A new associate editor is joining G3: Genes|Genomes|Genetics. We’re excited to welcome Emily Clark to the editorial team.

Emily Clark
Associate Editor

Emily Clark is a research group leader at the Roslin Institute, University of Edinburgh, in Scotland. Her research group provides highly annotated genomes for farmed animals as resources to inform genome editing, genomic selection, and fundamental biology. She has a particular interest in how the genome is expressed and regulated across tissues and developmental stages and in different populations of sheep and goats. Using this information she is working towards improving the link between genotype and phenotype in these species, in both tropical and temperate regions of the globe. Recently, she led a white paper describing the next decade of research priorities for the global Functional Annotation of Animal Genomes Consortium (FAANG). She is also co-coordinator of the EuroFAANG Research Infrastructure project which aims to provide access to sustainable genomic resources for farmed animal genotype and phenotype research across Europe.

A new study reveals genetic changes that affect social behavior in chickens.

We have a number of phrases that relate human behavior to that of chickens; for example, when you accuse someone of acting “chicken,” you’re likely calling them a coward. If someone is running around like a chicken with their head cut off, they’re probably frantic and disorganized. The reality of chicken behavior is, of course, more complex than these cliches; chickens naturally live in groups and exhibit many of the same social behaviors that other animals do, like anxiety and seeking out friends. Some chickens are more sociable than others, but what accounts for this difference? In a report published in GENETICS, Johnsson et al. analyzed the genes and behavior of chickens to find out.

The authors were specifically interested in social reinstatement (SR) in chickens. Social reinstatement measures how sociable a bird is; it is calculated by removing a chicken from its fellows and observing how long it takes to seek them out again. The authors performed this test on hundreds of chickens who were also genotyped with a SNP array. They identified correlations between genetic and phenotypic differences using quantitative trait locus analysis. The authors also analyzed gene expression in the chickens’ hypothalamuses—which play an important role in behavior and sociality—to bolster their findings.

A number of SNPs correlated with different social reinstatement scores. For example, differences in the gene TTRAP, which is associated with neurodegeneration and early-onset Parkinson’s disease, strongly correlated with differences in SR. Other neuron-associated genes, like PRDX4, also had correlations with SR—as were some genes that, until now, had never been associated with neurology or behavior.

These findings are correlative, and further research will be needed to prove a causal link between the identified genes and behavior. However, by identifying a list of candidate behavior-related genes, researchers have promising places to start looking for causal links, rather than running around like… well, you get it.

CITATION:

Genetics and Genomics of Social Behavior in a Chicken Model

Martin Johnsson, Rie Henriksen, Jesper Fogelholm, Andrey Höglund, Per Jensen, Dominic Wright

GENETICS Early online March 12, 2018; DOI: 10.1534/genetics.118.300810

http://www.genetics.org/content/early/2018/03/12/genetics.118.300810 

Over twenty years ago, somatic cell nuclear transfer (SCNT) let scientists successfully clone the first mammal—Dolly the sheep. Despite advances since then, the efficiency of this process remains low. In the July issue of G3, Srirattana and St. John report a method to deplete cattle donor cells of mitochondrial DNA and efficiently generate blastocysts from these depleted donors.

In SCNT, a nucleus taken from a mature, differentiated somatic donor cell is placed into an oocyte whose nucleus has been removed. Together, this newly created cell goes on to form an embryo whose nuclear genome is identical to the donor cell’s. The low efficiency of SCNT is thought to be partially due to incomplete epigenetic reprogramming of the new embryo. In fact, treatment of embryos with the histone deacetylase inhibitor trichostatin A (TSA) is widely used to enhance SCNT in mouse.

Nuclear DNA isn’t the only genetic information in the cell, though. Mitochondria house a distinct genome that is maternally inherited, and mitochondrial DNA (mtDNA) from donor cells can be randomly transmitted from the donor cell to the embryo. The mixing of mtDNA from the two initial cells complicates the process of SCNT.

Normally, an organism inherits its mtDNA from its mother, but SCNT embryos have two different sets of mtDNA—donor cell and oocyte—to deal with, and the interplay between the two can cause genomic instability, aneuploidy, poor embryo quality and implantation rates, and metabolic defects.

