Unusual Occurrence of Domestication Syndrome Amongst African Mole-Rats: Is The Naked Mole-Rat A Domestic Animal?

TYPE Hypothesis
and Theory
PUBLISHED 28November 2022
DOI 10.3389/fevo.2022.987177
Unusual occurrence of
OPEN ACCESS domestication syndrome
amongst African mole-rats: Is
EDITED BY
Edivaldo Herculano Correa De Oliveira,
Evandro Chagas Institute,
Brazil
REVIEWED BY
the naked mole-rat a domestic
animal?
Ricardo Lehtonen Rodrigues Souza,
Federal University of Paraná, Brazil
Stan Braude,
Washington University in St. Louis,
United States Guillermo Serrano Nájera 1* and Koryu Kin 2
*CORRESPONDENCE
Guillermo Serrano Nájera School of Life Sciences Research Complex, University of Dundee, Dundee, United Kingdom,
1
guillermo.serrano-najera@gen.cam.ac.uk
2
Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Spain
SPECIALTY SECTION
This article was submitted to The Naked mole-rat (NMR) is becoming a prominent model organism due to
Behavioural and Evolutionary Ecology,
a section of the journal its peculiar traits, such as eusociality, extreme longevity, cancer resistance, and
Frontiers in Ecology and Evolution reduced pain sensitivity. It belongs to the African mole-rats (AMR), a family of
RECEIVED 05 July 2022 subterranean rodents that includes solitary, cooperative breeding and eusocial
ACCEPTED 10 October 2022 species. We identified and quantified the domestication syndrome (DS)
PUBLISHED 28 November 2022
across AMR, a set of morphological and behavioural traits significantly more
CITATION
Serrano Nájera G and Kin K (2022) Unusual
common and pronounced amongst domesticated animals than in their wild
occurrence of domestication syndrome counterparts. Surprisingly, the NMR shows apparent DS traits when compared
amongst African mole-rats: Is the naked to the solitary AMR. Animals can self-domesticate when a reduction of the
mole-rat a domestic animal?
Front. Ecol. Evol. 10:987177. fear response is naturally selected, such as in islands with no predators, or to
10.3389/fevo.2022.987177 improve the group’s harmony in cooperative breeding species. The DS may
COPYRIGHT be caused by alterations in the physiology of the neural crest cells (NCC),
© 2022 Serrano Nájera and Kin. This is an a transient population of cells that generate a full range of tissues during
open-access article distributed under the
terms of the Creative Commons Attribution development. The NCC contribute to organs responsible for transmitting the
License (CC BY). The use, distribution or fear response and various other tissues, including craniofacial bones. Therefore,
reproduction in other forums is permitted,
mutations affecting the NCC can manifest as behavioural and morphological
provided the original author(s) and the
copyright owner(s) are credited and that alterations in many structures across the body, as seen in neurocristopathies.
the original publication in this journal is We observed that all social AMRs are chisel-tooth diggers, an adaption to hard
cited, in accordance with accepted
academic practice. No use, distribution or soils that requires the flattening of the skull. We hypothesise that chisel-tooth
reproduction is permitted which does not digging could impose a selective pressure on the NCC that triggered the DS’s
comply with these terms.
appearance, possibly facilitating the evolution of sociality. Finally, we discuss
how DS traits are neutral or beneficial for the subterranean niche, strategies
to test this hypothesis and report well-studied mutations in the NMR that are
associated with the NCC physiology or with the control of the fear response.
In conclusion, we argue that many of the NMR’s unconventional traits are
compatible with the DS and provide a hypothesis about its origins. Our model
proposes a novel avenue to enhance the understanding of the extraordinary
biology of the NMR.
KEYWORDS
naked mole-rat, African mole-rat, eusociality, domestication, neural crest, digging

behaviour, chisel-tooth digging
Frontiers in Ecology and Evolution 01 frontiersin.org

Serrano Nájera and Kin 10.3389/fevo.2022.987177
Introduction The family of African mole-rats (AMR, family Bathyergidae)

