#TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

One of the earliest events in development is the switch to self sufficiency. Soon after an egg is fertilized, the new individual must activate its genome and cease relying on maternally-provided RNA, a change known as the maternal-to-zygotic transition. Epigenetic reprogramming is central to this process; epigenetic marks, including DNA methylation and histone modifications, must be completely remodeled for the zygotic genome to begin expressing its own RNA. In her presentation at TAGC, Jadiel Wasson from the Katz lab at Emory University described what happens when some of that epigenetic machinery is missing.

Wasson studies a demethylase called KDM1A that removes the H3K4me2 epigenetic mark from histones; this mark is thought to be a “memory mark” that helps daughter cells know what genes to transcribe. She and her colleagues showed that KDM1A is expressed in oocytes and in early embryos. To determine its function in development, they deleted KDM1A in mouse oocytes, meaning it was missing when the zygote was fertilized; this was lethal. They performed crosses where the male had normal KDM1A, but the female lost KDM1A in the germline. Embryos from these crosses failed to undergo the maternal-to-zygotic transition and did not survive.

Wasson then deleted KDM1A in the female germline in a way that resulted in embryos with only a partial loss of KDM1A function. The majority of these mice died during embryogenesis, but a few survived to adulthood. These animals displayed extreme obsessive-compulsive tendencies as measured by a marble burying assay; in fact, they displayed more severe obsessive-compulsive behavior than an established mouse model of OCD (see Shmelkov 2010). This provides a striking case of altered epigenetic programming at fertilization that leads to a behavioral phenotype weeks later.

Control mouse in the marble burying assay

Mutant mouse in the marble burying assay

Top: marbles before assay; Middle: marbles after control mouse; Bottom: marbles after mutant mouse

Development (M): Development and Morphogenesis.
M270 Wasson: KDM1A required for maternal-to-zygotic transition and proper genome reprogramming after fertilization

CITATIONS

Shmelkov, S.V., Hormigo, A., Jing, D., Proenca, C.C., Bath, K.G., Milde, T., Shmelkov, E., Kushner, J.S., Baljevic, M., Dincheva, I., Murphy, A.J., Valenzuela, D.M., Gale, N.W., Yancopoulos, G.D., Ninan, I., Rafii, F.S.L.S. 2010. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice. Nat Med, 16:598-602. doi: 10.1038/nm.2125 http://www.nature.com/nm/journal/v16/n5/full/nm.2125.html

Wasson, J.A., Simon, A.K., Myrick, D.A. Wolf, G., Driscoll, S., Pfaff, S.L., Macfarlan, T.S., Katz, D.J. 2016. Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally. eLife, 5e:08848. doi: 10.7554/eLife.08848 https://elifesciences.org/content/5/e08848

Guest post by Mathieu Hénault. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

Most traits are controlled by more than one gene, and interactions between the effects of genes (GxG) can modify phenotypes in a non-additive manner; this phenomenon is called epistasis. Results presented by David M. Rand at The Allied Genetics Conference support the idea that phenotypes may be under an even more complex control: GxG interactions can depend on the environment (E), giving rise to higher-order GxGxE interactions.

Rand’s team looked at GxG interactions between nuclear and mitochondrial genomes (mitonuclear interactions). Defects in these interactions are known to cause many human diseases. The team engineered a panel of Drosophila fruit flies that have mitochondria from foreign strains, creating new combinations of previously unmatched nuclear and mitochondrial genomes. They grew these strains on four different types of food and observed extensive phenotypic variation among mitonuclear genotype combinations (GXG), notably in development time. In some cases, time required for pupae eclosion for a particular mitonuclear genotype varied strikingly with the diet of the flies, revealing the presence of GxGxE interactions.

This study suggests that, for a gene to produce a phenotype, the challenge of interacting with different environments may be as great as the challenge of interacting with related genes. This layer of interactions goes beyond the complexity introduced by epistasis and makes the course of evolution harder to predict. The results also suggest the success of mitochondrial replacement therapies will likely depend on interactions between source mitochondrial genotypes and recipient’s nuclear genotypes, which may themselves depend on the environment experienced by each individual.

TAGC Program Number P396

Can epistasis or GxE be predictable? Lessons from mitonuclear interactions in Drosophila.

D.M. Rand, J. A. Mossman, L. A. Biancani, C.-T. Zhu. Brown Univ, Providence, RI.