To combat this problem, Srirattana and St. John depleted the mtDNA from cattle donor cells by using 2’,3’-dideoxycytidine (ddC), which inhibits the mtDNA-specific DNA polymerase gamma but doesn’t affect nuclear DNA. They compared embryos made from mtDNA-depleted cells to nondepleted cells, and they looked at the effect of TSA treatment on both depleted and nondepleted cells.

They found that mtDNA-depleted donor cells can generate viable blastocysts that contain only oocyte mtDNA—as is the case in blastocysts formed by sperm fertilization. Donors depleted of mtDNA had a lower rate of blastocyst generation than nondepleted cells, but the use of TSA brought the blastocyst rate back to that of nondepleted donors. Srirattana and St. John also showed that gene expression differed between blastocysts created from depleted and nondepleted cells; they found that differentially expressed genes were largely involved in embryonic development, suggesting the use of mtDNA-depleted donor cells can alter development of the cloned embryos.

This work demonstrates that depleting mtDNA from donor cells is an effective tool for creating SCNT embryos with mitochondrial genomes inherited only from the oocyte. Such embryos will hopefully avoid some of the problems created by mixing incompatible mitochondrial genomes and may one day make SCNT easier and more efficient for cattle scientists and others who rely on this cloning technique.

CITATION:

Manipulating the Mitochondrial Genome To Enhance Cattle Embryo Development
Kanokwan Srirattana, Justin C. St. John
G3: Genes, Genomes, Genetics July 2017 7: 2065-2080;
https://doi.org/10.1534/g3.117.042655
http://www.g3journal.org/content/7/7/2065

Humans built the modern world with the help of domestic plants and animals. A byproduct of our many domestication experiments is a series of excellent long-term controlled evolutionary comparisons that are helping geneticists understand adaptation. In a study published in the May issue of G3, Fleming et al. identify genomic regions under natural selection in indigenous African and European chicken populations that optimize survival in these very different environments.

Commercially raised chickens have been bred to thrive in the highly controlled environment of modern farms, but domesticated chickens have been living with humans in different regions across the globe for thousands of years. Heritage chicken breeds that are specific to certain geographic areas still carry the traits selected for in their ancestors that allow them to survive in harsher conditions. The authors of this study chose collections of such chickens from Northern Europe, where farm animals must endure cold and snow, and from Africa and the Middle East, where extremely high temperatures are the main obstacle for survival.

After genotyping a large sample of African and European chickens at a selection of SNPs across the whole genome, they used patterns of variation to identify regions associated with the ability to survive stressful temperatures. They found large genomic regions on three different chromosomes that were significantly different between the two populations of chickens and looked at variation within the groups to identify genomic regions that appeared to be under selection.

The authors found different genome regions were under selection in African and European chickens, showing that the basis of adaptation to these very different environments is genetically distinct. In African chickens, a large region on chromosome 27 stood out as significant in all analyses. This region includes several genes that have been previously implicated in heat stress responses in other animals. Some are linked to heart function and blood vessel formation, which may help these animals thrive in high temperatures.

In Northern European chickens, significant regions were scattered across several chromosomes, with one large region on chromosome 2. One gene in this area has been shown to alter feathering patterns, suggesting that changes to the birds’ plumage might give them an advantage in the cold through improved ventilation or insulation. Additional candidate genes linked to insulin secretion and other metabolic activities suggest that energy regulation could promote the ability to tolerate cold.

Though the birds in this study are not maintained commercially, understanding what makes them suited to their environments may have important implications for mainstream chicken farmers. Current commercial chickens are more susceptible to environmental stress than these distant relatives, and the threat of climate change means they may have to adapt quickly.

CITATION

Genomic Comparison of Indigenous African and Northern European Chickens Reveals Putative Mechanisms of Stress Tolerance Related to Environmental Selection Pressure

Damarius S. Fleming, Steffen Weigend, Henner Simianer, Annett Weigend, Max Rothschild, Carl Schmidt, Chris Ashwell, Mike Persia, James Reecy and Susan J. Lamont

G3: Genes, Genomes, Genetics May 1, 2017 vol. 7 no. 5 1525-1537; https://doi.org/10.1534/g3.117.041228

http://www.g3journal.org/content/7/5/1525

Like any revolutionary technology, domestic horses changed human society. The incredible speed and strength of these animals opened up new opportunities to spread trade, language, and culture. For thousands of years, horses have been helping build human society by pulling wagons and plows and carrying soldiers and travelers on their backs. Horse husbandry changed humanity, but along the way we changed horses too.