is a well-recognised model to study the evolution of cooperative
The reduction of the fight-or-flight response is a hallmark of breeding (Faulkes and Bennett, 2016). This family of subterranean
domestication (Belyaev, 1969). From the Neolithic period, many rodents contains solitary, social cooperative breeders and two
animals adapted to the anthropogenic environment by reducing eusocial species: The naked mole-rat (NMR) and the Damaraland
reactivity to humans and perhaps increasing their social mole-rat. Eusociality is an extreme form of cooperative breeding
tolerance (Tchernov and Horwitz, 1991). Surprisingly, there is a where species show sexual suppression, reproductive division of
set of physical traits that often appear in domestic mammals but labour, overlapping generations and cooperative care of the young
not in their wild equivalents, known as the domestication (Burda et al., 2000). In the case of eusocial AMRs, most members
syndrome (DS). The DS includes depigmentation, a shorter renounce to reproduce and specialise in digging, defence, or
snout, decreased brain size, floppy ears, reduced or missing teeth pup-caring, whilst a single queen continuously produces offspring
and hairlessness, amongst other traits (Darwin, 1868; Sánchez- (Faulkes and Bennett, 2001). The NMR presents the most extreme
Villagra et al., 2016). These traits rarely occur in the wild, and and unusual traits of its family: it is eusocial, forms extensive
usually, only a subset of them is present in each individual or colonies (Jarvis, 1981), and exhibits resistance to hypoxia, delayed
variety of a domestic species. DS most probably was not directly senescence, cancer resistance, poor control of body temperature
selected by humans (Darwin, 1868); but instead, it appeared as a and reduced sensitivity to pain (reviewed in Braude et al., 2021).
side effect of selecting for tameness (Belyaev, 1969). Experiments Its scientific name Heterocephalus glaber (“atypical bald head”),
with wild foxes, rats and minks show that DS traits can appear as also refers to its rare morphological traits: it is hairless (except for
a side effect of artificially selecting for tameness (Trut, 1999; Trut sensory hairs), has wrinkled skin, and a flat skull with a reduced
et al., 2009; Singh et al., 2017; Wang et al., 2018). However, they number of molars when compared with the other AMR (Jarvis and
can also appear in wild animals when selective pressures favour Sherman, 2002). Strikingly, many of these morphological traits can
a reduced fight-or-flight response (self-domestication), as it be accounted as part of the DS. Is the NMR a domestic animal?
occurs in islands with no predators (Ramis and Bover, 2001; Here we propose that the social behaviour of AMR is the
Cooper et al., 2014; Sánchez-Villagra et al., 2016). Finally, these product of self-domestication. We document that DS traits are
traits can be observed in primates, including humans more prominent in social AMR species, especially in the
(Theofanopoulou et al., 2017; Sánchez-Villagra and van Schaik, NMR. We focus on the NMR because it presents the most extreme
2019; Zanella et al., 2019), bonobos (Hare et al., 2012), and morphological and behavioural phenotype, and it is the best-
marmoset monkeys (Ghazanfar et al., 2020), where it has been studied member of the family. We propose that many of the
suggested that the reduced aggression associated with the DS unusual NMR traits could be the result of a mild-neurocristopathy
could have been selected to enhance cooperative breeding. that recapitulated the DS. We discuss the possible interactions
There have been many attempts to explain why selecting for between the DS, the subterranean niche, and the digging mode.
tameness result in the distinct morphological traits encompassed Finally, we suggest that the appearance of the DS facilitated the
by the DS, including changes in thyroid function (Crockford, 2004; evolution of eusociality in AMRs and argue that this integrative
Karlsson et al., 2016; Fitak et al., 2020), in the metabolism of the theory will aid NMR research on many fronts.
adrenaline (Keeler et al., 1970; Nätt et al., 2007; Cagan and Blass,
2016), or the retention of juvenile traits in the adult animal (Shea,
1989; Geiger et al., 2017). Recently, a new, more comprehensive Domestication syndrome in the
theory proposed that the DS syndrome is derived from mutations naked mole-rat
affecting the development of the hypothalamic–pituitary–adrenal
(HPA) axis and the sympathetic nervous system (Wilkins et al., The AMR family comprises six genera and more than 15
2014). The HPA axis converts the perception of dangerous stimuli species. All family members are subterranean rodents and present
into a hormonal response by transmitting information to the a complete set of morphological, physiological, and behavioural
adrenal medulla, which results in the release of glucocorticoids adaptations to the underground environment. However, genera
and adrenaline, leading to a long-term elevated reactivity differ in some essential traits regarding their head, digging
(Sapolsky, 2005). Similarly, the sympathetic nervous system behaviours, and sociality. Surprisingly, many differences between
mediates the short-term fight-or-flight response and directly the social AMR, especially the NMR, and the solitary species can
stimulates the adrenal glands. Mutations producing a be accounted for as part of the DS. We compiled a list of the DS
hypofunctional HPA axis could result in the reduced fear response traits across the AMR family.
characteristic of domestic animals. Remarkably, the sympathetic
nervous system, the adrenal glands, skin melanocytes, bone and
cartilage in the skull and teeth, amongst other tissues, are derived Skull
from the neural crest cells (NCC). This way, mild neurocristopathies
(disorders derived from defects in the NCC) could explain The skulls of domestic animals present many characteristic
tameness and the DS simultaneously (Wilkins et al., 2014). traits. Many domestic animals (e.g., dog, fox, pig, sheep, goat, cat,

mouse, cow, and human) present a reduced snout in comparison Sánchez-Villagra and van Schaik, 2019; Lord et al., 2020). Most
to their wild counterparts (reviewed in Sánchez-Villagra et al., AMR species share the same dental formula (I 1/1, C 0/0, P 1/1,
2016; Sánchez-Villagra and van Schaik, 2019). Amongst M 3/3; 20 teeth; Table 1), except for Heliphobius (Gomes Rodrigues
subterranean rodents, the relative length of the snout is largely and Šumbera, 2015), that shed their premolar teeth and substitutes
determined by their digging behaviours: forelimb diggers use their them with new molars giving a higher, variable number from 20
claws to scratch soft, sandy soil and possess more prominent faces, to 28 teeth; and the NMR (Gomes Rodrigues and Šumbera, 2015)
whilst chisel-tooth diggers use their incisors to exploit harder soil which only presents 3 molars (occasionally only 2) in each ramus
and have a relatively wider cranium (Lacey and Patton, 2000). for a total of 14–16 teeth (Kingdon, 2014). Therefore, the NMR
Chisel-tooth diggers show enlarged zygomatic arcs (cheek bones) also presents a reduced, variable number of teeth, when compared
and shorter rostra, associated with larger masseter and temporalis with other AMRs.
muscles, presumably to enhance the bite force (Lacey and Patton,
2000; Mcintosh and Cox, 2016).
We gathered the width and length of the skull of the AMR, Ear
other African Hystricognath (the closest relatives to the AMR: Old
World porcupines, the dassie rat and the cane rat) and examples Another common trait of the DS is reduced or malformed ears
of genetically unrelated convergent mole-rats (from genus Spalax, (e.g., dogs, horses, pigs, rabbits, cattle, guinea pig; reviewed in
Spalacopus, and Tachyoryctes). We calculated the ratio between the Sánchez-Villagra et al., 2016; Lord et al., 2020). NCC contribute
length and the width of the skull for the chisel-tooth diggers in our to the formation of all the components of the ear, and hearing
data set (Figure 1, see Materials and methods in the defects are common in Human neurocristopathies (Ritter and
Supplementary Material). In comparison, exclusive forelimb Martin, 2019). Ears of AMR lack pinna whilst their closest
diggers (other African Hystricognath and Bathyergus mole-rats) relatives, the other African Hystricognath, all have well developed
tend to have a more prominent snout (Supplementary Figure 1). external auricles (Schlitter et al., 2014). The quantitative
At the same time, Tachyoryctes members, which dig with both comparison of the NMR ear components with other AMRs
their limbs and teeth, present closer cranial proportions to (B. suillus, C. hottentotus, F. micklemi, G. capensis, and
exclusive chisel-tooth diggers (most AMR, Spalax and Spalacopus). H. argenteocinereus) suggest that the NMR has a degenerated ear
We show that the NMR has a disproportionally shorter snout even (Mason et al., 2016). They have a very narrow, semi occluded
for a chisel-tooth digger, probably due to a statistically significant external canal, a smaller than expected and fused malleoincus, a
reduction of the rostral length (Mcintosh and Cox, 2016). The poorly ossified part of the malleus, weakly developed long process
relative shortening of the NMR’s snout compared to other chisel- of the incus, lack of structural stiffness of the stapes, reduced
tooth diggers is a typical DS trait. number of cochlear turns, and a relatively small auditory bulla
All AMR species share a similar diet of geophytes, tubers and (Mason et al., 2016). Furthermore, the ear morphology in the
rhyzomes (Kingdon, 2014). Unfortunately, there is no data available NMR shows a considerable intraspecific variation which could
about the relative hardness of the plants (Dominy et al., 2008) suggest that the ear is subjected to a relaxed selective pressure
consumed by AMR in comparison with the hardness of the soil. (Mason et al., 2016). Finally, some studies indicate that the NMR
However, it seems unlikely that any tuber or rhyzome offer more has relatively poor hearing, whilst other studies suggest that the
resistance than the soil. In addition, whilst all AMR species eat similar auditory system is just adapted to the subterranean niche
plants (Kingdon, 2014), they inhabit areas with different soil (reviewed in Braude et al., 2021).
properties (Faulkes and Bennett, 2013). Solitary forelimb diggers
(Bathyergus) are restricted to more humid environments where
digging is easier, whilst chisel-tooth diggers-especially the social Brain
species-tend to inhabit regions with harder soils (Faulkes and Bennett,
2013). Therefore, it seems that the type of soil correlates better with Domestic animals (e.g., dog, cat, pig, alpaca, rabbit, mouse,
the head morphology, digging behaviour and sociality (see The horse) usually have smaller brains than their wild counterparts
subterranean niche and self-domestication below), than the type of (reviewed in Sánchez-Villagra et al., 2016). Specifically, they tend
diet, which suggests that the properties of the soil are the main to show an exacerbated reduction of the forebrain (mink, horse,
determinant of the skull proportions amongst AMR. pig, fox; Trut et al., 1991; Kruska, 2005; Wilkins et al., 2014). The
brain size of the AMR has been quantitatively analysed under the
hypothesis that social animals evolve larger brains in Kverková
Dentition et al. (2018). However, on the contrary, they found that social
AMR species have relatively smaller brains than solitary ones, with
The skull of domestic animals often manifests dental a statistically significant reduction in forebrain neurons. In
abnormalities such as crowding of the cheek teeth or a reduction particular, the NMR has a significantly smaller brain mass and
of teeth size or number (dogs, pigs, mouse, human; reviewed in fewer neurons in comparison with the other AMR
Kleisner and Stella, 2009; Sánchez-Villagra et al., 2016; (Supplementary Figure 1 in Kverková et al., 2018). This apparent

