Red fox genome assembly identifies genomic regions associated with tame and aggressive behaviours

Articles https://doi.org/10.1038/s41559-018-0611-6 Corrected: Author Correction Red fox genome assembly identifies genomic regions associated with tame and aggressive behaviours Anna V. Kukekova 1*, Jennifer L. Johnson1, Xueyan Xiang2, Shaohong Feng2, Shiping Liu2, Halie M. Rando 1, Anastasiya V. Kharlamova3, Yury Herbeck3, Natalya A. Serdyukova4, Zijun Xiong 2,5, Violetta Beklemischeva4, Klaus-Peter Koepfli6,7, Rimma G. Gulevich3, Anastasiya V. Vladimirova3, Jessica P. Hekman1,13, Polina L. Perelman4,8, Aleksander S. Graphodatsky4,8, Stephen J. O’Brien7,9, Xu Wang 10,14, Andrew G. Clark10, Gregory M. Acland11, Lyudmila N. Trut3 and Guojie Zhang 2,5,12* Strains of red fox (Vulpes vulpes) with markedly different behavioural phenotypes have been developed in the famous longterm selective breeding programme known as the Russian farm-fox experiment. Here we sequenced and assembled the red fox genome and re-sequenced a subset of foxes from the tame, aggressive and conventional farm-bred populations to identify genomic regions associated with the response to selection for behaviour. Analysis of the re-sequenced genomes identified 103 regions with either significantly decreased heterozygosity in one of the three populations or increased divergence between the populations. A strong positional candidate gene for tame behaviour was highlighted: SorCS1, which encodes the main trafficking protein for AMPA glutamate receptors and neurexins and suggests a role for synaptic plasticity in fox domestication. Other regions identified as likely to have been under selection in foxes include genes implicated in human neurological disorders, mouse behaviour and dog domestication. The fox represents a powerful model for the genetic analysis of affiliative and aggressive behaviours that can benefit genetic studies of behaviour in dogs and other mammals, including humans. T he red fox (Vulpes vulpes) and the domestic dog (Canis familiaris) are closely related species that only diverged about 10 million years ago within the family Canidae1. However, these two species occupy very different ecological niches. The red fox has a geographic range wider than that of any other wild species in the order Carnivora2 and has even become a common resident of many major cities3–6. The dog, on the other hand, has become widespread for a different reason: it was domesticated from the grey wolf at least 15,000 years ago7,8 and became ‘man’s best friend’. There is no evidence that the fox was domesticated historically, although a red fox was found co-buried with humans in a Natufian grave from 14.5–11.6 thousand years ago at a southern Levant site in northern Jordan9, the same geographic region where the oldest coburials of humans and dogs are found10. The first strong evidence of fox domestication comes instead from the late nineteenth century, when the farm breeding of red foxes for fur began in Prince Edward Island, Canada11. Though many animal species are not well-suited to breeding in captivity12, fox breeding has continued successfully for more than a century11,13–17. Conventional farm-bred foxes have adapted to the farm environment, yet their behaviour still clearly differentiates them from dogs because they generally exhibit fear or aggression toward humans. In 1959, the experimental domestication of farm-bred foxes began at the Institute of Cytology and Genetics of the Russian Academy of Sciences18–23. For over 50 generations, foxes were selected for positive responses toward humans, leading to the establishment of a tame strain of foxes that are eager to interact with humans from a very young age21,24. Beginning in the late 1960s, a complementary strain of foxes selected for aggressive behavior toward humans was also developed and has proceeded for more than 40 generations22,23. A conventional population comparable to the farm-bred founder population of both selected strains has also been maintained but was not subjected to deliberate selection for behaviour. The fox strains have remained outbred during the entire course of the breeding programme, and a strong genetic contribution to the behavioural differences between the tame and Animal Sciences Department, College of ACES, University of Illinois at Urbana, Champaign, IL, USA. 2China National Genebank, BGI -Shenzhen, Shenzhen, China. 3Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. 4Institute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. 5State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. 6Smithsonian Conservation Biology Institute, National Zoological Park, Washington DC, USA. 7Theodosius Dobzhansky Center for Genome Bioinformatics, Saint Petersburg State University, Saint Petersburg, Russia. 8 Novosibirsk State University, Novosibirsk, Russia. 9Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL, USA. 10Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA. 11Baker Institute for Animal Health, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA. 12Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark. 13Present address: The Broad Institute of MIT and Harvard, Cambridge, MA, USA. 14Present address: Department of Pathobiology, Auburn University, Auburn, AL, USA. *e-mail: ; 1 Nature Ecology & Evolution | VOL 2 | SEPTEMBER 2018 | 1479–1491 | www.nature.com/natecolevol 1479 Articles NATuRe EcOlOgy & EvOluTiOn aggressive strains has been confirmed20,23,25,26. Unlike modern dogs, which have been selected for a wide variety of traits, these fox strains were selected solely for behaviour, and the shifts in their behaviour were recent and well documented. Maximizing the scientific value of these experimental fox populations requires the development of genomic tools for the fox. In contrast to the dog, whose karyotype consists of 38 pairs of acrocentric autosomes in addition to the sex chromosomes, the red fox karyotype comprises 16 pairs of metacentric autosomes, the sex chromosomes and 0–8 supernumerary B chromosomes27,28. Synteny between the dog and fox chromosomes has been established but at a low resolution29–33, hindering identification of the regions in the dog genome that correspond to genomic regions of interest in the fox. Here, we present the sequence assembly of the red fox genome and a population genetic analysis of whole re-sequenced genomes of foxes from the tame, aggressive and conventional farm-bred populations. Selection on the tame and aggressive strains is likely to have influenced genetic diversity and the fixation of variants across the genome, yielding a robust model for understanding the genetic basis of variation in social behaviour, (...truncated)