A new review paper by Pablo Librado and colleagues in the October issue of Genetics tells the story of how the modern horse came to be. They track the genetic changes that led from wild horses living on the Eurasian steppes 5,500 years ago to the many highly specialized breeds of domestic horse that exist today.

Modern horses have been shaped into distinct breeds with different talents and specialties. Compare a racing thoroughbred with a draft horse like a Clydesdale —they’re extremely different animals now, but they both descend from the same ancestral group of wild horses. Comparing the DNA variation of all different kinds of domestic horses and their only living wild relative, Przewalski’s horse, can reveal the genetic changes that occurred during domestication. Librado and colleagues emphasize that another crucial tool used for tracing the horse lineage is ancient DNA, which is extracted from bones of animals that have been dead for thousands of years. The oldest successfully extracted DNA came from the skeleton of a wild horse that lived in the Yukon between 560,000 – 780,000 years ago. Such samples are especially important because there are very few wild horses left alive, and modern horse breeding practices have obscured the genomic signature of early domestication qualities like geography. Thanks to data from ancient DNA, geneticists have learned that a previously unknown group of now-extinct wild horses were also ancestors to modern horses.

Remarkably, the majority of Y-chromosomes carried by modern domestic horses can be traced back to just a few stallions. This could be because only a few males were originally used in domestication, but it could also result from carefully controlled modern breeding practices where a single male sires a huge number of offspring. The ultimate cause of this very low Y-linked diversity is still debated, but strict selective breeding has almost certainly contributed. In contrast, a much larger number of females than males contributed ancestry to domestic horses. According to Librado and colleagues, it seems that wild mares were continuously introduced into human-controlled herds throughout the process of domestication.

Turning a wild animal into a domestic one that will tolerate humans involves a long process of selecting for traits like docility and friendliness. In the case of hard-working horses, desirable traits also included strength, endurance, and gait. This kind of selective breeding leaves a very clear mark in the genome.  By comparing the genomes of modern domestic horses with very ancient domestic horses, geneticists were able to identify many genes linked to selected traits, including genes involved in coat color, skeletal structure, the circulatory system, and brain development and behavior.

Photo by Softeis via Wikimedia. The speed and stamina of modern racing thoroughbreds are the results of extensive artificial selection.

Similarly, comparing modern breeds can identify the genes that make each breed so different. Librado and colleagues describe how scientists have used this approach to identify gene variants involved in the superior racing ability of thoroughbreds and alternative gaits like those used in competitive jumping and dressage. Lesser known traits have also been investigated, like extreme cold tolerance in Yakutian horses. Their ability to survive harsh Siberian winters has been linked to genome regions that influence coat hair density and metabolism. Many domestic breeds suffer from a high frequency of inherited illnesses due to harmful gene variants being inadvertently selected alongside a beneficial trait. Genetic work has identified the genetic cause of muscle defects in Belgian draft horses, which interestingly enough may have once been a beneficial trait under the harsher conditions of its working past.

In many ways, understanding the history of horses is a vital part of understanding our own story. Yet many traditional horse breeds are now endangered, and unanswered questions about the genetics of horse domestication remain. In this review, Librado and colleagues urge haste to conserve this source of unique variation before it is too late.

Librado, P., Fages, A., Gaunitz, C., Leonardi, M., Wagner, S., Khan, N., Hanghøj, K., Alquraishi, S., Alfarhan, A., Al-Rasheid, K., Der Sarkissian, C., Schubert, M., & Orlando, L. (2016). The Evolutionary Origin and Genetic Makeup of Domestic Horses. Genetics, 204(2), 423-434. DOI:10.1534/genetics.116.194860

http://www.genetics.org/content/204/2/423.article-info

In 1931, Sewall Wright—a quiet American geneticist specializing in livestock and guinea pigs—published a GENETICS paper that changed how we study evolution. Wright’s “Evolution in Mendelian populations” was one of the founding documents of population genetics and was among the first formal frameworks to reconcile Mendel’s laws of inheritance with Darwin’s vision of natural selection. In the January 2016 issue of GENETICS, Senior Editor Nick Barton introduces Wright’s 1931 opus as one of the journal’s 100th anniversary Classics.

