Lagomorpha as a Model Morphological System

Abstract

Due to their global distribution, invasive history, and unique characteristics, European rabbits are recognizable almost anywhere on our planet. Although they are members of a much larger group of living and extinct mammals [Mammalia, Lagomorpha (rabbits, hares, and pikas)], the group is often characterized by several well-known genera (e.g., Oryctolagus, Sylvilagus, Lepus, and Ochotona). This representation does not capture the extraordinary diversity of behavior and form found throughout the order. Model organisms are commonly used as exemplars for biological research, but there are a limited number of model clades or lineages that have been used to study evolutionary morphology in a more explicitly comparative way. We present this review paper to show that lagomorphs are a strong system in which to study macro- and micro-scale patterns of morphological change within a clade that offers underappreciated levels of diversity. To this end, we offer a summary of the status of relevant aspects of lagomorph biology.

Full text

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REVIEW
published: 01 July 2021
doi: 10.3389/fevo.2021.636402
Edited by:
Rodney L. Honeycutt,
Pepperdine University, United States
Reviewed by:
Conrad Matthee,
Stellenbosch University, South Africa
John Wible,
Carnegie Museum of Natural History,
United States
Thomas Martin,
University of Bonn, Germany
*Correspondence:
Brian Kraatz
bkraatz@westernu.edu
Specialty section:
This article was submitted to
Phylogenetics, Phylogenomics,
and Systematics,
a section of the journal
Frontiers in Ecology and Evolution
Received: 04 January 2021
Accepted: 14 May 2021
Published: 01 July 2021
Citation:
Kraatz B, Belabbas R,
Fostowicz-Frelik Ł, Ge D-Y,
Kuznetsov AN, Lang MM,
López-Torres S, Mohammadi Z,
Racicot RA, Ravosa MJ, Sharp AC,
Sherratt E, Silcox MT, Słowiak J,
Winkler AJ and Ruf I (2021)
Lagomorpha as a Model
Morphological System.
Front. Ecol. Evol. 9:636402.
doi: 10.3389/fevo.2021.636402
Lagomorpha as a Model
Morphological System
Brian Kraatz1*, Rafik Belabbas2, Łucja Fostowicz-Frelik3,4,5 , De-Yan Ge6,
Alexander N. Kuznetsov7, Madlen M. Lang8, Sergi López-Torres5,9,10,
Zeinolabedin Mohammadi11 , Rachel A. Racicot12,13, Matthew J. Ravosa14 ,
Alana C. Sharp15 , Emma Sherratt16, Mary T. Silcox8, Justyna Słowiak5,
Alisa J. Winkler17,18 and Irina Ruf13
1Department of Anatomy, Western University of Health Sciences, Pomona, CA, United States, 2Laboratory
of Biotechnologies Related to Animal Reproduction, Institute of Veterinary Sciences, Blida 1 University, Blida, Algeria, 3Key
Laboratory of Vertebrate Evolution and Human Origins, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese
Academy of Sciences, Beijing, China, 4CAS Center for Excellence in Life and Paleoenvironment, Beijing, China, 5Institute
of Paleobiology, Polish Academy of Sciences, Warsaw, Poland, 6Key Laboratory of Zoological Systematics and Evolution,
Institute of Zoology, Chinese Academy of Sciences, Beijing, China, 7Borissiak Paleontological Institute, Russian Academy
of Sciences, Moscow, Russia, 8Department of Anthropology, University of Toronto Scarborough, Toronto, ON, Canada,
9Division of Paleontology, American Museum of Natural History, New York, NY, United States, 10 New York Consortium
in Evolutionary Primatology, New York, NY, United States, 11 Department of Biology, Faculty of Science, Gorgan, Golestan,
Iran, 12 Department of Biological Sciences, Vanderbilt University, Nashville, TN, United States, 13 Abteilung Messelforschung
und Mammalogie, Senckenberg Forschungsinstitut und Naturmuseum Frankfurt, Frankfurt am Main, Germany,
14 Departments of Biological Sciences, Aerospace and Mechanical Engineering, and Anthropology, University of Notre Dame,
Notre Dame, IN, United States, 15 Evolutionary Morphology and Biomechanics Group, Institute of Life Course and Medical
Sciences, University of Liverpool, Liverpool, United Kingdom, 16 School of Biological Sciences, The University of Adelaide,
Adelaide, SA, Australia, 17 Roy M. Huffington Department of Earth Sciences, Southern Methodist University, Dallas, TX,
United Stats, 18 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States
Due to their global distribution, invasive history, and unique characteristics, European
rabbits are recognizable almost anywhere on our planet. Although they are members of
a much larger group of living and extinct mammals [Mammalia, Lagomorpha (rabbits,
hares, and pikas)], the group is often characterized by several well-known genera (e.g.,
Oryctolagus,Sylvilagus,Lepus, and Ochotona). This representation does not capture
the extraordinary diversity of behavior and form found throughout the order. Model
organisms are commonly used as exemplars for biological research, but there are a
limited number of model clades or lineages that have been used to study evolutionary
morphology in a more explicitly comparative way. We present this review paper to show
that lagomorphs are a strong system in which to study macro- and micro-scale patterns
of morphological change within a clade that offers underappreciated levels of diversity.
To this end, we offer a summary of the status of relevant aspects of lagomorph biology.
Keywords: Lagomorpha, Leporidae, Ochotonidae, evolution, morphofunction, model organism, morphology,
phylogeny
INTRODUCTION
Lagomorpha (rabbits, hares, and pikas) is a globally distributed (barring Antarctica) extant
mammalian order within the larger superorder Euarchontoglires (rodents, lagomorphs, treeshrews,
colugos, and primates) (Murphy et al., 2001). The order consists of herbivorous species across
two extant families, the Ochotonidae (pikas) and the Leporidae (rabbits and hares) (Stock, 1976;
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Forsyth et al., 2005;Hoffmann and Smith, 2005;Burgin et al.,
2018;Smith et al., 2018;Figure 1). There are presently 12 living
lagomorph genera recognized, subsuming 108 recognized species
(see Burgin et al., 2018 for a recent treatment). These genera
are distributed unequally between two families; the Leporidae
contains 11 genera, the most well-known being Lepus (hares and
jackrabbits), Sylvilagus (cottontails), and Oryctolagus (European
rabbit) (Naff and Craig, 2012;Graham, 2015) while Ochotonidae
includes only a single living genus, Ochotona (pikas) (Hoffmann
and Smith, 2005;Ge et al., 2012;Smith et al., 2018;Figure 2).
Lagomorphs have featured prominently in the set of non-
human model organisms that have driven many advances within
the biological sciences over the last century, particularly to
understand genetic, genomic, or developmental processes that
drive biological change (Leonelli and Ankeny, 2013). Recent
research on understanding the genome level architecture of
life has included the European rabbit (Oryctolagus cuniculus),
the mountain hare (Lepus timidus), the snowshoe hare (Lepus
americanus), and the American pika (Ochotona princeps)
(Marques et al., 2020). Oryctolagus and Ochotona have often
served as the model lagomorphs in larger scale comparative
studies of mammals (e.g., Sánchez-Villagra et al., 2017;Hecker
et al., 2019). Though such studies have revealed much about
broad patterns among mammals, often in an evolutionary
context, there has been little comprehensive comparative work
done within the lagomorph clade.
Monaghan (2014, p. 1019), through the lens of behavioral
ecology, argue that the modern concept of model organisms
FIGURE 1 | A representative selection of extant lagomorphs, including: (A) Lepus americanus (snowshoe hare); (B) Lepus europaeus (European hare); (C) Lepus
californicus (Black-tailed jackrabbit); (D) Nesolagus timminsi (Annamite striped rabbit); (E) Oryctolagus cuniculus (European rabbit); (F) Romerolagus diazi (Volcano
rabbit); (G) Sylvilagus audubonii (Audobon’s cottontail); (H) Sylvilagus palustris (Marsh rabbit); (I) Ochotona curzoniae (Black-lipped pika). All images from Myers et al.
(2020).
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FIGURE 2 | Phylogeny of selected extant lagomorph species by Ge et al. (2013).
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has limited some insights within the biological sciences away
from a more intentional focus “to understand the processes
responsible for the diversity that we see in animal form
and function.” Because such mechanisms often can be best
understood by studying lineages and clades, we argue that
Lagomorpha represent an ideal clade with which to explore
these processes. Chapman and Flux (1990) have made such an
argument for lagomorphs, which we expand here to include
current scientific standings.
Among vertebrates, the radiations of anole lizards (Anolis) are
a strong example of a clade that has served as a model system to
study integrative processes in evolution and adaptive radiations
(Sanger and Kircher, 2017). Extensive work on Anolis has
included the historical, genetic, and developmental basis of anole
diversity (e.g., Losos, 2011;Sanger et al., 2012;Sherratt et al., 2015;
Corbett-Detig et al., 2020;Velasco et al., 2020). Though Anolis
represents a strong comparative system, it is limited at scales
that span longer geological periods. Lagomorpha are anchored
by an extensively used model organism, the European rabbit
(O. cuniculus), but include a rich fossil record that goes back
to the Paleocene, a diverse group of living lineages, significant
morphological and ecological disparity, and functional variation
in multiple key aspects of behavioral biology. The goal of this
review is to summarize key biological features of the lagomorph
clade to highlight how they represent an ideal group to investigate
both macro- and micro-level questions in morphological biology.
LAGOMORPH BIOLOGY
Rabbits and hares are found in forests, in open scrub, or
savannah in Eurasia, Africa, and North, Central, and northern
South America. Additionally, the European rabbit and hare have
been introduced into Australia and South America (Chapman
and Flux, 1990;Ge et al., 2013). Lagomorphs are hind-gut
fermenters and require cecotrophy as well as at least a 15%
crude fiber diet to maintain gastrointestinal health. Leporids are
typically crepuscular and most active during the twilight hours
at sunrise and sunset. They eat a wide variety of herbaceous
material and grasses represent 30% of the plant food species
ingested (Ge et al., 2013;Delaney et al., 2018). Pikas require a
more specialized environment than hares and rabbits. They are
most often found at high elevations in cold semiarid regions
(Delaney et al., 2018). Pikas are distributed mainly throughout
Asia, Eastern Europe, and western North America (Berkovitz
and Shellis, 2018). They consume a wide variety of herbaceous
plants, but grasses are a much smaller component of the diet
than in that of rabbits and hares (Ge et al., 2013). The eyes of
lagomorphs are laterally positioned, providing a circular field of
vision (Delaney et al., 2018).
