-known for their role in apoptosis, it is particularly noteworthy that mutations in CED-3 caspase do not only affect the ability of the small daughter cell to die. CED-3 caspase also appears to function in the division of the parental cell, suggesting a more complicated role of this molecular executioner during development.

CITATION:

Caenorhabditis elegans ced-3 Caspase Is Required for Asymmetric Divisions That Generate Cells Programmed To Die

Nikhil Mishra, Hai Wei, Barbara Conradt

GENETICS November 1, 2018 vol. 210 no. 3 983-998; https://doi.org/10.1534/genetics.118.301500

A Wnt protein involved in the formation of the human ovary plays an important role in female zebrafish sex development.   

Even though zebrafish are a well-studied research model, how these fish develop into males or females remains rather obscure—in part because the sex of lab strains is not determined by sex chromosomes. Research published in GENETICS reveals that one of the genes critical for proper development of mammalian ovaries seems to play a related role in zebrafish, providing insight into this major difference between fish and mammals.

In humans and other mammals, Wnt4 encodes a signaling molecule that antagonizes the male-promoting signal FGF9 and is crucial to the proper development of the ovaries. Though they lack an Fgf9 ortholog, zebrafish have two Wnt4-like genes—wnt4a and wnt4b—so Kossack et al. investigated whether these genes might play a role in zebrafish sexual development.

The authors first performed a phylogenetic analysis to better understand how the Wnt4-like genes have changed over evolutionary time. Zebrafish have two such genes, while mammals only have one, so two evolutionary scenarios are possible: either fish gained an extra copy of the gene, or mammals lost a copy that was originally present. The authors found that the latter scenario is more likely; both reptiles and birds have two such genes, making it more likely that  mammals lost one of their copies. Further analysis revealed that wnt4a is likely the ortholog of mammalian Wnt4, whereas wnt4b was lost in mammals after they split from birds.

The authors next used RT-PCR to examine the expression patterns of the two genes. They detected wnt4a, but not wnt4b, in the ovaries of female zebrafish. In contrast, only wnt4b was detected in the testis of male fish. They also found that wnt4a was dynamically expressed in gonads during development in a non-sex-specific manner.

Fish mutant for wnt4a develop predominantly—though not exclusively—as males, which supports the idea that wnt4a is involved in either differentiation into a female or the maintenance of a female phenotype throughout development. Analysis of mutant embryos during development suggests that wnt4a likely promotes female development since most mutant embryos developed as males rather than “reverting” to males from an initially female phenotype.

Interestingly, wnt4a mutants were unable to produce progeny when mated to each other or to  wild-type. Closer inspection revealed that wnt4a-mutant fish of both sexes had malformed reproductive tracts. Even though viable eggs and sperm could be obtained from their gonads, mutant fish were unable to release their gametes, preventing them from reproducing.

These findings suggest that Wnt4-like genes have been involved in female development of a diverse array of animals—including our fishy ancestors that swam the oceans some 450 millions year ago.

CITATION:

Female Sex Development and Reproductive Duct Formation Depend on Wnt4a in Zebrafish

Michelle E. Kossack, Samantha K. High, Rachel E. Hopton, Yi-lin Yan, John H. Postlethwait, Bruce W. Draper

GENETICS January 2019 211: 219-233; https://doi.org/10.1534/genetics.118.301620

http://www.genetics.org/content/211/1/219

An opportunistic human pathogen makes itself at home on old oaks.

At one point or another, most people have played host to the common yeast Candida albicans. Around 40-60% of healthy adults carry around it in their mouth or guts; in immunocompromised people, however, this normally harmless cohabitant becomes a deadly pathogen. Generally thought to only grow in warm-blooded animals, C. albicans has occasionally been isolated from plants—from blades of grass in a New Zealand pasture to gorse and myrtle plants on a sheep-grazed hill in Portugal to an African tulip tree in the Cook Islands. Are these just cases of misplaced yeast, or can C. albicans really thrive outside a warm body? In a report in GENETICS, Bensasson et al. describe the genomes of three C. albicans strains isolated from the barks of oak trees in an ancient wood pasture, providing genetic evidence that this yeast can live on plants for extended periods of time.  