FIGURE 1
Relation between the length and width of the skull in African mole rats, their closes relatives, and convergent subterranean rodents. Chisel-tooth
digging subterranean rodents present a smaller skull length/width ratio than forelimb diggers. The naked mole-rat (Heterocephalus glaber, NMR)
has a significantly shorter snout even when compared to other chisel-tooth digging African mole-rats. Each data point is coloured according to its
social or phylogenetic attributes as indicated in the figure. The shape represents digging mode. The linear regression line for chisel-tooth diggers
with 95% confidence intervals is shown, together with the regression line based on phylogenetic generalized least squares (PGLS). All data was
retrieved from Kingdon (2014) See Materials and methods in the SM for more details. PGLS was calculated using the evolutionary tree in
Supplementary Figure 2.
contradiction could be explained by the self-domestication caudal vertebrae occurred in a few domesticated species (dog,
hypothesis, which instead predicts the smaller brain size of NMR. cat, sheep; Sánchez-Villagra et al., 2016). Moreover, many
domestic animals show a shortening of the limbs (Sánchez-
Villagra et al., 2016) and, likewise, the legs of the AMRs are
Body and heart generally described as “short and slender” (Schlitter et al.,
2014). Recent analysis show that the forelimbs of NMR are less
A body size reduction occurred in early domestic breeds specialised and paedomorphic than the rest of AMR (Montoya-
(pig, dog, cow, goat, and sheep) as a natural adaptation to the Sanhueza et al., 2022). Finally, a reduced heart size is one of
human environment (Tchernov and Horwitz, 1991). It could the most common traits amongst domesticated species (e.g.,
also be associated with self-domestication in islands (reviewed mouse, rat, guinea pig, pig, dog; Sánchez-Villagra et al., 2016).
in Sánchez-Villagra et al., 2016), probably because of small or Currently there are not quantitative comparisons of AMR
absent predation and low interspecies competition. The body heart sizes; however, allometric analysis suggests that the NMR
size of AMR varies exponentially amongst species. Social AMR has a disproportionally small heart in comparison with
species tend to be smaller than the solitary ones (Table 1), with another rodent, the mouse (Grimes et al., 2013).
the NMR being the smallest (∼30 g) and B. suillus the heaviest
(∼1 kg). In addition to its arguable dwarfism, the body of the
NMR differs because it possesses a long tail (50% head-body Skin and fur
length), whilst the other AMR present very short tails
[8%−24% head-body length, depending on the genus (Table 1; Probably, complete or partial depigmentation is, along with
Schlitter et al., 2014)]. Similarly, changes in the number of increased tameness, the most frequent trait in the DS, appearing