Among lagomorphs, the pikas are generally smaller (12–
25 cm long; 100–400 g), with short limbs and small ears
compared to their larger rabbit and hare counterparts (Ge
et al., 2013;Delaney et al., 2018). Rabbits and hares have a
short tail and lack or have minimal sexual dimorphism (e.g.,
Chapman and Ceballos, 1990;Fa and Bell, 1990; though see Orr,
1940 on sexual dimorphism in Sylvilagus); pikas lack an external
tail and both sexes have a cloaca-like structure and lack sexual
dimorphism (Graham, 2015). Most leporid males have testes
located in a scrotum in front of the penis and females possess two
to five pairs of mammary glands. Embryonically, the mammary
glands develop from the mammary line (ridge), as is typical
for placentals. However, it was found that, in the European
rabbit, the anterior pair of mammary glands appear separately
above the mammary ridge, in the axilla region of the forelimb
(Propper, 1976). Gestation is 21–30 days in Ochotonidae and 24–
55 days in Leporidae. Ochotonidae are typically altricial, though
in some species the neonates are covered with fur. Leporidae
show both patterns, altricial (Brachylagus idahoensis,Bunolagus
monticularis,O. cuniculus, and Sylvilagus spp.) and precocial
(Lepus spp.) species (Lissovsky, 2016). Pentalagus furnessi,
Poelagus marjorita,Pronolagus rupestris, and Romerolagus diazi
are altricial as well but the young are variable with respect to
fur at birth. For some rare species of Pronolagus,Nesolagus
spp., and Caprolagus hispidus, almost no information is yet
available due to their rarity (Lissovsky, 2016;Schai-Braun and
Hackländer, 2016). This is representative of our anatomical
knowledge of lagomorphs, while there are comprehensive treaties
on Oryctolagus cuniculus (Krause, 1884;Bensley, 1921;Barone
et al., 1973) other species are much less studied.
SYSTEMATICS
Within the 11 extant leporid genera there are approximately
75 species and 35 species in the single extant ochotonid genus,
Ochotona (Hoffmann and Smith, 2005;Ge et al., 2012, 2013;
Burgin et al., 2018). A summary of the fossil record of the
Lagomorpha by Ge et al. (2013) includes about 45 genera and
more than 190 species of Leporidae, and about 32 genera and
180 species of Ochotonidae (for both families, these are formally
nominated taxa). The following sections highlight key features of
these groups and the status of systematic relationships.
Key Craniodental Characters
Lagomorpha have been defined by a broad set of specific
characters, most of which are related to mastication and
locomotion, due somewhat to the relevant abundance of related
osteological regions in the fossil record (e.g., López Martínez,
1985;Asher et al., 2005, 2019;Wible, 2007;Lopez-Martinez, 2008;
Koenigswald et al., 2010). The living lagomorph families can be
easily distinguished by several morphological characters. Besides
obvious external anatomical traits such as size and shape of the
outer ear and limb proportions, there exist discrete craniodental
differences between the two families: e.g., proportions of the
rostrum and absence or presence of fenestration and pitting
of the os maxillare and bones of the posterior skull (Wood,
1940;Angermann et al., 1990;Wible, 2007). As in rodents, all
lagomorphs have hypselodont (evergrowing) incisors, which are
unreplaced deciduous teeth. They differ from rodents in having
a second set of small permanent upper incisors. The dental
formula in leporids is: I 2/1, C 0/0, P 3/2, M 3/3 with 28 total
teeth and in ochotonids is: I 2/1, C 0/0, P 3/2, M 2/3 with 26
teeth (Graham, 2015;Delaney et al., 2018). See Wible (2007),
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Fostowicz-Frelik and Meng (2013), and Ruf (2014) for a review
of lagomorph cranial literature. Soft tissue structures such as
the cephalic arterial system (Bugge, 1974) also can be used for
investigation of fossil species because adjacent bony structures
(e.g., foramina, sulci) serve as proxies.
In contrast, taxonomy and systematic relationships at the
genus and species level, and the phylogenetic position of certain
fossil taxa, remain unresolved due to possible homoplastic
evolution of certain characters (Robinson and Matthee, 2005;
Kraatz et al., 2010;Fostowicz-Frelik and Meng, 2013;Asher et al.,
2019). For instance, the premolar foramen was regarded as a
synapomorphic character of Ochotonidae although a puzzling
pattern among extant Lagomorpha became evident (Corbet,
1983: lateral palatal foramen); however, a study using broad taxon
sampling including fossil species clearly revealed its diversity and
homoplastic nature among Lagomorpha (Fostowicz-Frelik and
Meng, 2013). In his comprehensive comparative description of
the external craniomandibular anatomy of O. princeps,R. diazi
and further selected Leporidae, Wible (2007) complemented and
refined a character matrix comprising 229 traits including 92
craniomandibular characters (Meng et al., 2003;Asher et al.,
2005). To date, intracranial structures are underrepresented in
phylogenetic studies of Lagomorpha. Recent studies on the nasal
and ear region defined new intracranial characters that can
significantly contribute to a deeper understanding of lagomorph
systematics, evolution, and morphofunction. For example, extant
Ochotonidae and Leporidae differ significantly in the number
of turbinals (Ruf, 2014). The former have a reduced number of
olfactory turbinals and lack the interturbinal in the frontoturbinal
recess. The turbinal pattern in the ethmoturbinal recess of
Leporidae shows certain apomorphic character states (number of
ethmo- and interturbinals) in several clades that can also be used
for systematic purposes at the genus and species level (Ruf, 2014).
The middle ear morphology of extant Lagomorpha reveals
unique family-specific patterns of the anterior attachment of the
malleus by means of the processus anterior and its processus
internus praearticularis; however, the phylogenetic polarization
of this character still was pending (Maier et al., 2018). A first
attempt to polarize the observed patterns could be achieved
by the first high-resolution computed tomography (µCT) study
on intracranial structures in a fossil lagomorph; Palaeolagus
haydeni reveals that early ontogenetic stages of Ochotona may
represent the plesiomorphic lagomorph pattern (Ruf et al., 2021).
This clearly shows the potential of µCT investigations of fossil
Leporidae and Ochotonidae for elucidating the evolution of
intracranial characters.
Traditionally, dental characters play a major role in lagomorph
taxonomy and systematics, especially in fossil species, and
there is extensive literature summarizing this important system
(e.g., Dawson, 1958;Hibbard, 1963;White, 1991;Averianov
and Tesakov, 1997;Patnaik, 2002;Kraatz et al., 2010;Winkler
and Tomida, 2011). The occlusal pattern of anterior premolars
(particularly p3) is highly diagnostic, even on a lower taxonomic
level. However, although most individuals within an extant or
fossil population will have the diagnostic pattern, there often are
individuals (in particular, younger ones with less occlusal wear)
preserving a pattern that would suggest assignment to a different
taxon (Hibbard, 1963). The masticatory pattern, also reflected in
the occlusal morphology and the number of shearing blades of
the cheek teeth, separates most Ochotonidae from all but two
genera (Romerolagus diazi and Pronolagus) of extant Leporidae
(Koenigswald et al., 2010). Beside systematic relationships and
some species-specific patterns, this character complex provides
insight into the evolution of functional adaptations. The lagicone
structure, a complex enamel structure on the buccal occlusal
surface of stem lagomorphs and certain Ochotonidae (López
Martínez, 1985), becomes reduced in fossil European ochotonids;
thus, the shearing function in pikas is increased. In most
Leporidae the grinding function is enhanced by crenulation
of specific enamel bands (Koenigswald et al., 2010). The two
living lagomorph families also can be distinguished by the
enamel pattern (schmelzmuster) of their incisors, a key character
complex in terms of evolution and morphofunction of Glires
(Martin, 1999, 2004). Generally, the incisors of Leporidae show
a single-layered schmelzmuster in concert with multi-layered
Hunter-Schreger bands (HSB). This pattern is derived from a
double-layered schmelzmuster as observed in an undetermined
leporid from the early Eocene of Kyrgyzstan and in some
Mimotonidae. In contrast, Ochotonidae have a multi-layered
schmelzmuster with modified HSB and enamel patterns differing
in upper and lower incisors (Martin, 1999, 2004).
Key Postcranial Characters
Overall, the body-plan of lagomorphs is relatively uniform
throughout their evolutionary history. There are two basic
archetypes, which are represented by two extant families: the
longer legged rabbits and hares, and shorter legged, rather
stocky ochotonids. The ochotonid-like morphotype (or small,
relatively short-limbed rabbits) dominated during the Paleogene,
which suggests that true cursorial abilities appeared within
lagomorphs later in the early Neogene. However, the structure
of the lagomorph hindlimb with the closely connected tibia
and fibula (fused already in the late Eocene Palaeolagus), and a
unique direct calcaneo-fibular contact known from the Middle
Paleocene duplicidentate of China (Fostowicz-Frelik, 2017)
indicate cursorial adaptations since the groups’ inception. The
calcaneus is known in several Eocene lagomorphs, including the
Asian Dawsonolagus and Strenulagus (Li et al., 2007;Fostowicz-
Frelik et al., 2015a) and North American Palaeolagus (Wood,
1940). In most Paleogene lagomorphs, calcaneal structure is
similar to Ochotona; the latter is somewhat stockier (compared
to that of leporids) with a proportionally shorter tuber and
calcaneal body. The calcaneal canal is a striking synapomorphy
of Lagomorpha (Bleefeld and Bock, 2002).
Beginning with the Mio-Pliocene radiation, the postcranial
skeleton of Leporidae acquires more cursorial adaptations.
Overall, the limb bones become slenderer and the tibiofibula
and foot complex (including also tarsal elements) elongate (e.g.,
Fostowicz-Frelik, 2007). Studies of Neogene leporid postcrania
based on large samples and/or complete specimens are relatively
uncommon. Most studies focus on cursorial and fossorial
adaptations, for example, (1) a partial skeleton of Trischizolagus
(early Pliocene, Moldova; Averianov, 1995) suggests it was less
cursorial than Hypolagus and was a strong digger, although not as
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fossorial as Oryctolagus; and (2) a large sample of Serengetilagus
(based on forelimb anatomy; hindlimb not yet studied) ally
this genus with smaller, relatively less cursorial leporids such
as Oryctolagus and suggest it may have been semi-fossorial
(early Pliocene, Tanzania; Winkler et al., 2016). As an example,
from Ochotonidae, Dawson (1969) described the osteology of an
abundant, albeit geologically younger (Quaternary, ca. 2.6 Ma to
200 BP) species Prolagus sardus from collections primarily from
Corsica and Sardinia. Dawson concluded that the species “was
probably not suited for speed over any great distance but was
probably fairly adept at digging and well adapted for climbing and
scrambling. . .” (Dawson, 1969, p. 187).
Phylogenetic Placement of Lagomorpha
The placement of Lagomorpha within the larger mammalian
clade had been problematic for over a century (see Kraatz et al.,
2010 for a review) due to an incomplete fossil record that did
not include important stem lagomorphs. The earliest molecular
phylogeny based on the eye lens protein alpha-crystallin revealed
a close phylogenetic relationship of rabbits to primates (de
Jung et al., 1977). That work also showed that rodents and
lagomorphs form a supraordinal group (Glires) based on the
interphotoreceptor retinoid binding protein (IRBP) (de Jung
et al., 1977;Stanhope et al., 1992, 1996). New fossil discoveries
such as the primitive rodent Tribosphenomys from strata of
transitional Paleocene-Eocene age in Inner Mongolia (China)
and Mongolia (Meng et al., 1994;Asher et al., 2005) began to
support the close relationship between lagomorphs and rodents
as cohort Glires. However, 91 orthologous protein sequences
supported Lagomorpha as more closely related to Primates
and Scandentia (treeshrews) than they are to rodents (Graur
et al., 1996). The monophyly of a Glires clade was supported
by complete mitochondrial genomes (Lin et al., 2002) and was
consistent with the result of three nuclear studies, which included
the von Willebrand Factor, an interphotoreceptor retinoid-
binding protein, and an Alpha 2B adrenergic receptor (Huchon
et al., 2002). Subsequently, a phylogenetic reconstruction based
on 18 homologous gene segments confirmed Glires as a sister
taxon to primates, colugos and treeshrews (Douady and Douzery,
2003). Analyses based on eight housekeeping genes further
confirmed the monophyly of Glires (Kullberg et al., 2006).