Article : http://www.genetics.org/content/203/1/463

Mathieu Hénault

About the author:

Mathieu is an undergraduate student in Dr Christian R. Landry’s lab at Université Laval (Quebec City, Canada). His research interests are mitonuclear interactions and microbial speciation. http://landrylab.ibis.ulaval.ca/

Guest post by Caroline Berger. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

You might remember the flickering cilia of little Paramecia  from the classroom, where these ciliate species can be easily observed with a binocular microscope. Historically, Paramecium has been used to study processes such as mating-type inheritance and phagocytosis. However, thanks to the emergence of new genetic tools, the genome of Paramecium is now under the microscope.

Sequencing the genomes of several members of the Paramecium aurelia complex, a group of 15 species, revealed that these ciliates encode 40,000 protein-coding genes—that’s twice as many as humans! This abundance of genes is the result of three Whole-Genome Duplications (WGD). Although this kind of duplication is common in eukaryotes, most of the duplicates are thought to eventually be lost through the accumulation of mutations that destroy function.

Results presented at The Allied Genetics Conference reveal that in some cases, Paramecium has retained both genes in a duplicate pair for long stretches of evolutionary time. What evolutionary forces could have prevented duplicated gene loss? In his talk, Jean-Francois Gout (Indiana University) proposed a model based on dosage constraints. Genomic and transcriptomic analysis of three P. aurelia species demonstrated that both copies are retained as long as they maintain constant total expression levels (summed over the duplicates). The first step towards gene loss would be expression level divergence: once a threshold of imbalance is reached, the copy with the lowest expression can be lost because its deletion will not impact the total amount of proteins produced. Similar results in yeast species confirmed these conclusions: the fate of many duplicated genes is a random walk along the line of conserved total expression level. This study also highlights the importance of ciliates; from classrooms to the lab, these emergent model organisms allow us to better understand the forces driving genome evolution.

TAGC Program Number C13

Maintenance and loss of duplicated genes by dosage subfunctionalization in Paramecium.

Jean-Francois Pierre Gout
Indiana University
Article: http://mbe.oxfordjournals.org/content/32/8/2141

Caroline Berger

About the author: Caroline Berger is a PhD student at Université Laval, Québec, interested in the evolution of protein interactions. She loves writing – from science news to short stories. Twitter: @BergerCaroline5

Guest post by Deepika Vasudevan. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

The microbes in our guts seem to affect almost every aspect of human health, from the obvious (e.g. metabolism¹) to the unexpected (e.g. behavior²). Several of these paradigms have stemmed from studies in model organisms that have been later validated in humans. This year, The Allied Genetics Conference featured a workshop on the gut microbiota of the fruit fly, Drosophila. One interesting study presented in the session revealed that the gut microbiota alters host alcohol metabolism and sensitivity.

Results presented by Malachi Blundon, a graduate student in the McCartney and Minden laboratories at Carnegie Mellon University, showed that “germ-free” flies, which lack a microbiota, have decreased sensitivity and increased tolerance to alcohol. Alcohol sensitivity and tolerance in humans and Drosophila is controlled in part by the enzyme Alcohol Dehydrogenase (ADH), which metabolizes potentially harmful alcohols into useful aldehydes. Human ADH mutations, commonly found in Eastern Asian populations, decrease both alcohol tolerance and the risk of dependence. Furthermore, people with alcoholism have been reported to have an altered microbiota. The causal relationship between this “dysbiosis” and alcoholism is unknown.

Blundon and his colleagues found that germ-free flies have a higher level of ADH in their heads compared to control flies. Without their gut microbiota, the flies remained mobile significantly longer after exposure to ethanol vapor, and were less likely to die after repeated alcohol exposure. When germ-free flies had their microbiome restored, their ethanol sensitivity returned to levels similar to the control group. Ongoing studies in their lab include examining whether the microbiota also affects alcohol preference in Drosophila and identifying the specific microbe that mediates the alcohol response.

Blundon hopes these studies will provide insight into the possible roles that the microbiota have on alcohol metabolism and alcohol abuse disorders.

Drosophila gut stained for Lactobacillus brevis (magenta) using fluorescent in situ hybridization (FISH), and for gut cell nuclei (blue). A type of simple alcohol exposure chamber can be used to test for alcohol sensitivity and tolerance in Drosophila. Images courtesy of Scott Keith and Malachi Blundon, McCartney Lab, Carnegie Mellon University.