TABLE 1 Selected domestication syndrome traits in the African mole rats.
Species Sociality Digging Chisel- Total Brain/ Weight Tail- White White Breeding Max Colony
mode tooth teeth Body (g) Body forehead forehead litters/ size
digger weight length patch patch year
rostrum ratio ratio (size) (frequency)
length/
width
ratio
Heterocephalus Social Chisel- Reduced 16* Reduced 33.9 50% NA NA Aseasonal 4 75 (2–300)
glaber tooth
Cryptomys Social Chisel- Normal 20 Expected 65.8 15% Small In some Seasonal 2 5 (2–14)
hottentotus tooth individuals
Fukomys Social Chisel- Normal 20 Expected ? 7% ? Usually present ? ? ?
bocagei tooth
Fukomys Social Chisel- Normal 20 Expected 76.4 7% Conspicuous In some Aseasonal 4 5–9
darlingi tooth individuals individuals
Fukomys Social Chisel- Normal 20 Expected 95 15% Conspicuous Most ? ? ?
kafuensis tooth individuals
Fukomys anselli Social Chisel- Normal 20 Expected 96.1 8% Conspicuous Most Aseasonal 2 12 (2–25)
tooth individuals
Fukomys Social Chisel- Normal 20 Expected 161 18% Large Always Aseasonal 3 11 (2–41)
damarensis tooth
Fukomys foxi Social Chisel- Normal 20 Expected ? 8% ? Usually present ? ? ?
tooth
Fukomys zechi Social Chisel- Normal 20 Expected 217 8% ? Usually present ? ? 4 (1–7)
tooth
Fukomys Social Chisel- Normal 20 Expected ? 10% Conspicuous Usually present ? ? ?
ochraceocinereus tooth
Fukomys Social Chisel- Reduced 20 Expected 370 8% Very small In some Aseasonal 3 2–20+
mecchowi tooth individuals
Heliophobius Solitary Chisel- Normal 28* Expected 190.1 9% Small In some Seasonal ? NA
argenteocinereus tooth individuals
Georychus Solitary Chisel- Normal 28 Expected 181 13% Small Often Seasonal 2 NA
capensis tooth
Bathyergus Solitary Forelimb Increased 28 Expected 439 24% ? Often Seasonal 1 NA
janetta
Bathyergus Solitary Forelimb Increased 28 Expected 896 18% Small In some Seasonal 2 NA
suillus individuals
WHP: White forehead patch, not applicable (NA) for NMR because of its complete depigmentation. Colony size is NA for the solitary species. Interrogation mark (?) denotes missing data,
* denotes a variable number of teeth (see Dentition). All data were retrieved from Kingdon (2014), except from “Brain/Body weight ratio” obtained from Kverková et al. (2018), and
“Chisel-tooth digger rostrum” which compares the rostrum length of with the chisel-tooth digger trend as calculated in Figure 1.
in at least some varieties of each known domestic species forehead patch have not been quantified amongst different
(Sánchez-Villagra et al., 2016). In particular, a white forelock is species. The currently available interspecies data, albeit
a common characteristic of domestic animals and a noticeable incomplete and not completely quantitative (Kingdon, 2014),
feature of the Waardenburg syndrome, a human suggest that the white forehead patch tends to be more
neurocristopathy (Wilkins et al., 2014). Furthermore, the white prominent and frequent amongst social species and reduced
forelock has been recently associated with the self-domestication and only occasionally present in the solitary mole-rats (Table 1).
phenotype in marmoset monkeys (Ghazanfar et al., 2020). The NMR appearance departs from the other AMRs because of
Interestingly, most AMR species occasionally present a white its complete depigmentation, hairlessness, and skin folds.
forehead patch of variable size (Figure 2). A recent report found However, all these attributes are also characteristic of some
no correlation between the size of the white forehead patch and domestic variates (dog, cow, pig, goat, rabbit; Sánchez-Villagra
the behaviour amongst F. anselli individuals (Begall et al., 2022). et al., 2016) and can be understood as a more extreme
However, to our knowledge, the frequency and size of the white domestication phenotype.

FIGURE 2
White forehead patch in domestic species and African mole rats. Domestic species and some neurocristopathies are associated with large white
patches on the forehead. Most African mole-rats present a white forehead patch which size and frequency could be associated with their social
behaviour (Table 1). All images are available under Creative Common License. Authorship credit of the images in Supplementary Table 1.
Reproductive biology Whilst domestic animals seem to present an earlier sexual

maturity, most of the individuals in a NMR colony never
A combination of body size reduction, earlier sexual reproduce, and they remain all their life sexually suppressed in a
maturation, increased litter size, non-seasonal oestrus cycles, pre-pubertal state until the breeding members need to be replaced
and a decrease in sexual dimorphism generally allow domestic (Faulkes et al., 1990, 1991). This phenomenon can be seen as an
animals to have higher reproductive rates than their wild extreme version of neoteny. Indeed, neoteny has been classically
counterparts (Tchernov and Horwitz, 1991; Sánchez-Villagra used to explain many of the characteristic reproductive and
et al., 2016). Non-seasonal reproduction, higher annual behavioural changes that occur during domestication (Sánchez-
reproductive output, and absent or reduced sexual dimorphism Villagra et al., 2016). Many of the characteristic traits of the NMR
seem to be more frequent amongst social AMR (Cryptomys, can be considered neotenic (Skulachev et al., 2017; Buffenstein
Fukomys, Heterocephalus), whilst the solitary, forelimb diggers et al., 2020) such as the lack of hair, absence of scrotum or the
(Bathyergus) present marked sexual dimorphism decline of bone mineralisation with age (Buffenstein, 2008), which
(Kingdon, 2014). could be simultaneously related to the extraordinary social
The lack of behavioural and morphological sexual organisation and longevity of this species.
dimorphism is exceptionally noticeable in the non-reproductive
members of a NMR colony (MacManes and Lacey, 2012): The
males lack scrotum, the females have an imperforated vagina; and, Hormones and social behaviour
unlike any other mammal, the phallus (clitoris or penis), the
anogenital distance, and the perineal muscles are sexually Glucocorticoids mediate the long-term response to
monomorphic (Jarvis, 1981; Peroulakis et al., 2002; Seney et al., environmental and social stressful situations. A reduction of the
2009). They also lack sexual dimorphism in femoral bone concentration of corticosteroid hormones characterises both
structure and quality (Pinto et al., 2010) and forebrain regions domestic animals (Belyaev, 1969; Trut, 1999; Wilkins et al., 2014;
(Holmes et al., 2008), which has been associated with the retention Kikusui et al., 2019) and subordinate individuals in cooperative
of a pre-pubertal phenotype in the worker castes (Holmes et al., breeding species (Creel, 2001; Sapolsky, 2005). In domesticated
2007; Swift-Gallant et al., 2015; Peragine et al., 2017). animals, the reduction of glucocorticoids could lower aggressive