A survey of budding yeast on oaks in Europe turned up three new strains of C. albicans; they were found only on some of the oldest trees. After ensuring that the new strains were indeed new tree-based isolates (and not merely laboratory contaminants), the authors conducted a phenotypic investigation. All three strains showed most of the standard traits of C. albicans, including the ability to grow at the elevated temperatures expected in a mammal; however, they were not identical. One of the strains was not as salt tolerant as the others, would not grow on soluble starch, and switched to a different growth form under particular nutritional conditions.

The authors next sequenced the genomes of the new strains; this was the first time C. albicans from a non-animal source have been sequenced. Genomic analysis showed that the three strains were relatively distantly diverged from each other, and the new sequences were compared with over 200 yeast sequences previously isolated from humans and other animals to create a phylogenetic tree. Interestingly, all three of the tree strains showed more similarity with clinical strains than with each other.

The authors also analyzed the levels of heterozygosity—a measure of genetic variation—within the tree strains and found that these strains are more heterozygous than typical clinically isolated strains, which suggests that life on trees subjects the yeast to different selection or mutation pressures than life in humans. Higher heterozygosity could be a result of yeast evolving in conditions where they have to reproduce asexually, which would make mutations more likely to accumulate, thus increasing allelic variation. This difference also supports the idea that these yeast grow in the wild, rather than being recent emigrants from a warm-blooded host.

These findings may have implications beyond the shady groves of the New Forest; understanding the wild life of C. albicans could shed light on the evolution and lifestyle of the yeast found in humans and help us better understand how virulent strains emerge and damage human health.

CITATION:

Diverse Lineages of Candida albicans Live on Old Oaks

Douda Bensasson, Jo Dicks, John M. Ludwig, Christopher J. Bond, Adam Elliston, Ian N. Roberts, Stephen A. James

Genetics January 2019 211: 277-288; https://doi.org/10.1534/genetics.118.301482

http://www.genetics.org/content/211/1/277

The gene Ade2 links metabolism and sleep in the fat bodies of Drosophila.

All animals need to eat and sleep. In fact, these critical behaviors are intertwined: animals adjust their sleep needs based on food availability and energy storage. In a Featured article in G3, Yurgel et al. delved into the molecular mechanisms that connect sleep and metabolism in the fruit fly.

A growing body of evidence suggests that the fat body, an adipose-like organ in Drosophila responsible for fat storage and detoxification, regulates complex behaviors—but little is known about its relationship to sleep. Somewhat analogous to the mammalian liver, the fat body secretes hormones that influence fly behaviors, much the same way that human organs like the pancreas and stomach secrete hormones that trigger hunger or satiation, which in turn drive you to eat—or not.

Because sleep and metabolism are so interconnected, the authors hypothesized that genes in the fat body that are associated with hunger might also play a role in regulating sleep. Using RNAi, they knocked down the expression of 113 genes previously reported to be upregulated in the fly fat body under conditions of starvation. They then measured how long these flies slept compared to controls.

The screen showed that decreasing fat body expression of  Ade2, a highly conserved purine biosynthesis gene, caused flies to sleep, on average, 200 minutes less than controls—a reduction of ~20%. Since homozygous mutations in Ade2 are lethal, the authors confirmed that flies with heterozygous mutations also sleep less than wild-type, phenocopying the knockdown results.

Expressing additional Ade2 in the fat bodies of mutant flies partially rescued the short sleep phenotype; however, overexpression of Ade2 in wild-type fly fat bodies had no effect on sleep. This suggests that Ade2 is needed for normal sleep, but additional Ade2 isn’t enough to increase that normal sleep duration.

Other behaviors, including walking activity and arousal threshold, are connected to sleep behaviors in the fly. Ade2-deficient flies showed no change in arousal threshold, but some mutants trended toward increased walking activity. The authors interpret this increased walking activity as similar to the hyperactivity observed in starving flies.

Analysis of energy stores revealed decreased levels of triglycerides and free glucose but normal levels of glycogen—consistent with a starvation state. Energy stores that mirror starvation are consistent with the hyperactivity observed in the walking activity assays, since that behavior is also seen in starving flies. These data led the authors to propose that Ade2 is required for normal storage of triglycerides and free glucose and that its loss puts the fly into a starvation-like state, which in turn promotes sleep.

Typically, genetic studies of behavior have focused on the nervous system, but this study highlights the importance of also considering non-neuronal factors like fat tissue, which may be significant pieces of the puzzle.