This was further evidenced by genome level data, including
the monophyly of Glires, their close relationship with Primates,
Scandentia and Dermoptera; and that all these taxa together
formed the clade of Euarchontoglires (=Supraprimates) (Kumar
et al., 2013;Foley et al., 2016;Esselstyn et al., 2017;Upham et al.,
2019;Genereux et al., 2020).
Phylogenetic Relationships Within
Lagomorpha
Early studies of morphological and ecological traits of extant
lagomorphs resulted in different phylogenetic hypotheses
(Dawson, 1981;Stoner et al., 2003). Considerable homoplasy
in the morphology of leporid species was identified by
Corbet (1983) after examining 21 morphological characteristics
for 22 leporid species. More recent morphometric studies of
lagomorphs have also found a high degree of homoplasy, low
phylogenetic signal, and adaptive divergence in skull shape
(Ge et al., 2015;Kraatz and Sherratt, 2016;Feijó et al., 2020).
These studies highlight the difficulties in reconstructing a robust
phylogeny for lagomorphs, particularly at the intergeneric level,
by using morphological data. Relationships of extant genera
were reconstructed based on the combined matrix of five nuclear
and two mitochondrial DNA fragments: Ochotona is the earliest
diverging taxon, which represents a relict genus of Ochotonidae;
Nesolagus,Poelagus, and Pronolagus form an early diverging
monophyletic clade within Leporidae. Romerolagus,Lepus,
Sylvilagus,Brachylagus,Bunolagus,Oryctolagus,Caprolagus,
and Pentalagus form another clade of Leporidae (Matthee et al.,
2004;Robinson and Matthee, 2005). The general phylogenetic
structure of the tree was supported by genomic orthologous
retroposon insertion sites (Kriegs et al., 2010).
Within Lagomorpha, Lepus and Ochotona represent the most
speciose extant genera. Molecular phylogenies within each of
these genera have been extensively studied. The early studies are
generally based on a single locus mitochondrial DNA marker,
cytochrome b (CYTB) (Yu et al., 1996;Halanych et al., 1999;Niu
et al., 2004). Five major species groups within Ochotona were
recognized: the northern group, the surrounding Qinghai-Tibet
Plateau group, the Qinghai-Tibet Plateau group, the Huanghe
group, and the Central Asia group (Niu et al., 2004;Lanier
and Olson, 2009). Subsequently, more genes were included,
for example, the dataset of CYTB 12S, ND4, and the control
region of the mitochondrial genome revealed the Chinese hare
(Lepus sinensis) is not a monophyletic group, with three species
groups recognized within Lepus: North America species group,
South Africa species group and the Eurasia species group
(Wu et al., 2005;Liu et al., 2011). Recent studies based on
exome of the whole genome supported five subgenera of extant
Ochotona:Alienauroa,Conothoa,Ochotona,Lagotona, and Pika,
with divergence time and phylogeographic analyses inferring the
last common ancestor of extant pikas first occurred in the middle
Miocene, approximately 14 Ma (Wang et al., 2020).
Mito-nuclear discordance was shown in Lepus (Kinoshita
et al., 2019) and Ochotona (Lissovsky et al., 2019), which could
be the result of incomplete lineage sorting, sex-biased dispersal,
asymmetrical introgression, natural selection, or Wolbachia-
mediated genetic sweeps. The genome of four lagomorph species
(O. cuniculus,L. timidus,L. americanus, and O. princeps) has
been sequenced and annotated (Marques et al., 2020). These
data provide references for more deep level studies in exploring
the morphology, behavior, as well as population genetics of
lagomorphs. However, more novel sampling is still needed for
a complete phylogenomic analyses of Lagomorpha. Moreover,
integrating data from fossils with extant species probably will
provide a more comprehensive overview on the evolutionary
history of lagomorphs.
THE FOSSIL RECORD
Lagomorphs of modern aspect are known in the fossil record
since the Early Eocene (ca. 52 Ma) of China (Li et al., 2007;
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Wang et al., 2010) and Mongolia (Lopatin and Averianov, 2008).
The Asian record of Lagomorpha precedes that of North America
by over 10 million years, and that of Europe by almost 20 Ma. Asia
is considered the diversification center for the Duplicidentata,
treated as a more inclusive group including crown lagomorphs
and species more closely related to extant lagomorphs than
rodents. Many of these earliest species are characterized by a
double set of the upper and lower incisors and are referred to
the ancestral Mimotonidae (Meng and Wyss, 2001;Fostowicz-
Frelik et al., 2015b;Fostowicz-Frelik, 2017), an extinct fossil
group restricted to China, Mongolia, and Kyrgyzstan (Li, 1977;
Li and Ting, 1985;Averianov, 1994;Asher et al., 2005;Li C.
K. et al., 2016;Fostowicz-Frelik, 2020). The mimotonids are a
paraphyletic group with two distinct lineages: the small Paleocene
mimotonids (Li, 1977;Li C. K. et al., 2016;Fostowicz-Frelik,
2020) and the large Eocene forms (Bohlin, 1951;Averianov,
1994;Meng et al., 2004;Asher et al., 2005;Fostowicz-Frelik
et al., 2015b). One of the large forms, Mimolagus, likely survived
to the Eocene–Oligocene boundary (Bohlin, 1951; see also
Zhang and Wang, 2016) and was the terminal representative
of the mimotonids (Fostowicz-Frelik et al., 2015b). Although
Lagomorpha and Mimotonidae share many similarities in dental
structure, most of these characters are plesiomorphic; thus, none
of the mimotonids could be unquestionably named the direct
ancestor of lagomorphs. All the Eocene lagomorph taxa and a
substantial part of the Oligocene species are regarded as stem
lagomorphs, although they frequently show similarities to either
of the crown groups (Leporidae and Ochotonidae, see Fostowicz-
Frelik and Meng, 2013).
The earliest findings of non-mimotonid stem lagomorphs
come from the latest Early Eocene of Asia: Dawsonolagus from
Inner Mongolia, China (Li et al., 2007), and Arnebolagus from
Mongolia and Kyrgyzstan (Averianov and Lopatin, 2005;Lopatin
and Averianov, 2008, 2020). By the Middle Eocene, China
and Kyrgyzstan witnessed the first lagomorph diversification,
yielding multiple genera (Li, 1965;Tong, 1997;Averianov and
Lopatin, 2005;Meng et al., 2005;Fostowicz-Frelik et al., 2012,
2015a;Fostowicz-Frelik and Li, 2014;Li Q. et al., 2016).
By the end of the Eocene, the lagomorph fauna of Asia
was enriched, in particular, by Desmatolagus (Meng et al.,
2005), a key lagomorph genus for the Oligocene in Asia
(Erbajeva and Daxner-Höck, 2014).
Asian Eocene lagomorphs were very small, with an estimated
body mass under 150 g (Fostowicz-Frelik et al., 2015b). Starting
from the Middle Eocene, Asian lagomorphs doubled in size, but
even then, most of the Paleogene genera did not exceed the
size of a large Ochotona (ca. 250 g). With the beginning of the
Oligocene, the Desmatolagus lineage became diverse, abundant,
and widespread throughout Central Asia (Sych, 1975;Huang,
1987;Wang, 2007), surviving until the Miocene, and possibly
entering Europe (Early Oligocene, Vianey-Liaud and Lebrun,
2013) and North America (Late Oligocene; Dawson, 2008). Along
with Desmatolagus, in the late Early/Middle Oligocene, the first
plausible representatives of crown lagomorphs appear in Asia:
Sinolagomys (an early ochotonid from China and Mongolia; see
Erbajeva et al., 2017) and Ordolagus (probably an early leporid
from China; Bohlin, 1942).
In North America, the lagomorph fossil record starts in
the late Middle Eocene (ca. 42 Ma; see Dawson, 2008).
Two genera, Mytonolagus and Procaprolagus, are known from
this period and likely represent two different immigrations
from Asia (Dawson, 2008). There is a significant increase in
diversity in the Lagomorpha of North America beginning in
the Late Eocene: this includes genera with true hypselodont
cheek teeth such as Chadrolagus (Gawne, 1978;Fostowicz-
Frelik, 2013) and the first representatives of Palaeolagus and
Megalagus (Dawson, 1958, 2008). At the Eocene-Oligocene
boundary (EOB), a turnover in the lagomorph fauna is observed,
defined by a shift from unilateral hypsodonty (i.e., high-crowned,
evergrowing lingual sided and low-crowned buccal sided cheek
teeth) toward a hypselodont condition in their cheek teeth (‘full’
hypsodonty). Among Megalagus and Palaeolagus, the unilaterally
hypsodont species went extinct at the EOB and were replaced
by species either with greatly reduced buccal roots, or fully
developed hypselodont cheek teeth. Litolagus, with its advanced
cranial morphology, may represent either crown Leporidae
(see Fostowicz-Frelik, 2013) or an advanced stem taxon. Later
during the Early Oligocene, other hypselodont species appear, for
example, Palaeolagus burkei may be closely related to Litolagus
or it may have convergent traits in dentition and bulla structure,
which could be a result of adaptations to more open habitats
of the North American plains. All lagomorph lineages that
originated during the Eocene-to-Oligocene interval in North
America went extinct by the Early Miocene (Dawson, 2008).
In Europe, the earliest lagomorphs are known from the Early
Oligocene of France (Ephemerolagus nievae;Vianey-Liaud and
Lebrun, 2013) and Germany (Shamolagus franconicus;Heissig
and Schmidt-Kittler, 1975, 1976). The remains are scarce, and
their appearance is limited only to the type localities, but
these genera clearly represent two distinct lineages. Lagomorph
lineages reappearing in Europe by the end of the Oligocene
(Tobien, 1974, 1975) are regarded as either primitive ochotonids
(McKenna, 1982) or as stem line representatives (Fostowicz-
Frelik and Meng, 2013). These lineages persist in Europe from the
Late Oligocene (Fostowicz-Frelik, 2016) until the Early Miocene
(Tobien, 1974).
The Early to Middle Miocene (beginning ca. 23 Ma) is
characterized by the last records of the stem lagomorphs and the
worldwide radiation of the Ochotonidae (Dawson, 2008;Ge et al.,
2013). The Early Miocene record of stem Lagomorpha consists
mostly of derived Desmatolagus (Lopatin, 1998;Wang et al.,
2009) and Asian representatives of Amphilagus, a Late Oligocene-
Early Miocene genus from Europe, which has been reported
recently also from Mongolia and Siberia (Erbajeva, 2013;Erbajeva
et al., 2016). In North America, the earliest Miocene marks
the last appearance of taxa such as Megalagus and Palaeolagus
(Dawson, 2008). In Europe a plethora of Ochotonidae appeared
in the Early Miocene, for example Alloptox and Prolagus
(Tobien, 1974, 1975;López Martínez, 2001). In the Early and
Middle Miocene taxa such as these existed alongside the stem
lineages, which went extinct no later than the Middle Miocene
(Tobien, 1974;Fostowicz-Frelik et al., 2012). Prolagus, first
reported from the Early Miocene, was the most speciose and
long-lived lineage of the European ochotonids and the last
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species, P. sardus, survived in the Mediterranean until historic
times (Lopez-Martinez, 2008). Simultaneously, starting from the
Middle Miocene, a lineage leading to extant Ochotona, the only
surviving member of the Ochotonidae, arose in Central Asia
(Wang et al., 2009;Fostowicz-Frelik and Frelik, 2010): this lineage
also flourished in Asia during the Pliocene.
