From cats to rats: two studies on domestication and tameness

Anyone who has ever read Charles Darwin is acutely aware of his fascination with domestication – particularly how he fancied fancy pigeons. Darwin drew on his domestication obsession while writing his book, The Variation of Animals and Plants under Domestication, in which he outlined his ‘provisional hypothesis’ of pangenesis (heredity). In the century and a half since, researchers studying the domestication of plants and animals have continued to advance our knowledge of the genetic mechanisms underlying heredity and selection. Here, I interviewed the authors of two recently published studies that elegantly examined the genetics of tameness and domestication in cats and rats.

Domestic Cats:

The road to a kitten-video-dominated world began ~9.5 thousand years ago when cats first showed up in human settlements in Cyprus – thousands of years after the domestication of dogs (though the dog domestication date is hotly debated). This means that, compared to dogs, cats have been subject to artificial selection by humans for a much shorter period of time. It is possible that this explains the relatively low amount of phenotypic variation across domestic cat species (e.g., the difference between a wolf and a Chihuahua is orders of magnitude larger than the difference between a wild cat and a house cat). However, there are still clear behavioral differences between domestic cats and wild cats, which is why I wouldn’t suggest trying to cuddle with a wild cat. So what gives? Are these behavioral (and some morphological) changes reflected in the genome? How do the genetics of cat domestication compare to their counterparts, the dogs? This is where a new study by Michael Montague and colleagues comes in (Montague et al. 2014).
First, Montague et al. created a new-and-improved domestic cat reference genome by deeply sequencing the genome of a cat named Cinnamon. With this new reference genome in hand, the authors then moved to compare domestic to wild cats by sequencing genomes of 22 domestic cats (from 6 breeds) and 4 wild cats. Using this pooled sequence data, the authors probed for regions of the genome that showed signals of positive selection – regions with high divergence (Fst) from wild cats and low diversity (heterozygosity) in domestic cats. This analysis revealed a paltry number of genic regions:

“Since cat domestication is relatively recent, and since some populations of wildcats actively interbreed with populations of domesticated cats, we anticipated that the domestic cat genome and the wildcat genome would be very similar,” said Montague.

Interestingly, about half of the 12 genes that fell in these regions have a known neuronal function. These genes are implicated in memory, fear-conditioning, and stimulus-reward learning – traits that would clearly benefit any cat that wanted to live with humans. Montague said,

“We hypothesized that these differences play a role in the behavioral differences between wildcats and more docile domestic cats.”

These findings are important because it provides some support for the hypothesized role that neural crest cells might have in mammalian domestication, as predicted by the “domestication syndrome” (Wilkins et al. 2014).
Taken together, the authors findings suggest that:

selection for docility, as a result of becoming accustomed to humans for food rewards, was most likely the major force that altered the first domesticated cat genomes.

In the future, Montague plans to:

“sequence more cat breeds and wildcat populations, in the hopes of disentangling some of the questions related to the timing and origins of cat domestication. We are also very interested in other genetic characteristics in the domestic cat that relate to differences in facial and tail morphologies, the large variety of fur coloration patterns, and the various feline diseases that are comparable to diseases that affect us as well.”

In a related study on rats…
Many of us have heard of Dmitry K. Belyaev’s famous fox domestication study. What many of us don’t know is that he began a similar experiment on rats around the same time. Approximately 64 rat generations ago (i.e. since 1972), researchers have been artificially selecting a line of rats for tameness (or aggressiveness) towards humans. Each generation, the 30% most tame rats and 30% most aggressive rats are selected to breed for the next generation. This artificial selection has led to two behaviorally distinct lines of “tame” and “aggressive” rats.

In an attempt to understand the genetic underpinnings of tameness, Frank Albert and colleagues decided to generate an F2 intercross population of ~700 rats in 2009 (Albert et al, 2009). These rats spanned the continuum from tame to aggressive. With these rats in hand, the authors used genetic mapping methods to identify only two quantitative trait loci (QTL) for tameness – a surprisingly low number given the extreme behavioral differences between the “tame” and “aggressive” rat lines. One possible reason for only detecting two QTL for tameness was that they used a method (Haley Knott regression; HKR) that assumes fixation of the “tame” or “aggressive” alleles. Author, Frank Albert said,

“this would mean that all animals from the tame line are homozygous for the “tame” allele, and that all aggressive animals are homozygous for a different “aggressive” allele. This assumption holds whenever people cross inbred lines, for example in mice, yeast, worms or flies. However, our rats are not (fully) inbred: the tame and the aggressive population are both heterozygous at many sites in their genomes.”