CITATION:

Ade2 Functions in the Drosophila Fat Body To Promote Sleep

Maria E. Yurgel, Kreesha D. Shah, Elizabeth B. Brown, Carter Burns, Ryan A. Bennick, Justin R. DiAngelo, Alex C. Keene

G3: Genes, Genomes, Genetics

November 2018 8: 3385-3395; https://doi.org/10.1534/g3.118.200554

http://www.g3journal.org/content/8/11/3385

Machine learning and access to ever-expanding databases improves genomic prediction of human traits.

In theory, a scientist could predict your height using just your genome sequence. In practice, though, this is still the stuff of science fiction. It’s not only your genes that affect height—environment also plays a role—but the larger problem is that height is affected by tens of thousands of individual genetic variations. This is also true of other complex traits, such as susceptibility to particular diseases. To get closer to accurate genomic prediction of human traits, geneticists are using new approaches to harness the vast amounts of sequence data becoming available. In GENETICS, Lello et al. describe a machine learning approach to the problem that allowed them to make predictions within a few centimeters of reality.

“To me, genomic prediction is the actual decoding of the genome,” says senior author Stephen Hsu from Michigan State University. A theoretical physicist by training, Hsu explains that his lab became interested in the problem of genomic prediction several years ago as the cost of genotyping continued to drop and more datasets became available. They had previously argued that they could predict complex traits, like height, if they only had enough data.The release of nearly 500,000 UK Biobank genotypes allowed them an opportunity to test this hypothesis.

A genomic prediction approach is quite different from the more familiar genome-wide association study (GWAS). GWAS methods test each SNP one at a time, looking for statistically significant contributions to the phenotype. In contrast, genomic prediction makes use of all SNPs at once in trying to build the best possible predictors.

The authors took the Biobank genotype and phenotype data and used a type of regression to identify the combination of SNPs that, taken together, best correlate with the trait of interest. Since only a subset of SNPs influence each trait—even the thousands of loci that control height are only a tiny fraction of the total number of SNPs identified —they also introduced a penalization factor that prevents the model from including unneeded SNPs. They were essentially trying to solve an optimization problem: identify the fewest number of variables (i.e. SNPs) that will allow for the best prediction about the outcome (i.e. trait).

Having generated their algorithm, the authors then put it to the test. They constructed models for height, heel bone density, and educational attainment, and they found that their algorithm worked well, particularly for height. For example, it produced a nearly 0.65 correlation with actual height, and predicted heights were usually within a few centimeters of actual heights. “Our predictor actually captures almost all the heritability that we could expect to find,” says Hsu.

With enough data, Hsu believes, accurate genomic prediction for complex traits will no longer be sci-fi. As more and more genotypes are obtained, Hsu predicts that this kind of prediction could be applied for most traits in as little as five years.

CITATION:

Accurate Genomic Prediction of Human Height

Louis Lello, Steven G. Avery, Laurent Tellier, Ana I. Vazquez, Gustavo de los Campos, Stephen D. H. Hsu

Genetics October 2018 210: 477-497; https://doi.org/10.1534/genetics.118.301267

http://www.genetics.org/content/210/2/477

Parent-of-origin effects help determine how lab rats respond to stress.

Although your father and mother each contribute a copy of your genes, these copies don’t always play equal roles. Instead, one parent’s gene can have a disproportionate effect on the offspring’s phenotype, resulting in complex patterns of inheritance. In G3: Genes|Genomes|Genetics, Mont et al. examined such effects in the behavior of lab rats.

One example of parent-of-origin effects (PoE) is genomic imprinting, a phenomenon in which only either the maternal or paternal allele of a gene is expressed. Imprinting is associated with a range of developmental and behavioral phenotypes in mammals, and disruption of certain imprinted genes can cause human diseases like Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes.

Although a great deal of work has been done on PoE in mice, much less is understood in rats, which show more complex behaviors. Thus, the authors began their study with a broad assessment of 199 phenotypes in a large cross of rats for which parental information was available. To look for potential examples of PoE, they developed a way to separate out the portion of trait variance that was dependent on inheritance in the usual sense—where there is no difference between maternally and paternally inherited alleles—from that which contrasts the mother versus the father. The latter component can arise from several causes, including true PoE, maternal effects (i.e. gene expression in the mother that influenced offspring taits), paternal effects (the equivalent for the father), and environmental effects from sharing a cage with the mother and some of the siblings. If there were no PoE, then values for each parent would be equivalent; however, the authors found that they were different for 86% of the phenotypes assessed.