The earliest known ochotonids from North America are from
near the Oligocene-Miocene boundary: all these early immigrants
went extinct not later than ca. 9 Ma (Dawson, 2008). Ochotona
was first reported in North America in the Late Miocene: this
genus was geographically and taxonomically diverse during the
Late Miocene-Pliocene in the Northern Hemisphere (Erbajeva
et al., 2015). The genus decreased in diversity and relative
abundance beginning in the Pleistocene (ca. 2.6 Ma; Erbajeva
et al., 2015).
The earliest lagomorphs to reach Africa were representatives
of the Asian sinolagomyine ochotonids, which dispersed into
Africa as far as southern Africa in the Early Miocene (Winkler
and Avery, 2010). Extinction of the African sinolagomyines by
the Middle Miocene was coincident with the global extinction of
archaic ochotonids by the end of the Middle Miocene (Erbajeva
et al., 2015). The only post Middle Miocene reports of ochotonids
from Africa are Prolagus, reported from the Late Miocene to Early
Pleistocene of northern Africa (López Martínez, 2001;Winkler
and Avery, 2010). In contrast to the ochotonids, Ge et al. (2013)
noted that the diversity of the Leporidae was relatively modest
during much of the Miocene, increasing around the Miocene-
Pliocene transition, and with high diversity continuing into the
Pliocene and Pleistocene.
The earliest record of leporids in Africa is in the Late Miocene
(Winkler and Avery, 2010) as part of a geographically widespread
and relatively abrupt dispersal of leporids at ca. 8 Ma that Flynn
et al. (2014) called the Leporid Datum. Leporids dispersed from
North America to northern Asia, spread throughout Eurasia, and
entered Southern Asia (by 7.4 Ma) and Africa (ca. 7 Ma) (Flynn
et al., 2014). Ge et al. (2013) correlated the geographic dispersal
and increase in diversity of the leporids around the Late Miocene
(and the opposite response of the ochotonids) with a period of
global cooling and drying, and the expansion and diversification
of C4 plants (at the expense of the C3 plants) in tropical and
temperate areas.
KEY FUNCTIONAL GENES OF
LAGOMORPHS
Wild populations of lagomorphs are greatly affected by two
diseases, rabbit hemorrhagic disease and myxomatosis. The genes
relating to the immune system and these diseases are well
studied. These are, for example, interleukins, chemokines and
chemokine receptors, Toll-like receptors, antiviral proteins (RIG-
I and Trim5), and the genes encoding fucosyltransferases that
are utilized by rabbit hemorrhagic disease virus as a portal for
invading host respiratory and gut epithelial cells (Pinheiro et al.,
2016). Fourteen IgA (immunoglobulin A) subclasses have been
identified in O. cuniculus, eleven of which are expressed. In
contrast, most other mammals have only one IgA, or in the
case of hominoids, two IgA subclasses (Pinheiro et al., 2018).
VHn genes are a conserved ancestral polymorphism that has
been maintained in the leporid genome and being used for the
generation of VDJ rearrangements by both modern Lepus and
Oryctolagus (Pinheiro et al., 2019). Toll-like receptors (TLRs)
are one of the first lines of defense against pathogens and are
crucial for triggering an appropriate immune response: strong
selection of the TLR2 coding region among the Lagomorpha
suggests an evolutionary history that differs from other mammals
(Neves et al., 2019). A high level of variation in the tripartite
motif-containing protein 5 alpha (TRIM5) PRYSPRY domain of
Lagomorpha species that belong to the same genus was believed
to restrict retroviral infections (Águeda-Pinto et al., 2019). Recent
study revealed the winter coat color polymorphism of snowshoe
hares was associated to the genomic region of the pigmentation
gene Agouti (Giska et al., 2019;Jones et al., 2020). Genetic
variation at Agouti clustered by winter coat color occurs across
multiple hare and jackrabbit species (Jones et al., 2018).
HYBRIDIZATION IN LAGOMORPHA
Hybridization may accelerate speciation via adaptive
introgression or cause near-instantaneous speciation by
allopolyploidization (Abbott et al., 2013). There are many articles
referring to the hybridization, gene flow or reticulate evolution
of lagomorphs (Table 1). Previous studies reported hybridization
occurred within Lepus,Oryctolagus, and Ochotona usually
based on single, multilocus DNA markers, and microsatellite
loci (Chapman and Morgan, 1973;Wu et al., 2011;Koju et al.,
2017). In some cases, selective advantages of hybrid forms to
special climate condition in the contact zone and competitive
exclusion of parental forms causes hybrid superiority over
parental species (Mohammadi et al., 2020) because enhanced
reproductive success may be due to the selective advantages of
new combinations of mito-nuclear packages.
In addition, transitional phenotype of hybrids and
introgressions also encounter traditional taxonomy with
confusion in hybrid zones while reticulate and mosaic evolution
of the genome and incomplete lineage sorting especially within
nuclear loci also make application of new molecular tools such
as DNA barcoding for identification of species useless. Plausible
conspecificity have been raised from lack of morphological
diagnostic characters and low genetic divergence in phylogenetic
reconstructions based on some few nuclear loci (Liu et al.,
2011). There are still gaps in sampling from type localities of
some taxa (e.g., Lepus tibetanus pamirensis; type locality: near
Lake Sarui-Kul, Pamir Mountains) and gaps for understanding
the intraspecific genetic diversity (e.g., in Lepus saxatilis from
Africa, in Lepus melainus and all other kinds of Manchurian
hares). The taxon przewalskii is still controversial and the
taxonomic status of centrasiaticus has not been resolved due
to its morphological similarities to Lepus oiostolus, and its
morphometric (Cheng et al., 2012) and molecular affinity to
L. tolai (Wu et al., 2011;Smith et al., 2018). Possible paraphyly
of some taxa such as L. timidus and Lepus tolai in China (Wu
et al., 2005;Shan et al., 2020); Lepus capensis s.l. in Africa
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TABLE 1 | Research activities related to hybridization of Lagomorpha.
Species Data Major conclusion References
L. granatensis
L. europaeus
L. castroviejoi
L. corsicanus
L. timidus
L. capensis
L. arcticus
L. othus
L. americanus
L. californicus
L. townsendii
14 nuclear DNA and 2 mtDNA
fragments
Highly incongruent with mtDNA phylogeny using parametric bootstrap.
Simulations of mtDNA evolution under the speciation history inferred from
nuclear genes did not support the hypothesis of mtDNA introgression from
L. timidus into the American L. townsendii but did suggest introgression
from L. timidus into four temperate European species.
Melo-Ferreira et al.,
2012
L. europaeus
L. granatensis
Autosomal microsatellite loci
and X- and Y-linked diagnostic
loci
The lack of mtDNA differentiation across the boundary is mostly due to
sharing of mtDNA from a boreal species currently extinct in Iberia
(L. timidus) whose mitochondria have thus remained in place since the last
deglaciation despite successive invasions by two other species.
Melo-Ferreira et al.,
2014a
O. cuniculus algirus
O. c. cuniculus
Transcriptome and the target
enrichment datasets
Genes lying within differentiated regions were often associated with
transcription and pigenetic activities, including chromatin organization,
regulation of transcription, and DNA binding.
Carneiro et al.,
2014
L. americanus
L. townsendii
L. californicus
Eight nuclear markers and one
mitochondrial DNA
The isolation-with-migration model suggested that nuclear gene flow was
generally rare or absent among species or major genetic groups, coalescent
simulations of mtDNA divergence revealed historical mtDNA introgression
from L. californicus into the Pacific Northwest populations of L. americanus.
Melo-Ferreira et al.,
2014b
L. granatensis
L. timidus
100 nuclear SNPs The distribution of allele frequencies across populations suggests a
northward range expansion, particularly in the region of mtDNA
introgression.
Marques et al.,
2017
O. spp. Two mitochondrial (CYT B and
COI) and five nuclear gene
segments (RAG1, RAG2, TTN,
OXAIL and IL1RAPL1)
Conflicting gene trees implied mitochondria introgression from O.cansus to
O.curzoniae.
Koju et al., 2017
L. timidus
L. europaeus
6833 SNP markers Introgression is highly asymmetrical in the direction of gene flow from
mountain hare to brown hare, and that the levels of nuclear gene
introgression are independent of mtDNA introgression.
Levanen et al.,
2018
L. americanus Whole genome sequence Genetic variation at Agouti clustered by winter coat color across multiple
hare and jackrabbit species, revealing a history of recurrent interspecific
gene flow.
Jones et al., 2018
O. princeps 24 microsatellite loci Fine-scale population genetic analysis suggests gene flow is limited but not
completely obstructed by extreme topography such as glacial valleys, as
well as streams including the Colorado River.
Castillo Vardaro
et al., 2018
L. timidus
L.granatensis
Whole genome sequencing Post-glacial invasive replacement of L.timidus by L.granatensis. Outliers of
elevated introgression include several genes related to immunity,
spermatogenesis, and mitochondrial metabolism.
Seixas et al., 2018
(Lado et al., 2016) and L. timidus from northern Europe,
Siberia, and Fennoscandian regions (Waltari and Cook, 2005)
add to the complexity of the taxonomic status of some of the
members of the genus Lepus and essential need for revision
based on complete genome phylogenetic analyses. There
are many reports of hybridization between different species
like between L. tolai, and L. timidus with L. sinensis, from
L. sinensis into L. mandshuricus (Liu et al., 2011), between
L. tolai and L. yarkandensis (Wu et al., 2011), L. timidus into
L. granatensis and L. europaeus (Alves et al., 2003), from
L. europaeus into L. tolai (Mohammadi et al., 2020). Sharing
of the same haplotypes between two different species and some
cases of hybridization and introgression between sister taxa
have been also reported within pikas [e.g., between Ochotona
cansus and Ochotona curzoniae (Koju et al., 2017), Ochotona
dauurica and O.cansus (Lissovsky et al., 2019), O.curzoniae and
Ochotona nubrica (Yu et al., 2000;Niu et al., 2004;Lissovsky,
2014;Lissovsky et al., 2019)]. Moreover, lack of type specimens
and the probable presence of hybrid forms even in the type
localities, which makes molecular comparisons doubtful (e.g.,
for L. tolai; see Mohammadi et al., 2020) and have raised even
further questions concerning the taxonomy and evolutionary
relationships between taxa. More comprehensive studies are
needed to address taxonomic challenges remaining around
the North American white-tailed jackrabbit Lepus townsendii,
Lepus corsicanus from Italy, and Lepus castroviejoi from the
Iberian Peninsula.