behaviours and increase social tolerance, which could also Peripheral nervous system
be beneficial to maintain harmony within the group in cooperative Most of the structures of the peripheral nervous system
breeding species. In this line, both eusocial species F. damarensis (cranial and spinal nerves and ganglia; and enteric nervous
(Ganem and Bennett, 2004) and the NMR show little aggression system) are derived from the NCC (Prendergast and Raible,
amongst individuals of the same colony (O’riain and Jarvis, 1997). 2014). The NMR also manifest alterations in the cutaneous
However, whilst F. damarensis manifest lower aggression against innervation. It presents a significantly reduced ratio of
unfamiliar conspecifics, the NMR shows xenophobic behaviour unmyelinated nociceptive C-fibres and A-fibres in the saphenous
(O’riain and Jarvis, 1997; Barker et al., 2021; Toor et al., 2022). and sural nerves (1.5:1), whilst in other AMRs
In NMR colonies, the queen displays most aggressive (H. argenteocinereus, F. mechowii, F. damarensis, F. darlingi,
behaviours (Clarke and Faulkes, 2001); however, cortisol levels, C. hottentotus) and most mammals C-fibres generally are 3–4
the main glucocorticoid in the non-murine rodents (Buffenstein times more abundant (Smith et al., 2012). Innervation defects are
and Pinto, 2009), do not correlate with social or reproductive typical of certain neurocristopathies (Indo, 2009) and could
status either in the NMR (Clarke and Faulkes, 2001; Edwards be manifestation of mutations affecting the biology of NCC (see
et al., 2020) or F. damarensis (Medger et al., 2018) which suggest Trka below).
that social AMR do not suffer “stress of dominance” or “stress of
subordination” (Edwards et al., 2020). Thymus
Nonetheless, cortisol levels rise after the death of the queen NCC participate in the development of the stroma of the
producing a violent period when individuals fight for the thymus, an organ necessary for the maturation of the T-cells
succession (Clarke and Faulkes, 1997; Medger et al., 2019), or (Zachariah and Cyster, 2010); and consequently, the T-cell
in an individual isolated from the rest of the colony (Faykoo- population is affected in several neurocristopathies (Chinen et al.,
Martinez et al., 2018; Edwards et al., 2020), indicating that they 2003; Vega-Lopez et al., 2018). The NMR has a reduced thymus/
suffer from social stress as observed in marmoset monkeys body weight ratio and presents a poor delineation between cortex
(Smith and French, 1997) and tamarins (Ziegler et al., 1995), and medulla in comparison to mice (Lin and Buffenstein, 2021).
two cooperative breeding primates. Finally, in AMR species, Moreover, the immune system of the NMR differs from mice and
there are no significant differences in the basal blood humans in having predominantly myeloid cells and a notable
concentration of cortisol amongst non-pregnant females in one deficit in cytotoxic T-cells (Shebzukhov et al., 2019), which could
solitary species (G. capensis) and three social species be related to a defective thymus development due to alterations in
(F. darlingi, F. hottentotus pretoriae, F. damarensis). However, the NCC.
only the solitary species showed an elevation of cortisol levels
after repeated encounters with unfamiliar conspecific of the Thyroid
same sex (Ganem and Bennett, 2004). Altogether, these The NCC also contribute to creating the stroma of the thyroids
observations suggests that cooperative breeding species (Maeda et al., 2016) and altered thyroid function is a common
suppressed social stress to acquire social tolerance towards trait amongst neurocristopathies (Vega-Lopez et al., 2018), and it
members of the same species. has been previously associated with domestication (Crockford,
Oxytocin is also a mediator of the HPA axis that has been 2004). Interestingly, the NMR exhibits unique low levels of thyroid
associated with increased social cohesion and maternal hormone (Buffenstein et al., 2001; Buffenstein and Pinto, 2009).
behaviour in domesticated animals (Kikusui et al., 2019). In the
same line, the NMR expresses more oxytocin receptor levels in Gall bladder
the nucleus accumbens, a forebrain centre controlling Gall bladder derives from the NCC (Mawe et al., 1997).
monogamic, maternal and allomaternal behaviour in Although most vertebrates possess this gland, it is absent in the
comparison with the solitary G. capensis (Kalamatianos et al., NMR (Hill et al., 1957).
2010). Moreover, non-breeding individuals of a NMR colony
present more oxytocin-producing neurons than breeding
individuals, suggesting that oxytocin contributes to maintaining Gene candidates
the prosocial behaviour of the worker caste (Mooney and
Holmes, 2013). Here we discuss some well-studied mutations in the NMR that
are associated with the NCC physiology or with the control of the
fear response.
Other traits linked to an altered NCC
functionality
Trka
The NMR shows a series of peculiar biological traits that are
not generally included in the DS, but that could be explained Trka (tropomyosin receptor kinase A) binds to NGF (nerve
through defects in the physiology of the NCC. growth factor), promoting survival and differentiation of the