If imprinted loci are known to be rare, why are these PoE-related effects seemingly so pervasive? The rat results are consistent with experiments done in mice, which also found widespread PoE-like phenomena and suggested that these effects may be due in part to the indirect effects of imprinted loci—that is, the effects of imprinting can ripple through the genome to trigger many additional phenotypic consequences.

Of particular note, the authors found that coping behaviors—how the animals reacted to stress—showed some of the most significant differences between maternal and paternal contributions, which is suggestive of PoE. However, confounding variables, such as dominance, can also generate PoE, so further experimentation was required to confirm this finding.

To test for PoE related to coping behaviors, the authors crossed two rat strains: RHA and RLA. Stressed RHA rats tend to display active behaviors, such as fleeing, whereas RLA rats tend to be passive when stressed, either freezing or self-grooming. These behaviors were assessed in the offspring of reciprocal crosses using the elevated zero maze, in which rats are placed in a ring-shaped elevated platform with alternating open and walled sections. The rats are then observed for anxiety-like behaviors around the open sections, since rats prefer closed spaces when they are exploring a new environment. The behavior of offspring in the maze tended to fit the behavior profile of the maternal strain: rats with RHA mothers and RLA fathers exhibited more active behavior (matching their RHA mothers), and vice versa.

The authors suggest that these differences might be due to known differences in epigenetic modifications on neurotransmitter receptor genes in the two rat strains, although further research is needed to define the exact mechanism for this phenomenon.

CITATION:

Coping-Style Behavior Identified by a Survey of Parent-of-Origin Effects in the Rat

Carme Mont, Polinka Hernandez Pilego, Toni Cañete, Ignasi Oliveras, Cristóbal Río-Álamos, Gloria Blázquez, Regina López-Aumatell, Esther Martínez-Membrives, Adolf Tobeña, Jonathan Flint, Alberto Fernández-Teruel, Richard Mott

G3: Genes|Genomes|Genetics October 2018 8: 3283-3291;

http://www.g3journal.org/content/8/10/3283

https://doi.org/10.1534/g3.118.200489

Programmed ribosomal frameshifting has translational costs that may influence codon usage bias.

The genetic code has some redundancy—the same amino acid is often encoded by several codons. However, these codons are not necessarily equal in their effect, as evidenced by the codon usage bias observed in many organisms. The translation efficiency hypothesis posits that some codons are more easily translated than others, and these are the ones more commonly used. Based on this hypothesis, the codon usage bias index of a given mRNA should correlate closely with its translation efficiency—but in a report in G3: Genes|Genomes|Genetics, Garcia et al. explain why this might not always be the case.

Programmed ribosomal frameshifting (PRF) occurs when a ribosome stalls at specific sequences—appropriately termed “slippery sites”—which shifts  translation to a new reading frame. The authors were specifically interested in “-1 PRF” cases, where the ribosome moves a single nucleotide backward during translation. This phenomenon is ubiquitous across the tree of life, and it is generally used by eukaryotes as a way to regulate gene expression, but the authors wondered if it could also induce translational costs.

To test this, they used the database PRFdb to examine associations between -1 PRF signals and gene expression in yeast, determining that -1 PRF signals are less common in highly expressed genes. They also found that these signals tend to be present towards the start of open reading frames, which makes sense if the -1 PRF signals are causing translational costs—if the signals occur towards the start of the mRNA, translation is disrupted more quickly, so less energy is wasted. These lines of evidence support the idea that PRF signals do incur translational costs.

The authors then retested the association between codon usage bias and translational efficiency while accounting for the cost of -1 PRF signals. Using a set of mathematical models, they found that incorporating this data generally strengthened support of the translational efficiency hypothesis—that is, more costly transcripts were less often translated, whether the cost was incurred due to codon usage bias or -1 PRF signals. Better understanding these phenomena may help elucidate how translational efficiency is controlled.

CITATION:

Accounting for Programmed Ribosomal Frameshifting in the Computation of Codon Usage Bias Indices

Victor Garcia, Stefan Zoller, Maria Anisimova

G3: Genes, Genomes, Genetics October 2018 8: 3173-3183; https://doi.org/10.1534/g3.118.200185

http://www.g3journal.org/content/8/10/3173

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