TAGC Workshop: Drosophila Microbiota
Organizers: Brooke McCartney, Carnegie Mellon University; and Will Ludington, University of California, Berkeley
The microbiota affects ADH protein level and influences alcohol sensitivity in Drosophila
Malachi Blundon, Carnegie Mellon University, McCartney Lab

CITATIONS

1. Mikkelsen, K. H., Allin, K. H. & Knop, F. K. Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature. Diabetes Obes Metab 18, 444–453 (2016).
2. Dinan, T. G. & Cryan, J. F. Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome. Neuropsychopharmacology (2016). doi:10.1038/npp.2016.103

Deepika

About the author: Deepika Vasudevan is a postdoctoral researcher at NYU Medical Center who uses Drosophila to understand the effects of physiological stress on innate immunity, lifespan, and more. Follow her stream of scientific consciousness on Twitter @dvasudevan.

Guest post by Christian R. Landry. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

When building new phenotypes, evolution often draws on mutations of the intricate mechanisms that regulate gene expression. If such regulatory mutations are  associated with the affected genes themselves, they are known as cis regulatory mutations; if the mutations are associated with other genes they are said to act in trans. One trick that researchers have used to differentiate these two effects is to create F1 hybrids between their strains of interest, in which they can follow the expression of two alleles independently. Unequal expression of the two alleles reveals the influence of cis acting mutations. Most studies so far have measured mRNA abundance at steady state and have shown that mutations affecting how much mRNA is present are frequent within and between species. However, survival in a changing environment may depend less on the amount of mRNA produced and more on the time it takes to produce it.  But until recently it was largely unknown whether cis acting mutations also affect the timing of gene expression. Ching-Huah Shih, a postdoctoral fellow working with Justin Fay at Washington University, is exploiting the hybrid approach to learn whether cis regulatory variation that affects the dynamics of induction occurs in budding yeast populations and species.

To do so, he measures genome-wide mRNA abundance along a time-course of gene expression induction in hybrids. In a talk presented at the workshop on yeast diversity of the GSA Yeast Genetics Meeting, Ching-Hua showed that cis regulatory variation affecting induction dynamics is as abundant as variation affecting steady-state levels. One major question that emerges from this observation is whether dynamics and steady state levels can be optimized independently from each other by natural selection. Ching-Hua provided a partial yet key answer to this question by showing that species differences in steady-state levels are significantly associated with nucleotide substitutions in the promoter regions, whereas the dynamics are associated with insertions and deletions. Yeast promoter regions are rich in simple sequence repeats that evolve fast by gaining and losing repeat units. Natural selection may thus have plenty of variation to play with to fine-tune gene expression dynamics. One important challenge ahead will be to examine whether natural selection prefers tuning gene expression timing rather than abundance.   

P2068B Cis-acting variation in gene expression dynamics within and between Saccharomyces species. Ching-Hua Shih.

TAGC16 Workshop: Beyond cerevisiae: Exploiting yeast diversity in nature to understand genome evolution in diverse environments Organizers: Christian Landry, Universite Laval, Quebec, Canada, and Judith Berman, Tel Aviv University, Israel.

About the author: Christian R. Landry, Université Laval. Christian is doing research in evolutionary systems biology. You can follow him on twitter: @landrychristian and follow the work of his team at http://landrylab.ibis.ulaval.ca/

Guest post by Tyler Kent. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

Purging harmful mutations is the most common task of natural selection. In non-recombining populations this background selection process represents the “survival of the fittest” in action, but this genetic housekeeping also lowers a population’s genetic diversity. While traditional methods for modeling background selection typically assume that all harmful mutations have the same effect on fitness and undergo the same strength of selection, a new method presented at The Allied Genetics Conference aims to more accurately understand this process and its effects.

By considering the total fitness cost of harmful mutations in an individual, Ivana Cvijović (Harvard University) showed she can infer whether individuals in a sample were recent ancestors of each other or instead came from more distant historic lineages. When considering an individual’s fitness cost, its ancestor would have had a higher fitness that can be found by incorporating both the costs of all possible mutations and the chance of finding an ancestor at the correct fitness level. The inferred lineage structure can then reveal when an individual in the past had accumulated too many harmful mutations—a bubble of fitness cost which burst when it had become too unfit to survive.

When extended back in time, this bubble coalescent method can reconstruct the genealogy of populations that have experienced background selection of varying strengths and can accurately estimate their current diversity. Cvijović hopes that her method will help us to understand more of the nuances of background selection, many of which are lost using current methods.

The inference of fitness states of an individual’s ancestors, and the genealogy that results. Courtesy Ivana Cvijovic.