sensory neurons during embryonic development, and modulating mice and humans and could potentially explain the high social
the sensitivity to pain later in life (Lewin et al., 2014). Trka is tolerance of the NMR.
implicated in cell migration in normal and pathological conditions
(Wislet et al., 2018); and it is necessary for the formation of the
dorsal root and sympathetic ganglia by the trunk NCC in mouse HIF1α
(Smeyne et al., 1994).
In humans, mutations in the Trka gene produce congenital The NMR presents critical molecular adaptations to survive
insensitivity to pain (CIP) with anhidrosis (CIPA), a in hypoxic/hypercapnic environments produced by large numbers
neurocristopathy that results in a total loss of the C-fibres, lack of of individuals living in borrows (Park et al., 2021). For example,
nociception, inability to sweat (hypotrophic sweat glands), lack of the NMR carries a hyperactive version of HIF1α (Hypoxia
hair (bald patches in the scalp), poor thermoregulation, and oral Inducible factor 1 α), a transcription factor that regulates the
and craniofacial manifestation including missing teeth and nasal expression of dozens of genes in response to low-oxygen
malformations (Indo, 2009; Gao et al., 2013). Furthermore, CIPA conditions. In normal-oxygen conditions, HIF1α is targeted for
patients seem to be unable to learn new fears and probably fail to degradation by VHL (Von Hippel–Lindau tumour suppressor);
exhibit a fight-or-flight response (Indo, 2009). however, low-oxygen levels prevent the HIF1α-VHL interaction.
Knock out mice for Trka present a similar phenotype: The NMR possesses a unique mutation in HIF1α (T395I, Figure 3)
Abnormal peripheral small nerves fibres, deficient nociception, that prevents its interaction with VHL, as well as a mutation in
small body size, early death, and severe cell loss in trigeminal, VHL (V166I) which probably further reduces the ubiquitination
dorsal root, and sympathetic ganglia. However, they do not of HIF1α (Kim et al., 2011). Moreover, the NMR expresses higher
manifest anhidrosis, and over time they develop a mottled fur levels of HIF1α than mice in several tissues (Xiao et al., 2017).
with scabs (Smeyne et al., 1994; Indo, 2009). Trka null mice also Lastly, HIF1α probably promotes a glycolytic metabolism (Varum
show an acute decrease of the basal forebrain cholinergic neurons et al., 2011; Prigione et al., 2014), a less efficient pathway to obtain
(BFCNs). Notably, BFCNs have been implicated in the control of ATP than oxidative phosphorylation that works in the absence of
conditioned fear behaviours (Jiang et al., 2016), and mice lacking oxygen. Glycolysis produces lactic acid as a by-product, which
Trka signalling in the forebrain show defective fear conditioning blocks glycolysis by inhibiting PFK1 (phosphofructokinase 1). The
(Sanchez-Ortiz et al., 2012). Furthermore, Trka null mice show a NMR presents a unique adaptation to bypass the glycolysis block
defective thymus formation with no clear delimitations between during hypoxia by using fructose (instead of glucose) as a
the cortex and the stroma and a reduced number of thymocites substrate, enabling the glycolysis even in high lactic-acid
(Garcıa-Suárez et al., 2000). conditions (Park et al., 2017).
The NCC hypothesis states that domesticated animals suffer a Recently, it has been suggested that metabolic regulation
mild neurocristopathy produced by mutations that only partially is essential for the migration and differentiation of the NCC
reduce the activity of genes implicated in the NCC biology (Bhattacharya et al., 2021). Indeed, genetic disorders caused
(Wilkins et al., 2014). The NMR possess between one and three by mutations affecting the glucose metabolism produce severe
amino acid substitutions in the kinase domain of Trka that turn congenital disabilities with severe craniofacial deformations
the receptor hypofunctional which are absent or rare in other similar to neurocristopathies (Chappell et al., 2009; Smith
animals or amongst other AMR (Omerbašić et al., 2016). et al., 2014). The NCC switch to glycolytic metabolism during
Moreover, the expression level of Trka in the NMR is significantly delamination and migration and return to oxidative
lower than that of mouse (Lewin, 2020). It is tempting to see many phosphorylation during differentiation (Bhattacharya et al.,
of the traits of the NMR as partly produced by a mild version of 2021). In fact, HIF1α upregulates many NCC-specific genes
CIPA, caused by the reduced expression of a hypofunctional and increased, and reduced HIF1α activity results in defects
version of Trka. In this line, PRDM12 (PRDI-BF1 and RIZ in the NCC migration (Barriga et al., 2013). Furthermore,
homology domain containing protein 12), a transcription factor alterations in VHL are associated with the von Hippel–Lindau
downstream of Trka also associated with CIP in humans syndrome, a neurocristopathy that can cause a variety of
(Desiderio et al., 2019), shows lower expression and unique amino neoplasms, including the abnormal tissue growth of the
acid variants in the NMR (Lewin, 2020). Altogether, mutations in adrenal gland (Vega-Lopez et al., 2018). Intriguingly, more
the Trka pathway could explain the reduction in the C-fibres and than the 20% of the NMRs in a zoo study presented adrenal
the reduction in pain sensitivity in the NMR (Omerbašić et al., hyperplasia (Delaney et al., 2013).
2016); but also, the lack of fur and sweat glands, the poor
thermoregulation, the reduced and defective thymus, missing
teeth, shorter muzzle and the smaller forebrain. Indeed, Trka ASIC4
could provide a genetic connection between the neural crest and
the reduction of the forebrain suggested by the neural crest The NMR also presents adaptations to protect the brain
domestication hypothesis (Wilkins et al., 2014). Finally, Trka against acidification. Acidotoxicity occurs when the accumulation
mutations also seem to cause a reduction in the fear response in of lactic acid during hypoxia acidifies the medium to pathological

FIGURE 3
Conservation of HIF1α amongst African mole-rat and other subterranean rodents. The naked mole-rat (H. glaber) presents a unique mutation
(T395I) that presumably prevents being targeted for degradation. Alignment generated with ENDscript2 (Robert and Gouet, 2014) using data from
Eigenbrod et al. (2019).
levels, triggering the Ca2+ ASICs (acid-sensing ion channels; Xiong in the appearance of the DS. Chisel-tooth digging is an adaptation
et al., 2004). The NMR shows a significantly reduced expression to hard soils that requires the widening of the skull to enhance
of ASIC4 in the brain compared to mouse, which protects its brain the attachment of larger muscles (Lacey and Patton, 2000;
during acidosis (Husson and Smith, 2018). Furthermore, a recent Mcintosh and Cox, 2016). Therefore, hard soils could impose an
report has identified ASIC4 as a marker of the early differentiation evolutionary pressure on the cranial NCC to favour the widening
of the NCC (Faure et al., 2020), and ASICs expression has been of the rostrum that, in turn, caused the appearance of the
implicated in the processing of the fear response (Wemmie et al., morphological and behavioural side effects associated with the
2004; Vralsted et al., 2011; Taugher et al., 2017). In particular, DS. Furthermore, hard compacted soils can be better exploited in
ASIC4 in mice seems to modulate the freezing behaviour in the cooperation with other individuals to reduce the cost of
presence of predator odour, but not the shock-evoked fear burrowing extensive tunnels and improving the chances of
learning (Lin et al., 2015). This way, mutations affecting the finding dispersed food (Faulkes and Bennett, 2013).
expression of ASICs could reduce the fight-or-flight response in Consequently, the increased social tolerance associated with the
the NMR giving rise to a more docile phenotype. DS could be directly beneficial for subterranean rodents.
Curiously, amongst AMR, the only forelimb digger genus
(Bathyergus) is solitary and territorially aggressive, whilst all
The subterranean niche and social species (Fukomys, Cryptomys, Heterocephalus) are chisel-
self-domestication tooth diggers (Kingdon, 2014) which suggest that evolution of
sociality is easier in chisel-tooth digging species.
Although AMR and NMR present many of the expected Another factor that might have an important impact in the
attributes in underground rodents [fusiform body, short limbs, physiology of the NCC is the hypoxic subterranean
reduced external protuberances (Lacey and Patton, 2000)], many environment. Adaptations to low oxygen conditions that
other NMR’s traits cannot be simply explained by adaptation to affect the HIF1α gene-regulatory network and that promote a
subterranean niche (reduction of the forebrain, hairlessness, lack glycolytic metabolism could have an impact in the NCC
of sexual dimorphism, reduction of pain sensitivity, immature migration (see HIF1α). Nevertheless, it is probable that
thymus). Instead, these traits could be associated with a hypoxic environments only get relevant to changing the NCC
mild-neurocristopathy. physiology as subterranean species become more social with
Traditionally, the DS has been explained as a pleiotropic side larger colony sizes, as seen in the NMR, where hundreds of
effect of selecting for tameness (Belyaev, 1969; Wilkins et al., individuals can inhabit the same colony.
2014). However, it is conceivable that the DS is a side effect of Finally, some of the characteristic traits of the DS could
selecting for other traits associated with the NCC biology be either beneficial or neutral for a subterranean animal: the
different from the reduction of the adrenal glands and the dwarfism, reduction of the ear, shortening of the limbs and
peripheral nervous system as proposed by Wilkins et al. (2014). flattening of the rostrum could be beneficial for moving through
We propose that the selection of chisel-tooth digging could result tunnels and digging, whilst alterations in colouration are probably