To remedy this situation, Albert and colleagues reanalyzed their 2009 data using a newer QTL mapping method that doesn’t assume fixation – Flexible intercross analysis (FIA). This modeling approach quadrupled the number of tameness QTLs detected, from 2 to 8 QTLs. The study also measured gene expression in the brains of 150 of these rats, which allowed them to identify >600 expression QTL (eQTL) associated with tameness. Interestingly, many of these eQTL overlapped with a tameness QTL – in particular the strongest QTL (Tame-1). This suggests that selection for tame and aggressive rats has led to changes in the frequency of variants that influence brain gene expression and, likely, behavior.
Overall, co-author, Alex Cagan, said that these findings highlight:

that tameness in these rats clearly has a highly polygenic basis and that selection appears to have been acting on variants throughout the genome.

Cagan said that the next steps are:

to publish the genome-wide scans for selection that we have been performing. We want to see if the genes that we find under selection in these artificially selected lines of rats, mink and foxes are similar to the results coming out from genomic analyses of other domesticated species. If the answer is yes, it will be another level of validation that these selection experiments are a useful model for studying the process of domestication. A long term goal is to demostrate that the genes we identify contribute to behavior, and to ultimately understand the biology behind this.

Taken together, these studies highlight that the impact of domestication on the genome is not straightforward, and that complex traits, such as tameness, are not defined by just one gene.
What about regulatory variation?
Both of these studies primarily focused on regions that contained genes and a much finer resolution mapping approach is needed to pinpoint specific variants underlying domestication and tameness. Given the potential importance of variation in gene regulation in speciation, it is likely that variation in regulatory regions (e.g., enhancers) has been affected by domestication (as well as “rat-taming”).
So it looks like there is plenty to look forward to in the realm of cats, rats, and domestication.
References
Montague MJ, Li G, Gandolfi B, Khan R, Aken BL, Searle SMJ, Minx P, Hillier LW, Koboldt DC, Davis BW, Driscoll CA, Barr CS, Blackistone K, Quilez J, Lorente-Galdos B, Marques-Bonet T, Alkan C, Thomas GWC, Hahn MW, Menotti-Raymond M, O’Brien SJ, Wilson RK, Lyons LA, Murphy WJ & Warren WC (2014) Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication. Proc. Natl. Acad. Sci. doi: 10.1073/pnas.1410083111.
Heyne HO, Lautenschläger S, Nelson R, Besnier F, Rotival M, Cagan A, Kozhemyakina R, Plyusnina IZ, Trut L, Carlborg O, Petretto E, Kruglyak L, Pääbo S, Schöneberg T & Albert FW (2014) Genetic influences on brain gene expression in rats selected for tameness and aggression. Genetics 198, 1277–90 doi: 10.1534/genetics.114.168948.
Wilkins AS, Wrangham RW & Fitch WT (2014) The “Domestication Syndrome” in Mammals: A Unified Explanation Based on Neural Crest Cell Behavior and Genetics. Genetics 197, 795–808. doi: 10.1534/genetics.114.165423.
Albert FW, Carlborg O, Plyusnina I, Besnier F, Hedwig D, Lautenschläger S, Lorenz D, McIntosh J, Neumann C, Richter H, Zeising C, Kozhemyakina R, Shchepina O, Kratzsch J, Trut L, Teupser D, Thiery J, Schöneberg T, Andersson L & Pääbo S (2009) Genetic architecture of tameness in a rat model of animal domestication. Genetics 182, 541–54. doi:10.1534/genetics.109.102186.
Albert FW, Hodges E, Jensen JD, Besnier F, Xuan Z, Rooks M, Bhattacharjee A, Brizuela L, Good JM, Green RE, Burbano HA, Plyusnina IZ, Trut L, Andersson L, Schöneberg T, Carlborg O, Hannon GJ & Pääbo S (2011) Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection. Heredity (Edinb). 107, 205–14. doi:10.1038/hdy.2011.4.
Rönnegård L, Besnier F & Carlborg O (2009) Modelling dominance in a flexible intercross analysis. BMC Genet. 10, 30. doi:10.1186/1471-2156-10-30.
Haley CS & Knott SA (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity (Edinb). 69, 315–24. doi:10.1038/hdy.1992.131.