In the paper, Wright used mathematics to describe how genetic variation in a population is affected by migration, mutation, selection, and chance (genetic drift). He then applied these equations to argue for his “shifting balance” theory of evolution, an idea he would pursue and defend for more than fifty years.

In this theory, the optimal conditions for adaptive evolution occur only in large populations subdivided into partially-isolated groups. In the smaller subpopulations, genetic drift has an outsized influence that allows these groups to diverge more rapidly. Those subpopulations that happen onto a more adaptive combination of allels than the population as a whole will then spread and take over. In 1932 he presented an influential metaphor to accompany this theory – the famous “adaptive landscape” of fitness peaks and maladaptive valleys traversed by evolving populations. Large, freely mixing populations tend to get trapped in locally adaptive peaks, he argued, while subdivided populations can more efficiently explore the broader landscape of gene combinations.

A modern example of an adaptive landscape visualization. Height represents fitness, and the X and Y axes represent genotype. The colored lines represent different paths that a population could follow while evolving. “Visualization of two dimensions of a NK fitness landscape” by Randy Olson. CC BY-SA 3.0.

Though a theoretical work, Wright’s shifting balance theory was profoundly shaped by his immersion in the pragmatics of commercial animal breeding. “Evolution in Mendelian populations” was written as Wright was finishing up ten years as senior “animal husbandman” at the US Department of Agriculture, where he had developed sophisticated statistical tools to examine the Department’s extensive breeding records.

For example, he revealed that the shorthorn cattle breed had developed by patchwork change: bulls from a handful of the best herds were used to improve the whole breed. Wright argued that something similar would happen in evolution of natural populations.

Decades of careful observations of guinea pigs also inspired several aspects of his theory, including the power of genetic drift to drive differentiation between small populations. In a 1977 speech he described some of the extreme differences between stocks that had been inbred in parallel for many years:

“The very large animals of one strain (No. 13) had such short legs that they seemed to glide on the floor like oversized planarians. The small animals of strain No. 2 had legs as long or longer than the preceding and ran well off the floor. Those of strain No. 13 had rounded noses and bent ears. Those of No. 2 had pointed noses and erect ears. Those of strains No. 39 had notably swayed backs. Strain 35 had protruding eyes; strain 13 sunken ones. […]There were notable differences in temperament. The pigs of strain 13 could be picked up like sacks of meal while those of strains 2 and 35 would struggle and kick a hole in one’s wrist unless picked up properly.”

To Wright, these “cumulative accidents of sampling” demonstrate how small populations would be able to drift away from a locally adaptive peak in the fitness landscape, across a saddle to scale an even higher peak.

Wright in 1928, shortly after moving from the USDA to the University of Chicago. From Hill (1996).

Shifting balance theory was influential, but far from uncontested. It fueled a famous, life-long, and sometimes bitter conflict with another population genetics pioneer, R.A. Fisher, a debate that has continued in the field even after Wright’s death in 1988.

Wright was also one of the founders of the Genetics Society of America, serving as its third president (in 1934), and was a notoriously thorough reviewer for GENETICS. Read more about Wright’s work and life (including his ability to monologue about certain topics, among them guinea pigs) in Jim Crow’s affectionate obituary.

Read more on 100 years of GENETICS here at Genes to Genomes.

Browse the GENETICS Centennial collection at the journal website, with new content each month.

CITATIONS

Wright, S. (1931). Evolution in Mendelian populations. Genetics, 16(2), 97.
http://genetics.org/content/16/2/97.full.pdf+html

Barton, N. H. (2016). Sewall Wright on Evolution in Mendelian Populations and the” Shifting Balance”. Genetics, 202(1), 3.
http://genetics.org/content/202/1/3 Doi: 10.1534/genetics.115.184796

Chickens that “chicken out” in unfamiliar surroundings may shed light on anxiety in humans, according to research published in the January 2016 issue of the journal GENETICS.

Domestic chickens are much less anxious than their wild cousins, the red junglefowl. The new research identifies genes that contribute to this behavioral variation and reveals that several of the genes influence similar behaviors in mice. The authors argue that these results, combined with evidence from studies in humans, demonstrate the potential of the chicken to serve as a powerful model for understanding the genetic underpinnings of human behavior.