FIGURE 4
Domestication syndrome in subterranean rodents. (A) Evolution of the African mole-rats from a domestic to a wild morph. (B) The subterranean
niche could promote self-domestication. Chisel-tooth digging facilitates breaking hard ground, and a colonial, cooperative lifestyle reduces the
amount of work carried out of each individual. Therefore, coloniality and chisel-tooth digging could be adaptations to hard soils. Coloniality needs
a high degree of social tolerance, and chisel-tooth digging needs flat faces for large muscle attachments, which could serve as selective pressures
foe the neural crest producing the appearance of the domestication syndrome in subterranean rodents. Furthermore, large number of individuals
underground generate a hypoxic environment which could favour the appearance of defects in the neural crest development.
less critical to animals living underground. Therefore, once a DS (Vassallo et al., 2021). Indeed, forelimb digging is the primary
trait is selected (e.g., the flattening of the rostrum for chisel-tooth digging mode in Geomys and Ctenomys, whilst many Spalax
digging) the other associated traits will be maintained during species are head-lift diggers (Lacey and Patton, 2000).
evolution because they are beneficial or neutral for the Altogether, this suggest that that most subterranean rodents
subterranean environment. will not present domestication syndrome traits. Yet other,
In summary, we argue that the genes associated with the genetically unrelated, subterranean chisel-tooth digging
physiology of the NCC in the NMR have been under evolutionary species could also present signs of self-domestication. For
pressure (Figure 4). We propose that hard soils associated with example, Spalax ehrenbergi is a superspecies of chisel-tooth
chisel-tooth digging, in conjunction with the tolerance of digging subterranean rodents that inhabit the eastern
subterranean niche for DS traits, fostered the evolution of the DS Mediterranean from Israel to Egypt. Similarly, to AMRs, they
in AMR. AMR ancestors evolved more solitary and aggressive present morphological adaptations to living underground such
behaviours -a wild-like phenotype- as they radiated towards more as short limbs, wide crania (Figure 1), with varying coat
humid areas and encountered more resources and softer soils colouration with occasional white forehead patches (Wolff and
(Faulkes and Bennett, 2013). Indeed, whilst the solitary AMR Sherman, 2008). Strikingly, although they are described as
(Bathyergus, Georychus, and Heliophobius) are restricted to more solitary, chromosomally distinct species present different
humid environments where digging is easier, all social AMR are ratios of aggressive and “pacifist” individuals. The Egyptian
chisel-tooth diggers (Fukomys and Cryptomys) that mostly Spalax variant, which includes only “pacifist” animals, inhabits
inhabit coarse sandy soils and the eusocial AMR (NMR and the aridest environment (Beiles et al., 1992) and can
Damaraland mole-rat) tend to live in areas with hard, compacted be distinguished by its shorter mandible (Corti et al., 1996).
soils (Faulkes and Bennett, 2013). Furthermore, they present convergent genetic adaptations to
Still, the preferred digging mode in the great majority of the hypoxic environment (Fang et al., 2014; Zheng et al., 2022).
rodents is scratching the soil with their forelimbs Therefore, the Egyptian Spalax could also present DS traits.