The vast variety of introgression and evidence of hybridization
between two species in areas of sympatry and parapatry (e.g.,
between L. europaeus and L. tolai in Iran; L. europaeus and
L. timidus in Sweden; L. tolai and L. yarkandensis in Tarim Basin,
China) and the lack of evidence of hybridization in other cases
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of geographical sympatry (e.g., between L. europaeus and L. tolai
in Kazakhstan; between L. tibetanus,L. oiostolus, and L. tolai
in China; L. yarkandensis and L. timidus also in China) have
suggested the genus Lepus as a good natural model for studying
and tracing hybridization and the speciation process and also
highlights the insufficient taxonomic knowledge to identify many
of the taxa indicated as hybridized in scientific literature.
DOMESTICATION OF LEPORIDAE
The domesticated rabbit is derived from O. cuniculus and has its
history in early European cultures (Clutton-Brock, 1989). While
it is hypothesized that the Romans spread wild rabbits out of
the native Iberian Peninsula to much of Europe and British Isles,
they did not attempt to domesticate it. Several authors recounting
the history of rabbit domestication place the origin with French
Medieval monks (Clutton-Brock, 1989;Naff and Craig, 2012),
where rabbits were kept in hutches or walled gardens to be
fattened up for consumption, and thus selectively bred to increase
body size. The morphological diversity among the ∼50 breeds of
the domesticated rabbit known today is driven by body size (e.g.,
dwarf and giant forms), thus many differences in morphological
features are likely a result of allometry, the associated shape
changes with size, and heterochrony, the changes in timing of
development (e.g., Fiorello and German, 1997;Sánchez-Villagra
et al., 2017). Studies of morphological variation in companion
and laboratory rabbits are predominantly focused on pathological
and skeletal abnormalities resulting from their continual tooth
growth (e.g., Okuda et al., 2007;Böhmer and Böhmer, 2017;
Parés-Casanova and Cabello, 2020).
LAGOMORPH DEVELOPMENT
Our knowledge of lagomorph development is based primarily on
the common laboratory rabbit, O. cuniculus, because this species
is easy to keep and breed and therefore early ontogenetic stages
are readily available. O. cuniculus is an induced ovulator (Boussit,
1989;Delaney et al., 2018). Sexual differentiation is established on
the 16th day of embryonic development, and oogenesis continues
for about 2 weeks after birth (Mauleon, 1967;Kennelly et al.,
1970). Graafian follicles appear in the New Zealand breed at
12 weeks of age. Ovulation occurs between 10 and 12 h after
mating and the peak of fecundity is observed between 12 and
15 h post coitum (pc) (Harper, 1961;Thibault, 1967;Foote and
Carney, 2000). Based on the observations of Lopez-Bejar (1995),
embryos have completed their first cell cycle at 26 h pc, then
continue to divide to reach the 4-cell stage at 26–32 h pc, followed
by 8-cell (32–40 h pc), 16-cell (40–47 h pc), morula (47–68 h pc),
and blastocyst (68–76 h pc) stages. The embryo begins to implant
7 days after fertilization (DeSesso, 1996). The blastocyst loses
its zona pellucida, which is replaced by layers of glycoproteins
whose adhesive properties play an important role in implantation
(Alliston and Pardee, 1973). The ectoblast covers a deep layer
or endoblast. A medium or mesoblast layer is isolated between
the two previous layers. The embryo begins to lie down on the
8th day of gestation; then on the 11th day the head becomes
dominant in size and the limbs lengthen. From the 19th day (end
of organogenesis), the limbs are well formed, and the muzzle
lengthens. From 12th day of gestation, development of the bi-
discoid and hemochorial placenta will ensure the growth and
development of the fetus until parturition (Rodriguez et al.,
1985). The weight of the young rabbits does not change much
until the 16th day but then increases very quickly: between 24th
and 30th day, the rabbit fetus multiplies its weight by six (Bruce
and Abdul-Karim, 1973). Gestation is from 30 to 33 days.
Understanding the development of the mammalian
cranium requires the investigation from early prenatal to
adult stages (Gaupp, 1906;Novacek, 1993;Maier and Ruf,
2014). These data provide the ultimate baseline for character
polarization and a deeper understanding of ontogenetic
transformations into adult stages and thus, significantly
contribute to comparative anatomical, morphofunctional,
systematic and evolutionary studies (e.g., Maier and Ruf,
2014;Sánchez-Villagra and Forasiepi, 2017;Ruf, 2020). To
date models of cranial development in Lagomorpha are still
mainly based on Oryctolagus cuniculus (e.g., Voit, 1909;de
Beer and Woodger, 1930;Frick and Heckmann, 1955;Hoyte,
1961) because access to ontogenetic series is easy. Only a few
other species are known by pre- or perinatal stages, although
their cranial development has not been studied in as much
detail. These are: L. capensis (Eloff, 1950), Ochotona rufescens
and Ochotona roylei (Insom et al., 1990), and Ochotona sp.
(Frahnert, 1998). However, all these studies comprise single
or very few stages that were prepared as histological serial
sections. Postnatal ontogeny of the lagomorph cranium has been
mainly investigated based on osteological features, for instance,
skull size and shape changes in O. curzoniae,L. oiostolus, and
L. capensis (Lu, 2003;Zhang and Ge, 2014), growth of the
ear capsule in O. cuniculus (Hoyte, 1961). Regarding cranial
development, Lagomorpha, and especially Leporidae, can be
the ideal model organism because they comprise different
modes of reproduction (altricial, precocial) that help to elucidate
developmental and evolutionary constraints in lagomorph
evolution. The ontogenetic transformation of cranial features
in altricial versus precocial species provides key features to
character polarization and transformation serving as baseline
for the understanding of systematics, morphofunction, and
evolution of the respective species and clades. This has been
attempted recently by the study of perinatal dental eruption in
selected Glires (including O. cuniculus and L. europaeus) or the
comparison of chondrocranial transformations in altricial and
precocial Muroidea (Ruf, 2020;Ruf et al., 2020).
Comprehensive studies of the cranial development in selected
lagomorph species that include ontogenetic series spanning from
fetal to adult are still pending, although sufficient material of
selected species is certainly available in scientific collections.
This approach is essential to understand cranial characters
and adult patterns, as demonstrated by a recent study on the
auditory ossicles in lagomorphs (Maier et al., 2018). Based
on both histological serial sections of perinatal stages and
µCT scans of adult skulls of Ochotonidae and Leporidae,
Maier et al. (2018) revealed a family-specific pattern of the
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processus anterior and processus internus praearticularis of
the malleus. The perinatal stages provide insight into the
development of the two very different adult patterns that
correlate with adaptations in sound transmission and allow
for refining previous functional classifications of mammalian
auditory ossicles (Maier et al., 2018).
New Methods in Assessing Development
The cranial anatomy and development of prenatal to early
postnatal stages in mammals traditionally have been investigated
using histological serial sectioning (Hall, 2005). Although this
method is destructive and time consuming it allows the detailed
study of hard and soft tissue structures and has led to important
observations regarding the development of soft tissue (e.g., Maier
et al., 2002;Ruf et al., 2009). Advances in modern imaging
techniques such as µCT, allow for non-destructive investigation
of any ontogenetic stage, as well as rare, collection specimens.
Promising new diffusion based methods that increase the radio-
opacity (and thus contrast) of soft tissues in specimens prior
to µCT scanning are becoming more widespread and represent
a frontier in the study of development in a wide variety of
taxonomic groups (Metscher, 2009a,b;Gignac et al., 2016).
Phosphotungstic acid and inorganic iodine are the two stains
that are becoming increasingly common research tools; they are
relatively easy to handle and produce high-contrast X-ray images
of many soft tissues. Iodine (IKI and I2E) staining followed by
µCT scanning works particularly well with mammals, including
lagomorphs (Racicot and Ruf, 2020;Figure 3) and also is
reversible using simple destaining methods. Specimens still may
be processed for histological staining and sectioning or other
methods after µCT scanning, and thus provide a record of their
original internal and external three-dimensional geometries prior
to employing subsequent destructive methods.
While µCT scanning has become a standard method
for paleontologists, biologists, and museum researchers (e.g.,
Racicot, 2017), using staining to increase radio-opacity before
µCT scanning still is a relatively new approach. Some general
guidelines and examples of success with iodine staining and
scanning methods are described in the literature (summarized
in Metscher, 2009a,b;Gignac et al., 2016). Iodine provides clear
contrast between neural and other tissues because its inner shell
electron binding energy is similar to lower energy X-rays used in
scans and often is used in medical contexts.
The most conservative methodology for rare museum
specimens has been exemplified by recent work on cetaceans
(Lanzetti et al., 2018) and tested with a prenatal stage of a
lagomorph (Figure 3). Specimens that are preserved in formalin
may be directly placed either in pre-prepared or self-prepared
∼1% Lugol’s iodine solution (e.g., Figure 3). For specimens
preserved in 70% alcohol, metal iodide is mixed first in the
highest alcohol concentration possible (96–100%), then diluted
to 70% alcohol with iodine before beginning staining. Rotating or
moving the specimens either constantly or daily while staining is
recommended because the stain can settle.
Other staining methods have been employed but may not
work well with larger specimens. Phosphotungstic acid can be
used effectively, particularly after fixation with Bouin’s solution,
but penetration times are slower than iodine methods, and it is
unclear whether this method is reversible (Metscher, 2009a,b). It
has been suggested that specimens fixed in Bouin’s solution and
preserved in 70% alcohol can be stained with I2E before µCT
scanning (Metscher, 2009b) for effective increase in contrast.
After the staining and scanning process is completed, specimens
can be destained using 3% sodium thiosulfate dissolved in
deionized water (for formalin specimens) or 70% ethanol (for
ethanol specimens). The specimen subsequently can be used
for future research, including re-staining and/or sectioning as
desired. It is recommended to note in the documentation
associated with the specimen that the specimen has been stained
and µCT scanned previously. Some workers have noted that
DNA perhaps should not be extracted from specimens after this
procedure (Gignac et al., 2016) because the impact of staining on
FIGURE 3 | Sagittal µCT slices taken from generally the same area of the same O. cuniculus specimen (Racicot and Ruf, 2020), stained for different lengths of time
to show increasing contrast imparted by the Lugol’s iodine stain. (A) Stain penetration after 5 weeks and 2 days, (B) penetration after 7 weeks, (C) stain penetration
after 11 weeks and 2 days. Scale bar of 10 mm applies to all specimens.
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DNA analyses has not been explored: experiments along these
lines thus may be interesting. µCT scanning in combination
with iodine staining represents a promising frontier in studying
the development and ontogeny of lagomorphs, particularly in
rare species/museum specimens for which destructive methods
are unattractive options. Maintaining the 3D geometry of soft
tissues, while also ‘remotely’ observing these tissues with high
contrast will increase the natural history value of the specimens
by providing a permanent digital record that can also be used in
educational contexts.