“By necessity, human genetic studies of behavior often focus only on susceptibility to a mental health disorder. But what about more subtle differences in behavior? For example, what makes one person a little more anxious than others? And what makes someone a little bolder?” said study leader Dominic Wright, of Linköpings University in Sweden. “Animal models like the chicken allow us to address questions like these using controlled breeding experiments.”

But why choose the chicken as a model for anxiety? One reason is to take advantage of a “natural” genetics experiment, the transformation of red junglefowl in Asia into the modern domestic chicken. After thousands of years of breeding, the barnyard chicken has a different temperament to its jungle-dwelling counterpart: the chicken is more tame and less anxious. Anxiety behaviors in animals are typically measured by observing their activity in a brightly-lit, featureless space that they have never encountered before (an “open field test”). In this setting, wild junglefowl spend most of their time either frozen with fear or darting around rapidly. They also avoid the exposed center of the test arena. Domestic chickens, in contrast, move around the whole area at a less erratic pace.

In addition, the chicken genome has properties that can make it easier to study than the human or mouse genomes. It is relatively small—around a third the size of the mouse genome—and it is grouped into smaller linkage disequilibrium blocks. These blocks are groups of neighbouring genes that tend to be inherited together, rather than being split up during recombination at each generation. Having smaller chunks gives researchers greater resolution in pinpointing genome regions associated with a trait.

To look for genome regions that contribute to variation in anxiety behaviors, the researchers performed a quantitative trait loci (QTL) analysis on the hybrid offspring of White Leghorn domesticated chickens and red junglefowl (using an experimental design called an eighth generation advanced intercross). The hybrid birds inherited a patchwork of gene variants from their chicken and junglefowl ancestors and varied widely in their anxiety levels as measured by the open field test. By correlating the behavior and genome data for each bird, the team identified fifteen QTLs that contributed to the variation in behavior.

Each of these genome regions included many genes, so the next step was to hone in on specific genes of interest. The team narrowed down the search by examining the candidate genes’ activity in the hypothalamus, a region of the brain involved in regulating anxiety. The team examined expression QTLs—sequence variants that affected hypothalamic expression of a nearby gene— that were located within one of the behavior QTLs. These were considered plausible causal variants if they influenced gene expression in a pattern that correlated with the behavioral variation. For instance, the expression QTL might confer low expression of the candidate gene in individuals with high anxiety or vice versa.

Ten genes that fit these criteria were identified, of which six have previously been shown to have functions related to behavior. For example the gene ADAM10 is needed for embryonic brain development and protection against amyloid plaques in neurodegenerative disease, and influences learning and memory.

They then tested whether these ten genes also influenced behavior in studies of mice and humans. The mouse data came from a massive ongoing breeding experiment called the Mouse Heterogeneous Stocks cross, which includes behavioral data from open field tests just like those used in the chicken study. Four genes identified in the chicken data were also associated with anxiety behaviors in mouse. In several cases, the genes influenced the same aspect of the open field test —activity— for both mouse and chicken.

The candidate genes were also examined in data from human genome-wide association studies (GWAS). Three genes were associated with schizophrenia or bipolar disorder. Although anxiety behaviors were not directly measured in the human studies, the authors argue that results for other disorders may be revealing. For instance, a large proportion of people with bipolar disorder have diagnosed anxiety disorders. There may also be some complex overlaps between schizophrenia symptoms and anxiety behaviors.

Using data from animal experiments to explore human GWAS in this way can help detect associations that would otherwise be difficult to distinguish from statistical noise, says Wright. Because GWAS often include huge numbers of markers, they must be analyzed using very stringent significance thresholds that could obscure true associations.

“Though we can’t yet prove these genes have equivalent functions in chicken and humans, the data certainly raise the intriguing possibility that genes controlling variation in behavior can be remarkably conserved between a whole variety of species,” said Wright. “Understanding the genetics underlying the chicken results may provide fundamental insights into animal behavior, including normal behavioral variation in humans.”

CITATION

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior
Martin Johnsson, Michael J. Williams, Per Jensen, and Dominic Wright

Genetics, 202 (1), 327–340
http://www.genetics.org/content/202/1/327
http://dx.doi.org/10.1534/genetics.115.179010