Testing the NMR domestic phenotype and proposed experiments to test

self-domestication hypothesis our hypothesis.
Taken all these together, we propose that the high degree of
The self-domestication hypothesis for NMR presented in social tolerance necessary for the evolution of cooperative
this paper can be tested in various ways. First, new behavioural breeding and eusociality in AMRs might have occurred through
studies are necessary to evaluate the fear response in different self-domestication. Hard soils could impose an evolutionary
AMR species, for example through the evaluation of the pressure towards chisel-tooth digging, which requires a flatter face
freezing behaviour in classic fear-conditioning experiments to increase the muscle attachments. If the muzzle reduction occurs
where a mild electric footshock is applied after an acoustic through the selection of less active NCC, this could generate the
stimulus. However, the voltage threshold must be carefully pleiotropic effects seen in domestic animals and in
calibrated for each species because they potentially present neurocristopathies and might increase the social tolerance as a
very different pain sensitivities (Lewin, 2020). Alternatively, side effect. Moreover, the gathering of large number of individuals
the freezing behaviour could be measured in the presence of in subterranean tunnels generates a hypoxic environment which
the odour of a predator relevant for AMR species, for example, could lead to molecular adaptations that affect to the NCC
using snake or small carnivore faeces (Kingdon, 2014). development, further enhancing a self-domesticated phenotype.
We expect AMRs with a more domesticated phenotype to An increased social tolerance associated with self-
present an altered fear-conditioned behaviour compared to domestication could be beneficial for subterranean rodents
solitary, forelimb diggers. Furthermore, it is difficult to because a colonial, cooperative lifestyle reduces the digging
compare the aggressiveness and fear response of eusocial and work carried out for any individual and increases the chances to
solitary species, because cooperative breeders can be affected find disperse food (Faulkes and Bennett, 2013). Therefore,
by their ranking a reproductive status (Toor et al., 2022), combination of scarce resources in increasingly arid
variables that should be controlled. Gathering data on the size environments (Faulkes and Bennett, 2013, 2016), together with
and activity of the adrenal glands and stress hormones during the constraints imposed by hard soils and the underground
the fear response across different species could also environment, could create selective pressures that directly and
be informative to test this hypothesis. indirectly lead to the self-domestication of the
To test the implication of NCC in the evolution of AMRs AMR. Intriguingly, in this way, the properties of the soil could
we propose inter-species GFP-labelled NCC grafting experiments act simultaneously as a distal (Faulkes and Bennett, 2013) and
(Wilkins et al., 2014). We expect NCC from the NMR to show a proximal factors for the evolution of sociality. In other words,
deficient migration and/or differentiation in comparison with the evolution of sociality in subterranean rodents could
Bathyergus mole-rats. In addition, we expect that phylogenetic be initiated as a side effect of the underground environment and
analysis of genes undergoing positive and relaxed selection properties of the soil.
(Mitterboeck et al., 2017) amongst AMR will highlight genes Previously, neoteny has been used as a unifying biological
known for their involvement in NCC development or explanation of the many distinctive NMR’s morphological and
in neurocristopathies. physiological traits (Skulachev et al., 2017; Buffenstein et al.,
Finally, we propose the generation of an extensive database of 2020). Nevertheless, it is unclear what evolutionary pressures
subterranean and fossorial rodents containing their digging mode guided the evolution of a neotenic phenotype or how neotenic
and other relevant morphological and behavioural traits. Using traits relate to each other. Instead, we argue that the self-
this database in combination with statistical analysis corrected by domestication hypothesis is a more comprehensive framework for
phylogeny to avoid evolutionary relationships affecting the the evolution of the NMR. In fact, neoteny is often associated with
independence of the individual samples (Freckleton et al., 2002), a domestic phenotype, and neotenic and DS traits can
it would be possible to test if the digging mode in subterranean be confounded (Sánchez-Villagra et al., 2016). Our hypothesis
rodents is associated with DS traits and with an increased offers a clear rationale to explain many NMR’s attributes, how they
social behaviour. relate to each other and pinpoints the evolutionary pressures that
drove them.
The DS can be controversial due to the lack of a consistent
Discussion definition of the traits amongst different publications (Lord
et al., 2020). Under the mild neurocristopathy theory of
We showed that the NMR presents a phenotype compatible domestication, the DS is seen as a collection of pleiotropic
with the DS when compared with solitary AMRs. We suggest that effects of variable penetrance produced by mutations affecting
the DS could be beneficial for the evolution of life underground; the NCC, as can be readily seen in human neurocristopathies
and that the digging mode, determined by the properties of the (Wilkins et al., 2014; Vega-Lopez et al., 2018). Furthermore,
soil, could create an evolutionary pressure on the NCC that in viable animals, the effects of the mutations affecting the
generated the DS amongst AMRs. Furthermore, we highlighted NCC can be further confounded by compensatory mutations
some known mutations compatible with the evolution of a in some of the altered organs (Pavlicev and Wagner, 2012).

For example, all the components of the ear in the NMR show analysis. All authors contributed to the article and approved the
signs of degeneration and intraspecific variation (Mason submitted version.
et al., 2016), however the NMR accumulated positively
selected mutations affecting the cochlear hair bundles (Pyott
et al., 2020). A plausible interpretation is that the general ear Acknowledgments
degeneration produced by a mild-neurocrystopathy was later
compensated by mutations that readapted the NMR hearing GSN acknowledges support from an EASTBIO BBSRC PhD
to the subterranean environment. In addition, some other student training grant (1785593). KK acknowledges support
traits associated with DS are neutral in the subterranean through JSPS Overseas Research Fellowship (H28-1002) and la
niche, and as such, they will not be compensated. This relaxed Caixa postdoctoral junior Leader fellowship (LCF/BQ/
selective pressure in the underground environment could PI20/11760009). Both authors thank Kees Weijer for his
produce the exacerbation of certain traits, explaining perhaps comments and support, Juan Pedro Fernández Doctor for the
the highly variable white forehead patch or the defects in the illustrations of the African mole-rats and Silvia Estrada Arráez for
pain perception in the AMR family. Thus, the AMR could the representation of the Waardenburg syndrome.
show how the combination of positive compensatory
selection and relaxed selection can produce variations Conflict of interest
within the DS.
The study of the NCC could guide future research in the NMR The authors declare that the research was conducted in the
as an animal model and provide new clues to understand its absence of any commercial or financial relationships that could
extraordinary biological traits. The recognition of self- be construed as a potential conflict of interest.
domestication and its pleiotropic effects could lead to a deeper
understanding of the interactions of social behaviour and the
physical environment during evolution. Publisher’s note
All claims expressed in this article are solely those of the
Data availability statement authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
The original contributions presented in the study are included reviewers. Any product that may be evaluated in this article, or
in the article/Supplementary material, further inquiries can claim that may be made by its manufacturer, is not guaranteed or
be directed to the corresponding author. endorsed by the publisher.
Author contributions Supplementary material

GSN envisioned the project and wrote the first version of the The Supplementary material for this article can be found
manuscript. GSN and KK acquired, analysed the data, and revised online at: https://www.frontiersin.org/articless/10.3389/
and corrected the manuscript. KK carried out the phylogenetic fevo.2022.987177/full#supplementary-material
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Unusual Occurrence of Domestication Syndrome Amongst African Mole-Rats: Is The Naked Mole-Rat A Domestic Animal?

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TYPE Hypothesis

naked mole-rat, African mole-rat, eusociality, domestication, neural crest, digging

Frontiers in Ecology and Evolution 01 frontiersin.org

Introduction The family of African mole-rats (AMR, family Bathyergidae)

Frontiers in Ecology and Evolution 02 frontiersin.org

Frontiers in Ecology and Evolution 03 frontiersin.org

Frontiers in Ecology and Evolution 04 frontiersin.org

TABLE 1 Selected domestication syndrome traits in the African mole rats.

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Reproductive biology Whilst domestic animals seem to present an earlier sexual

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Frontiers in Ecology and Evolution 07 frontiersin.org

Frontiers in Ecology and Evolution 08 frontiersin.org

Frontiers in Ecology and Evolution 09 frontiersin.org

Frontiers in Ecology and Evolution 10 frontiersin.org

Testing the NMR domestic phenotype and proposed experiments to test

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Author contributions Supplementary material

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Frontiers in Ecology and Evolution 13 frontiersin.org

Frontiers in Ecology and Evolution 14 frontiersin.org

Frontiers in Ecology and Evolution 15 frontiersin.org

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