FUNCTIONAL MORPHOLOGY
Leporids are characterized by increased cursoriality, in general;
pikas are the least cursorial and jackrabbits the most cursorial,
with rabbits and cottontails (e.g., Sylvilagus) occupying an
intermediate position (Camp and Borell, 1937;Gambaryan,
1974). A small number of previous studies have discussed
the gradation in cursoriality among lagomorphs and sought
to identify morphological correlates of this behavioral cline
(Camp and Borell, 1937;Gambaryan, 1974;Bramble, 1989;
Kraatz and Sherratt, 2016). Among lagomorphs, leporids are
perhaps best known for their gait, in which maximum running
speeds of some species match the upper limit of racehorses
and greyhounds; a speed unknown for any other mammal
of leporid size. Leporid speeds vary from 40 km/h (11 m/s)
in Sylvilagus through 56 km/h (16 m/s) in O. cuniculus
and up to 72 km/h (20 m/s) in L. europaeus and Lepus
alleni (Garland, 1983). While leaping abilities are common
among most leporid lineages, they are also known to be
facultatively semiaquatic, scansorial, fossorial, or exhibit a
more generalized, non-hopping form of locomotion (Chapman
and Flux, 1990). The most comprehensive framework for
understanding lagomorph locomotion and locomotor apparatus
in an evolutionary perspective was proposed by Gambaryan
(1974), who suggested that lagomorphs originated as talus-
dwellers and, therefore, regarded ochotonids as living fossils
(Figure 4). The coupled half-bound action of the hindlimbs
in lagomorphs is suggested to be the adaptative remnant of
leaping from rock to rock. Among the variety of quadrupedal
asymmetrical gaits in mammals, Gambaryan (1974) distinguishes
two main categories: (1) true gallops, including the lagomorph
half-bound and (2) ‘the primitive ricochet.’ The latter should
not be confused with bipedal ricochet (i.e., proper hopping) of
kangaroos and jerboas. According to Gambaryan (1974), the
primitive ricochet is retained by many poorly running mammals,
including most of the rodents.
The main difference between the true gallop and the primitive
ricochet is the pattern of hindlimb motion during the extended
suspension. In the primitive ricochet hindlimbs start protraction
immediately as they finish their thrust and lose contact with the
ground. In contrast, in the true gallop, there is a considerable
delay in the hindlimb protraction where hindlimbs are held
in retracted position from the end of their contact phase and
throughout the extended suspension. The hindlimbs protract
in gallop (e.g., lagomorph half-bound) when the forelimbs are
landed; the forward swing of the hindquarters is much faster than
in the primitive ricochet. According to Gambaryan (1974), the
advantage of the hindlimb delay is the ability of an animal to
arrive at the landing point more precisely when the hindlimbs are
held fixed during a leap. Landing precision is crucial on irregular
substrates such as tree branches and rocks, but also, the hindlimb
delay would likely be advantageous while covering obstacles
FIGURE 4 | Stages of wild rabbit (O. cuniculus) gait as captured and described by Gambaryan (1974), including: (A) support on hindlimbs; (B) extended flight;
(C) support on forelimb; and (D) crossed flight.
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at high speeds. Gambaryan (1974) summarized lagomorph
locomotor patterns as a dorsomobile-metalocomotor type. While
a metalocomotor type implies the prevalence of the hindlimbs,
dorsomobile implies an additional active usage of the spine; more
exactly, the use of lumbar region. Lagomorphs not only actively
extend their spine with hindlimb thrust, but also flex their spine
when the forelimbs are landed, and the hindquarters need to be
rapidly protracted.
Recording Lagomorph Gaits
The first image sequences of lagomorph locomotion were
recorded as early as in 1893–1894 by Étienne-Jules Marey, which
capture a very slow half-bound of the white domestic rabbit
(O. cuniculus)1. However, images from those movies were not
included as illustrations in his subsequent publications (Marey,
1894, 1901). This is likely why Pablo Magne de la Croix, an
Argentinean Frenchman who was among the first to study the
evolution of quadrupedal gaits, had an incorrect impression on
the rabbit’s gait (Magne de la Croix, 1928, 1933, 1936); he only
depicted an extended (centrifugal) suspension, and no gathered
(centripetal) suspension stage in the locomotor cycle of the rabbit.
The former is characterized by the straightened spine, retracted
hindlimbs and protracted forelimbs, while in the latter the spine
is flexed, the hindlimbs are protracted and cross the retracted
forelimbs. In rabbits, with speed growth, there is at first no
suspension in the locomotor cycle, then the gathered suspension
appears (missed by Magne de la Croix), and finally the extended
suspension is added (not recorded by Marey). Both stages of
suspension were recorded by Gambaryan (1974) in the wild
European rabbit 80 years after Marey’s first observations. Also,
Gambaryan’s (1974) work was the first publication representing
the frames of cinematographic record of the running cycle of the
Alpine pika (Ochotona alpina). He noted that in pika the gathered
suspension is almost absent, but the extended stage is prolonged
to ensure leaping from stone to stone in their usual rocky habitat.
After Marey (1894, 1901) and Gambaryan (1974), there
appeared in scientific publications a few additional illustrations of
running lagomorphs. Dimery (1985) filmed wild rabbits at a high
frequency (300 frames per second) but depicted only the outlines
of the hindlimb movements. Bramble (1989) depicted the fast-
running cycle of Lepus californicus, showing both the gathered
and the extended suspension and filmed at 200 fps. Simons (1999)
depicted the fast-running cycle of the domestic rabbit with both
suspension stages filmed at 100 fps in X-ray to visualize viscera
movements. Bertram and Gutmann (2009) depicted the slow-
running cycle of L. townsendii with only one suspension stage.
Like in Marey’s faster rabbit, it appears after the forelimb thrust
and, thus, corresponds to the gathered suspension. However, the
forelimbs and hindlimbs are not really gathered under the body
but remain parallel to each other like in a pronking (stotting) gait
of gazelle or mara (Climaco das Chagas et al., 2019). Kuznetsov
et al. (2017) published a video recording image sequence of a
cornering maneuver of L. europaeus and also represented its gait
diagram for maneuver and fast forward running. As to pikas,
their half-bound gait was recorded due to successful keeping of
1https://www.youtube.com/watch?v=cqVlnVEcGwg
a population of O. rufescens in Germany and appeared in a series
of papers on locomotion of small mammals, with O. rufescens as a
central object (Witte et al., 2002;Hackert et al., 2006;Schilling and
Hackert, 2006). Both suspension stages were brief, so for pictures
of faster running pikas one must return to Gambaryan (1974).
Limb Architecture
Camp and Borell (1937) were the first to compare the hindlimb
bones and muscles of lagomorphs using a series of increasingly
cursorial taxa: Ochotona,Sylvilagus, and Lepus. They note a
tendency in this series in which muscle bellies become shorter,
and tendons become longer. The first research of the entire
postcranial locomotor apparatus of Mongolian species of pikas,
aimed at ecological interpretation, was a dissertation subject
of Cevegmid (1950), but has never been published. Klebanova
et al. (1971) presented a detailed account of postcranial bone
dimensions and muscle masses and attachments for six pika
and five leporid species. Lammers and German (2002) attempted
to find the specific features in the growth of limb bones of
the rabbit and chinchilla, both of which use a half-bound gait.
Williams et al. (2007a) quantified the hindlimb muscles and
tendons of L. europaeus. They did not cite the early paper by
Camp and Borell (1937) but explained their finding of increased
development of tendons in the hare’s hindlimb as an adaption
for elastic energy storage. The same authors (Williams et al.,
2007b) published a similar analysis of the forelimb muscles of
L. europaeus, showing that the tendons in the forelimb are less
developed than in the hindlimb. This implies that the forelimbs
have a smaller role in energy saving via elastic storage and recoil.
Reese et al. (2013) compared limb bone proportions between the
meadow-dwelling and talus-dwelling pikas and found differences
that they qualitatively attributed to the different actions of
digging in meadows versus leaping in rocks. Young et al. (2014)
took the same series of increasing cursoriality represented by
Ochotona,Sylvilagus, and Lepus, as was earlier studied by Camp
and Borell (1937) and Fostowicz-Frelik (2007) and performed a
morphometric analysis of fore- and hindlimb bones, examining
relative length and robusticity. Their results suggest that with
increasing cursoriality in lagomorphs, the proximal limb bones
become more gracile (decrease in robustness), while the distal
bones do not. They hypothesize that limb bone morphology
of lagomorphs is indicative of a trade-off between locomotor
economy (cursors requiring longer, gracile limbs) and the need
to be fracture-resistant (i.e., more robust) in the distal regions
involved in impact.
Locomotory Adaptations to Cornering
Although lagomorphs exhibit exceptional levels of
maneuverability, there is only one scientific publication
documenting this phenomenon (Kuznetsov et al., 2017). This
study is based on field records of the L. europaeus chased by
sighthounds. Hares’ stereotyped turn begins by a lateral kick
of a forelimb against the ground, which initiates the turn to
the opposite side of the kicking forelimb. Centripetal forces
are produced by the forelimbs, and the braking forces by the
hindlimbs. In contrast, the chasing dogs perform braking by
the forelimbs and therefore, sometimes somersault overhead.
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The anterior and posterior halves of the hares’ trunk yaw and
roll separately. Separate rolling employs axial rotation in the
thoracic region of the spine. The morphological application
of this study is the explanation of unique hypertrophy of the
musculus subclavius in lagomorphs with its expansion over the
whole scapula. This muscle became a specialized pronator of
the scapula (there is no other efficient pronator of the scapula
in mammals). Contracting together with the musculus serratus
ventralis cervicis, it ensures centripetal force production by
the forelimb and, first, the lateral kick at the touch-down of
the forelimb initiating the maneuver. In leporids, the musculus
subclavius comprises 1% of the total muscular mass of the
limbs, while in rodents no more than 0.5% (Gambaryan, 1974).
In pikas, it comprises 4% of the total muscular mass of the
limbs. The musculus serratus ventralis cervicis, which assists the
musculus subclavius in the lateral kick, comprises 1.5% of the
total muscular mass of the limbs in leporids, and 2.3% in pikas.
The greater relative mass of both muscles in pikas may highlight
their elevated ability for sharp turning and smaller prevalence
of the hindlimbs.
Locomotory Adaptations of the Spine
In the leporid vertebral skeleton, the most prominent structures
related to the unique role of axial bending during the half-bound
are the ventral spinous processes of the three anterior lumbar
vertebrae and the posterior two or three thoracic vertebrae
(Klebanova et al., 1971;Gambaryan, 1974). These processes
provide an additional attachment site for the major lumbar
flexors, which comprise 5–10% of the total muscular mass of
the limbs in lagomorphs but never more than 5% in ungulates
and carnivorans (Gambaryan, 1974). The antagonists extending
the spine are equivalent to 30% of the total muscular mass
of the limbs in leporids and 15% in pikas. In addition to the
unique ventral spinous processes, leporids also show a set of
skeletal features typical to other dorsomobile mammals. These
are the elongate and anteriorly inclined transverse processes and
short and anteriorly inclined dorsal spinous processes of lumbar
vertebrae (Gambaryan, 1974;Jones et al., 2018).