TAGC Program Number P367:
The genetic diversity of a population experiencing selection.
Ivana Cvijovic; Benjamin Good; Michael Desai
Harvard University, Cambridge, MA

About the author: Tyler Kent is a graduate student in the Wright Lab at the University of Toronto studying the evolution of genetic load. Follow him on twitter at @tylervkent.

Guest post by Julia Kreiner. #TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

A common perception of evolution sees only slow and consistent genetic change over thousands of generations. But geneticists are increasingly shedding light on examples of evolution over ecological timescales — genes tracking changes in the environment. At The Allied Genetics Conference, Emily Behrman (University of Pennsylvania) revealed that adaptation can occur even faster than we may have expected. Her findings show changes in the frequency of Drosophila life history phenotypes and the underlying genes are associated with changes in selection pressures between seasons.

In Behrman’s long-term data set, allele frequencies and the fitness of phenotypes change seasonally, on a scale comparable to the differences caused by living in distant geographic regions. During the summer, phenotypes that can exploit the undemanding conditions are favored, but winter selects for those that can best withstand harsher conditions. This is seen as stabilizing selection over years. Traditional examinations that use such longer time scales would detect only stabilizing selection, masking the finer scale fluctuating dynamics. Behrman interprets these dynamics of selection as playing an important role in maintaining variation in natural populations. This principle is likely true not only in fruit flies but across a wide variety of taxa.

Allele frequency change at ∼1750 seasonal SNPs. From Bergland et al.

TAGC Program number P332

Dynamics of seasonal adaptation in Drosophila melanogaster.

Emily L. Behrman¹, Alan O. Bergland^2,3, Dmitri A. Petrov², Paul S. Schmidt¹.

1) University of Pennsylvania, Philadelphia, PA; 2) Stanford University, Stanford, CA; 3) University of Virginia, Charlottesville, VA.

Further reading:  http://onlinelibrary.wiley.com/doi/10.1111/jeb.12690/abstract

About the author: Julia Kreiner is a graduate student at University of Toronto studying the rapid adaptation of herbicide resistance, a burnt out athlete, and a nature lover.

#TAGC16 Shorts are brief summaries of presentations at The Allied Genetics Conference, a combined meeting of seven genetics research communities held July 13-17, 2016 in Orlando, Florida.

Elbows, knuckles, and the other synovial joints in your body are mobile marvels of evolution. These joints allow a huge range of possible movements thanks to the presence of a cavity between the articulating bones that is lined by smooth cartilage and filled with a lubricating fluid. This elaborate structure, however, is highly susceptible to wear-and-tear, and inflammation of synovial joints leads to painful arthritis. Results presented at The Allied Genetics Conference last week reveal that, contrary to a widely held view, fish have synovial joints. The results reveal that these joints evolved before the last common ancestor of all bony vertebrates, opening up a promising new avenue for arthritis research.

Synovial joints were widely thought to have evolved as fish left the water and became tetrapods (amphibians, reptiles, birds, and mammals), and to be absent in ray-finned fish, the largest taxonomic group of vertebrates. Joanna Smeeton (University of Southern California) presented evidence for the hallmarks of synovial joints in the jaw hinge and pectoral fin joints of zebrafish, three-spine stickleback, and spotted gar, which are three ray-finned fish species separated by hundreds of millions of years of evolution.

These fish joints are freely movable and surrounded by a joint capsule, with articulating bones separated by a cavity. The cells lining the cavity express a proteoglycan known to lubricate synovial joints. Mutating the gene encoding this lubricant caused zebrafish to develop progressive deterioration of the jaw and fin joints, similar to the effect on mouse and human synovial joints of mutations in the homologous genes. Smeeton hopes a zebrafish model of synovial joint development and degeneration could provide important insights into arthritis and how this widespread chronic disease might be treated.

Adult zebrafish jaw joint stained with alcian blue (cartilage) and alizarin red (bone). Courtesy Joanna Smeeton.

TAGC Program Number Z589:

Fish synovial joints as new models for joint development and disease.

Joanna Smeeton¹ Amjad Askary ¹ Sandeep Paul ¹ Simone Schindler¹; Ingo Braasch^2,3; Nicholas A. Ellis⁴; John Postlethwait²; Craig T. Miller⁴; Gage Crump¹

¹University of Southern California, Los Angeles, CA; ²University of Oregon, Eugene, OR; ³Michigan State University, East Lansing, MI; ⁴University of California, Berkeley, CA.

Further reading: https://elifesciences.org/content/5/e16415