The red fox (Vulpes vulpes) has been the subject of a controlled breeding experiment in Russia, at the Institute of Cytology and Genetics of the Russian Academy of Sciences, to select for genetic determinants associated with domestication (principally, friendliness towards human beings; see, Dugatkin and Trut, 2017, How to Tame a Fox (and Build a Dog), University of Chicago Press).  The success of this program has provided a comparator for genetic experiments with conventional farm-bred red fox populations and aggressive foxes to identify these genes, as recently reported by an international group in Nature Genetics (see "Red fox genome assembly identifies genomic regions associated with tame and aggressive behaviours").  This study provides an interesting contrast with an earlier comparison (from a different group) between genomic DNA of the ancestral domesticated cat species, Felix sylvestris sylvestris and the common house cat Felis catus (see "Domestic Cat Genome Sequenced").

In summary, the comparative study identified 103 chromosomal regions "with either significantly decreased heterozygosity in one of the three populations or increased divergence between the populations."  One particularly strong candidate to be a genetic determinant of "tame" behavior was identified as SorSC1, encoding the primary trafficking protein for AMPA glutamate receptors and neurexins in fox brain.  This result "suggests a role for synaptic plasticity in fox domestication," which seems reasonable.  Interestingly, other genes "likely to have been under selection" include those associated with neurological disorders in human beings, as well as genes previously identified as being involved in mouse behaviors and domestication in dogs (providing a compelling natural control group; the lineages of domesticated dogs and the red fox diverged about 10 million years ago, prior to domestication of Canis familiaris from the grey wolf about 15,000 years ago).  As the study notes, "[t]here is no evidence that the fox was domesticated historically," and indeed the fox has evolved to have the broadest geographic range of any member of the Carnivora.

The study involved genomic DNA sequence comparisons of farm-bred foxes (which, while not still wild continue to exhibit fear or aggression towards humans) and two subsets of such foxes conditioned in diametrically opposed fashion for positive response to humans or aggression towards humans.  These animals have remained outbred throughout their development (~50 generations for friendly foxes and ~40 generations for unfriendly ones) and the foxes were otherwise not selected for any other traits (a distinction with the numerous dog breeds selected for many desired traits).  The genomic structure of foxes differs from the domesticated dog:  foxes have 16 pairs (38 pairs for dogs) of acrocentric (metacentric for dogs) autosomal chromosomes; each species has a pair of sex-determining chromosomes and the fox has an additional 0-8 supernumerary ("B") chromosomes.  These structural differences have made it difficult to compare fox and dog chromosomes histologically.

This study provides genomic DNA assembly and annotation for the three types of foxes having three types of responses to humans.  The assembled fox genomic DNA revealed 21,418 protein coding genes and that 84% of the sequencing scaffolds map to one dog chromosome, 15% to tow or more, and 1% could not be assigned.  A comparison of the three source genomes (10 foxes from each population) showed that there was "less divergence between the conventional and aggressive populations than between the tame and either the conventional or aggressive population" using single nucleotide polymorphism (SNP) comparisons (8,458,133 identified SNPs).  Of the 103 genomic regions identified as being associated with behavioral differences between these populations, "30 [were] identified in the tame population and 19 [were] identified in the aggressive population as showing a lower level of heterozygosity than would be expected due to genetic drift," and "[t]he longest regions were found on fox chromosomes 4, 8 and 14."

Turning to genetic fine structure for genes associated with tameness or its opposite, the study showed that 80% of the genes detected were expressed in brain.  These included "[s]everal receptor-coding genes for glutamatergic (GRIN2B, GRM6), GABAergic (GABBR1, GABRA3, GABRQ) and cholinergic (CHRM3, CHRNA7) synapses."  Also detected were genes known to be associated with human neurological diseases (and hence related to behavior and changes therein), including "13 genes associated with autism spectrum disorder, 13 genes associated with bipolar disorder and three genes located at the border of the Williams–Beuren syndrome deletion in humans."  In addition, six fox genes were detected that had been implicated in aggressive behavior in mice.  Some of these genes were represented by alleles having missense mutations having different frequencies in the three populations, including "[t]wo missense mutations in the autism-associated CACNA1C gene, CACNA1C-SNP1 (Ile937Thr) and CACNA1C-SNP2 (Thr1875Ile), with the CACNA1C-SNP1 allele being found only in the tame population and the CACNA1C-SNP2 allele found in both the conventional and aggressive populations but not in the tame population."  The researchers also found that certain alleles of the SorCS1 gene were associated with interaction behavior that attracted attention after an interaction as opposed to avoidance, based on the presence of insertion/deletion (indel) markers in proximity of this gene.  The study shows identification of "one haplotype (olv) with a frequency of 60.6% in the tame population that was not observed in the aggressive population, two haplotypes (trq and lav) that were rare in tame but frequent in the aggressive population, and a fourth haplotype (pch) that was found in both populations."  The authors conclude that "[t]he function of SorCS1 as a global regulator of synaptic receptor trafficking supports the role of SorCS1 in the regulation of behavioural differences between tame and aggressive foxes."

It seems apparent that such studies will be significant not only for identifying neurological changes that accompany domestication of animals, but also for better understanding genetic loci that may be implicated in human behaviors, including aggression.  Such understanding may lead to better ways to minimize the negative effects of unrestricted aggression in human populations.

*Anna V. Kukekova, Jennifer L. Johnson, Xueyan Xiang, Shaohong Feng, Shiping Liu, Halie M. Rando, Anastasiya V. Kharlamova, Yury Herbeck, Natalya A. Serdyukova, Zijun Xiong, Violetta Beklemischeva, Klaus-Peter Koepfli, Rimma G. Gulevich, Anastasiya V. Vladimirova, Jessica P. Hekman, Polina L. Perelman, Aleksander S. Graphodatsky, Stephen J. O'Brien, Xu Wang, Andrew G. Clark, Gregory M. Acland, Lyudmila N. Trut & Guojie Zhang

Image from British Wildlife Centre Wildlife by Airwolfhound, from the Wikimedia Commons under the Creative Commons Attribution-Share Alike 2.0 Generic license.