Vertebral range of motion was studied in vitro in three
lumbar joints (those between vertebrae L4–L7) of the rabbit
(Grauer et al., 2000). It was found that each lumbar joint can
be flexed ventrally by 12–15◦, extended dorsally by 6◦, bent
laterally by 4–8◦, and rotated axially to every side by about 1◦. The
prevalence of sagittal flexion and extension, as well as reduction
of axial twisting of the lumbar region is expected given what is
known about overall locomotor behavior in lagomorphs. In vivo
spine movements in the sagittal plane were studied for pikas
based on high-frequency filming in X-ray (Schilling and Hackert,
2006). Simons (1999) filmed rabbit running to study a visceral
piston hypothesis according to which the breath in gallop is
synchronized with the stages of locomotor cycle and with spine
sagittal bending. The inertia of the viscera, and especially of the
liver, are said to act as a pump for inhalation and exhalation,
while the activity of the diaphragm and rib cage muscles might be
virtually unnecessary. Simons (1999) falsified this hypothesis for
the rabbit by showing inappropriate mutual phasing of locomotor
and breathing cycles. Instead, an idea of pneumatic stabilization
of the thorax was suggested.
Cranial Kinesis and Locomotion
Cranial kinesis is the ability of bones of the cranium to move
relative to each other (as such, it is opposed to the mobility of
visceral skeleton, e.g., jaw opening and movements of the middle
ear ossicles). Cranial kinesis within leporids, unknown among
other mammals, has been suggested to play an important role
in locomotor behavior (Bramble, 1989), though the extent of
this kinesis of leporid has not yet been fully characterized. In
both ochotonids and leporids, ethmoid-orbital and otic-occipital
part parts of the braincase are partially separated laterally by
a piriform fenestra that passes subvertically along the posterior
border of os alisphenoideum and (in leporids) os squamosum
(Wible, 2007). Ventrally, the piriform fenestra comes into a
transverse fissure which separates os basisphenoideum from os
basioccipitale (in contrast to tight junction or even fusion of
those two bones in other mammals). Notably, this is not a
fetal, but an adult condition. Thus, the piriform fenestra and
basisphenoid/basioccipital fissure serve as an intracranial joint,
which Bramble (1989) suggests helps to dampen forces that occur
during the locomotor cycle of lagomorphs, especially in high-
speed hares. Due to soft tissue attachments across the intracranial
joint, the large ears of hares may also act to support and reset the
anterior (ethmoid-orbital) part of the cranium (Stott et al., 2010).
Bramble (1989) assumed that in steady quadrupedal running
the forelimbs produce a significant braking effect, while the
hindlimbs primarily accelerate the body. In fact, this was
a common assumption at that time, which was shared by
Gambaryan (1974) in his biomechanical considerations of a
wide variety of mammals. More recent force-plate recordings,
including those for pikas (Witte et al., 2002), show two significant
patterns that challenge earlier assumptions. First, the vertical
component of the ground reaction force in steady terrestrial
walking and running is always several times greater than the
horizontal component (longitudinal and transversal). Second,
the longitudinal horizontal component is directed posteriorly
(braking the body) in the first half of the contact phase, and
anteriorly (accelerating the body) in the second half. This is
true for both for the forelimb and the hindlimb. Therefore, the
rule is not the deceleration by the forelimb and acceleration by
the hindlimb, but deceleration in the first part of the contact
phase of every limb and acceleration in the second part. It is
also of note that large horizontal forces and accelerations take
place not in steady running but at the rapid start and stop of
the forward motion and in cornering. At the start and stop,
longitudinal forces prevail, while in cornering the transverse
forces are dominant. Thus, during cornering, the anterior part of
the skull may tend to yaw centrifugally. In fact, Bramble (1989)
has described the structure that prevents this distortion of the
head, although he did not appreciate its adaptive role. In leporids,
the os squamosum has a specific process, “the petrosal bar” which
protrudes far posteriorly, crosses the piriform fenestra, and is
housed by a matching “supratympanic sulcus” in the os petrosum.
Therefore, the left and the right petrosal bars brace the basicranial
block of the skull from both sides preventing lateral distortions in
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the kinetic zone in case of transverse accelerations. In such cases
the heavy ears fall aside (Kuznetsov et al., 2017) and cannot help
to save skull integrity.
BRAIN EVOLUTION
Rabbits are well-known laboratory mammals for which there
is an extensive historical record of the study of their brain
morphology starting in the late 19th century (see Lewis, 1882;
Mann, 1895; and references therein). Although the brain of
the domesticated rabbit (O. cuniculus) is well studied, little
is known about the evolution of the lagomorph brain. Until
recently, data on brain morphology of fossil lagomorphs were
derived from the fossil natural endocasts of Prolagus (Edinger,
1929), Hypolagus (Sych, 1967;Czy˙
zewska, 1985), and Palaeolagus
(Cope, 1884, but see Wood, 1940). These show similarities
with modern lagomorph brains, such as narrow frontal lobes.
The growing accessibility of µCT data has transformed the
way we understand endocranial anatomy, especially regarding
incorporation of quantitative data. The first virtual endocast of
a fossil lagomorph, Megalagus turgidus, was described by López-
Torres et al. (2020). The cranium of M. turgidus is the oldest
(early Oligocene; Olson, 1942) and most complete lagomorph
cranium for which mostly complete endocranial information can
be recovered. Historically, M. turgidus has been classified as a
leporid (Olson, 1942;Dawson, 1958, 2008), but more recently
it has been considered to belong to a more primitive lineage
outside crown lagomorphs (Lopez-Martinez, 2008). In the most
comprehensive relevant phylogenetic analyses, the position of
Megalagus as a stem lagomorph was supported (Fostowicz-
Frelik, 2013;Fostowicz-Frelik and Meng, 2013). The study of the
endocast of a stem lagomorph provides us with very valuable
information on the brain morphology of lagomorphs before the
split between the leporid and ochotonid lineages.
The endocast of Megalagus turgidus (Figure 5A) shows it
had larger olfactory bulbs relative to its endocranial volume
than any modern lagomorph. With respect to the cerebrum,
the frontal lobes of Megalagus are wider than those observed in
modern lagomorphs (narrow frontal lobes are a typical modern
lagomorph trait), but they also are not as expanded rostrally,
exposing much of the circular fissure. In contrast, ochotonids
generally exhibit exposure of a portion of the circular fissure,
and the circular fissure is covered in leporids (Figure 5B). The
endocast of Megalagus possesses only a lateral sulcus on the
neocortex, similar to the condition seen in leporids. The cerebral
outline in dorsal view is markedly different among Megalagus,
modern leporids, and modern ochotonids. The broadest point
in the cerebrum of Megalagus is approximately midway between
the rostral and caudal ends of the cerebrum, making the endocast
have a rather ovoid outline. In contrast, leporids and ochotonids
both have cerebra that are much broader in their caudal region
(Figure 5). Therefore, there was likely a shift in lagomorph
evolution to expand the caudal area of the cerebrum through
time. In the caudal end of the cerebrum, the midbrain is partially
exposed in Megalagus, similar to midbrain exposure in other
FIGURE 5 | Comparative morphology of the brain endocast in stem lagomorphs. (AMegalagus turgidus) and crown clades: Ochotonidae (BOchotona pallasi) and
Leporidae (COryctolagus cuniculus). The colors mark the brain areas of particular interest: yellow, olfactory bulbs; green, neocortical surface; blue, midbrain
exposure; pink, petrosal lobules. See the comparative metric data of selected indices: NcSR, neocortical surface ratio (the ratio of the neocortex surface area to total
endocast surface area); OBVR, olfactory bulb volume ratio (the ratio of the olfactory bulb volume to the total endocast volume); PLVR, petrosal lobule volume ratio
(the ratio of the petrosal lobule volume to the total endocast volume); all indices are percentage values. The images and metrical data are taken from López-Torres
et al. (2020).
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primitive Euarchontoglires (e.g., most plesiadapiforms; Silcox
et al., 2009, 2010;Orliac et al., 2014).
With respect to the modern lagomorph lineages, the range
of relative olfactory bulb size of ochotonids is found within
the range of leporids (López-Torres et al., 2020). In modern
leporids, the midbrain is completely covered, and in modern
ochotonids the midbrain is only slightly exposed (Figure 5C).
The endocasts of ochotonids are completely lissencephalic,
contrary to the endocasts of leporids, which only possess a
lateral sulcus on the neocortex. The main difference in the
cerebral outline between leporids and ochotonids is that the
antero-lateral margins of the cerebrum in dorsal view are
concave in leporids and either straight or slightly convex in
ochotonids. This makes leporids have a rather pear-shaped dorsal
outline, whereas in ochotonids it is more triangular (Figure 5).
Modern lagomorph lineages also differ in that leporids have a
proportionally longer (and larger) cerebrum than ochotonids
(López-Torres et al., 2020).
Some tentative conclusions can be sketched about trends in
the evolution of the lagomorph brain. Leporid and ochotonid
lineages differ in many aspects of brain morphology, including
the rostral expansion of the frontal lobes in leporids, a higher
relative petrosal lobule volume in ochotonids, and the caudal
expansion of the occipital region of the cerebrum in leporids.
With respect to the latter, Kraatz et al. (2015) and Kraatz and
Sherratt (2016) suggested a need for increased visual perception
of the substrate in leporids, which might explain the more
developed caudal region of the cerebrum in that group. In
contrast, Megalagus exhibits a more ‘primitive’ brain, sharing
more resemblances to endocasts that have been reconstructed
for early fossil rodents (i.e., ischyromyids; Bertrand and Silcox,
2016;Bertrand et al., 2016, 2019) and plesiadapiforms (Silcox
et al., 2009, 2010;Orliac et al., 2014). In particular, Megalagus
has fairly large, pedunculated olfactory bulbs, some extent of
midbrain exposure, and low neocorticalization. As in larger
plesiadapiforms and rodents, Megalagus develops a lateral
sulcus, with the brain being otherwise lissencephalic. These
similarities with primitive members of Euarchontoglires, such
as plesiadapiforms and primitive rodents, may indicate that
lagomorphs are an old, relatively basal lineage and that they are
conservative in their morphology.
LAGOMORPHS AS BIOMECHANICAL
MODELS
Rabbits were one of the first vertebrates for which the in vivo
range of sarcomere shortening was precisely measured with
diffraction techniques (Dimery, 1985). Contrary to the previous
expectations, the shortening range in 12 hindlimb muscles
appeared to be much less than 30%. The shortening employs the
plateau of the well-known force-tension curve, which is the best
for force production. Until now, similar data are available for
very few other vertebrate species other than humans and rabbits
(Burkholder and Lieber, 2001). Additionally, it has been shown
that the number of successive sarcomeres in myofibrils directly
depends on the excursions experienced by the muscle during
an individual’s growth. Koh and Herzog (1998) released the
musculus tibialis anterior from its retinacular restraint in 4-week-
old rabbits. Free of the restraint, the muscle gained increased
range for shortening and extension with the unchanged angular
amplitude in the ankle joint. Twelve weeks later the operated
muscles showed considerable difference from the control; muscle
fibers became longer, while the tendons became shorter. As
a byproduct, the force of operated muscle decreased. Rabbits
have also proven to be a convenient model animal for human
orthopedics. They are used in biomechanical modeling of the
joints of both the spine (Grauer et al., 2000) and the limbs
(Grover et al., 2007).
Cranial Biomechanics
Beyond those detailed by Bramble (1989), other morphological
features of the cranium have been associated with locomotion
including a pronounced ventral flexion of the facial region
and unique fenestrations in the posterior cranial bones and
lateral portion of the maxilla (DuBrul, 1950;Moss and Feliciano,
1977;Stott et al., 2010;Kraatz et al., 2015;Kraatz and
Sherratt, 2016). The unique rostral vacuity (Ochotonidae) and
fenestration (Leporidae) in lagomorphs were noted by Gray
(1867), and DuBrul (1950) suggested that the latticing of the
maxilla in Leporidae could increase the efficiency of speedy
locomotion by reducing weight of the rostrum, and potentially
contributing to Bramble’s (1989) anterior capital suspensory
system hypothesis. However, Moss and Feliciano (1977) argued
that these fenestrations are related to the lack of transmission of
masticatory forces through the lateral aspect of the rostrum. They
proposed that the more vertical orientation of the ramus of the
mandible in some leporids redirects incisal forces along the dorsal
and ventral aspects of the rostrum, and away from the lateral side.
Although this has yet to be tested, methods such as in vivo strain-
gage analysis coupled with in silico finite element analysis could
provide more resolution.
Leporids process food through differing modes of mastication
within a single bite cycle (Weijs, 1980), including incisor biting,
molar crushing and molar shearing, and the potential influence
of these modes on bone deposition and skull shape, including the
fenestrated rostrum, remains unknown. Biomechanical modeling
using multibody dynamics analysis has demonstrated varied
muscle lines of action and bite force magnitudes and directions
during a bite cycle (Watson et al., 2014). However, it is unknown
whether the largest and/or more frequent masticatory strains
across the whole cranium are generated through incisor biting,
and how these are directed through the rostrum, or by crushing
or shearing of food at the molars. What is evident is that
the bony form of the circumorbital region, cranial vault and
basicranium in lagomorphs is unlikely to be related to stresses
experienced during biting and chewing (Jašarevi´
c et al., 2010;
Franks et al., 2016, 2017). The debate about determinants of
skull form, however, continues, as faster, saltatorial species
such as hares and jackrabbits of the genus Lepus, have more
extensive fenestration and a more pronounced ventral facial
tilt (Kraatz et al., 2015;Kraatz and Sherratt, 2016). This is in
comparison to generalists, including cottontail and pygmy rabbits
(e.g., Sylvilagus spp. and B. idahoensis), suggesting that there
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may be a correlation between posture, locomotion, and rostral
fenestrations as well as mastication.
Feeding Apparatus
In many ways, the function of the lagomorph oral cavity
is especially well known among mammals. This is due
largely to in vivo studies of jaw-adductor muscle activity, jaw
kinematics and mandibular bone strain, and more recent work
on diet-induced adaptive plasticity in domestic white rabbits
(O. cuniculus). Rabbits exhibit a vertically deep facial skull and
a jaw joint correspondingly elevated above the toothrow that
that allows the jaw both rotational and translational movements
(Weijs and Dantuma, 1981;Crompton et al., 2006). Transverse
mandibular movements during the chewing cycle in rabbits
are similar to primates in being due to delayed activity of the
balancing-side deep-masseter muscle, which is in part related to
dietary stiffness, i.e., elastic modulus (Weijs and Dantuma, 1981;
Hylander et al., 1987, 2000;Weijs et al., 1989;Agrawal et al., 1997,
1998, 2000;Vinyard et al., 2006). Such kinematics are facilitated
via a partially fused mandibular symphysis, a midline anteriorly
located joint that closely binds the two jaw halves (Weijs and
Dantuma, 1981;Ravosa and Hogue, 2004;Ravosa et al., 2016).
Rabbits and diverse mammals have similar mandibular peak
strains during the mastication of mechanically challenging foods
(Weijs and de Jongh, 1977;Ravosa et al., 2010b). Rabbits
share feeding patterns with other mammals whereby items
with greater toughness and/or higher stiffness require larger
and protracted jaw-adductor forces during biting and chewing,
which results in greater occlusal forces and masticatory stresses
(e.g., Herring and Scapino, 1973;Weijs and de Jongh, 1977;
Hylander, 1979;Gorniak and Gans, 1980;Weijs and Dantuma,
1981;Dessem and Druzinsky, 1992;Hylander et al., 1992, 1998,
2000;Ravosa and Hogue, 2004;Vinyard et al., 2008). Rabbits
are likewise noteworthy due to extensive ontogenetic data about
the in vivo links among masticatory function, feeding behavior
and food mechanical properties (e.g., Weijs et al., 1987, 1989;
Langenbach et al., 1991, 2001;Langenbach and van Eijden, 2001;
Martin et al., 2020).
Skeletal adaptations are related to either high-magnitude,
singular loads or low-magnitude, cyclical loading. Although high
bite forces have long been linked to greater jaw robusticity
in mammals (e.g., Hylander, 1979), the dietary underpinnings
of repetitive or cyclical loading are still poorly known for
masticatory features. Rabbits are but one of two taxa for
which mechanically challenging foods are known elevate cyclical
loading (Ravosa et al., 2015;Nett et al., in press). Rabbits also
resemble mid-to-large sized mammals in exhibiting intracortical
remodeling, a skeletal repair mechanism related to microcrack
damage in adult bone that does not appear to characterize smaller
species (Bouvier and Hylander, 1996a,b;Hirano et al., 2000;
Lad et al., 2021).
Rabbits are perhaps the best studied mammals in terms of
dietary plasticity in the skull and jaws. A series of experiments
have explored the implications of dynamic changes in elevated
and cyclical loads on craniomandibular ontogeny and function
in rabbits subjected to long-term, naturalistic modifications of
dietary properties (Ravosa et al., 2007, 2016). Analyses have
explored ontogenetic variation in jaw-loading patterns due to
seasonality and fallback foods (Scott et al., 2014a,b); differences
in age-related performance of bone and cartilage in jaw joints
(Ravosa et al., 2007, 2008;Jašarevi´
c et al., 2010;Ravosa and Kane,
2017); reaction norms of bony vs. muscular components (Ravosa
et al., 2010a); regional and hierarchical variation in patterns of
cranial bone formation (Ravosa et al., 2007;Menegaz et al., 2009;
Franks et al., 2016, 2017;Terhune et al., 2020;Lad et al., 2021);
and morphological inference in the fossil record (Ravosa et al.,
2016). Another finding is that dietary plasticity in rabbit jaws is
similar to shorter-term studies of this phenomenon in monkeys,
hyraxes, ferrets and rats (Beecher and Corruccini, 1981;
Bouvier and Hylander, 1981, 1996a,b;Beecher et al., 1983;
Yamada and Kimmel, 1991;He and Kiliaridis, 2003;Lieberman
et al., 2004). These integrative analyses have marshaled a suite of
histological, imaging and engineering approaches to understand
masticatory development and phenotypic diversity in rabbits.
Despite the differential focus of such research on the role of
long-term plasticity in craniomandibular evolution and diversity,
such an ontogenetic perspective to the mechanobiology of
lagomorphs invariably lends itself to ongoing revolutions in
‘omics’ as well as clinical approaches to aging and pathobiology
of connective tissues.
CLINICAL MODEL
Understanding of the healthy rabbit masticatory system and
cranial morphology is important for diagnosis and treatment of
dental disease in rabbits (Harcourt-Brown, 2007;Lennox, 2008;
Jekl and Redrobe, 2013). The rabbit is also one of the most
used animals in clinical experimental modeling (Neyt et al.,
1998;Stübinger and Dard, 2013), often used to investigate the
remodeling of bone in response to dental implants (Kim and
Shin, 2018;Leventis et al., 2018;Manju et al., 2018) and impaired
muscle function (Balanta-Melo et al., 2019;Huang et al., 2019).
Rabbits are also a good clinical model for craniosynostosis, a
condition that involves the premature closure of cranial sutures
in infants. Craniosynostotic rabbits are the only existing colony
of any species affected by familial craniosynostosis in the world
(Mooney et al., 1998a,b;Cooper et al., 1999;Lyn Chong et al.,
2003). Suture defects must be artificially created to investigate
this question in any other species of mammal. Therefore, these
rabbits are the most similar non-human model to naturally
occurring craniosynostosis in other mammals and require less
surgical manipulation.
SUMMARY
Though model organisms are critical tools for understanding
much of the biology of life, larger systems of organisms can
offer a more dynamic and comparative framework to reveal
the tempo and mode of evolutionary change. Understanding
the adaptative processes that drive these changes is often
best accomplished by studying groups of closely related
organisms at multiple time scales. We offer the Lagomorpha
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Kraatz et al. Lagomorphs as Model System
(rabbits, hares, pikas, and their ancestors) as an exemplar
system in which to study the evolutionary patterns of
morphologic change. Anchored by the common laboratory
rabbit (O. cuniculus), the order offers a rich diversity of extant
species within the monogeneric Ochotonidae and the more
lineage rich Leporidae. The molecular phylogenetics of these
groups have been well studied, and indeed, four species have
established genome level architecture. Understanding lagomorph
intraordinal relationships has also advanced through a rich,
consistent fossil record that dates back nearly 50 million
years. The evolutionary trees are already in place to develop
phylogenetically constrained models of evolution, but more work
is needed combining molecular and morphological data into a
comprehensive phylogeny of lagomorphs.
Using existing phylogenetic frameworks and emerging
methods, lagomorphs are already an excellent system in which to
study a rich array of functional systems. The locomotor behavior
of these small mammals has been of long-standing interest,
and research within this system has increasingly incorporated
evidence from the fossil record, soft tissue systems, and novel
connections to the cranium. The expanding research on the
lagomorph cranium has shown important patterns of evolution
of the brain and auditory systems and new methods have only
increased the scope and breadth of research on the lagomorph
masticatory system. The European rabbit will continue to
remain a seminal research species for the biological sciences.
Most importantly, new methods have allowed researchers to
expand our knowledge more broadly among rabbit relatives,
offering a more explicitly evolutionary context. The emergence
of new methods of morphological research, an ever-improving
phylogenetic framework, and a growing interest in lagomorphs
will only serve to better place rabbits and all of their relatives as an
essential system in which we can better understand the patterns
and processes of evolutionary morphology.
AUTHOR CONTRIBUTIONS
BK and IR designed the idea for the review manuscript. All
authors contributed equally to the manuscript.
FUNDING
ES was supported by an Australian Research Council Future
Fellowship (ARC FT190100803). RR was funded by the
Alexander von Humboldt Foundation, which is sponsored by
the Federal Ministry for Education and Research (Germany).
Research discussed by MR herein was supported by the following
United States National Science Foundation grants (BCS-1749453,
BCS-1029149/1214767, and BCS-0924592/1214766).
ACKNOWLEDGMENTS
We dedicate this paper to the late Mary R. Dawson (1931–
2020) as a token of gratitude for her tremendous contribution to
the morphological and evolutionary exploration on lagomorphs.
We would like to thank the World Lagomorph Society and
the organizers of the 6th World Lagomorph Conference,
which was scheduled to occur in July of 2020 in Montpellier,
France, but postponed due to the global pandemic of COVID-
19. IR and BK had organized a session for that meeting
titled Lagomorphs as a Model Morphological System. In
lieu of that meeting and session, participants met virtually
on July 06, 2020 to outline this review paper. We all
look forward to gathering for a similar session in July of
2022 in Montpellier for the rescheduled World Lagomorph
Conference. We thank reviewers for their thoughtful and
helpful comments.
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Conflict of Interest: The authors declare that the research was conducted in the
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potential conflict of interest.
The reviewer TM declared a past co-authorship with one of the authors IR to the
handling Editor.
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