Marine Genomics 41 (2018) 1–5

Contents lists available at ScienceDirect

Marine Genomics
journal homepage: www.elsevier.com/locate/margen

Review

On the revolution of cetacean evolution T

Annalaura Mancia
University of Ferrara, Department of Life Sciences and Biotechnology, Ferrara 44121, Italy

A R T I C LE I N FO A B S T R A C T

Keywords: The order of Cetacea with 88 species including Odontoceti (or toothed whales) and Mysticeti (or baleen whales)
Genome is the most specialized and diversified group of mammals. The blue whale with a maximum recorded length of
Cetacean 29.9 m for 173 t of weight is the largest animal known to have ever existed, and any dolphin's brain is most
Evolution powerful and complex than any other brain in the animal kingdom, second only to primate's. Nevertheless,
Marine
Cetacea are mammals that re-entered the oceans only a little over 50 million years ago, a relatively short time on
Adaptations
the evolutionary scale. During this time cetaceans and humans have developed marked morphological and
behavioral differences, yet their genomes show a high level of similarity.
This present review is focused on the description and significance of newly accessible cetacean genome tools
and information, and their relevance in the study of the evolution of successful phenotypic adaptations asso-
ciated to mammal's marine existence, and their applicability to the unresolved disease mechanisms in humans.

1. Introduction
Complex creatures evolve from more simplistic ancestors naturally
over time. Within the random genetic mutations occurring at any time
in an organism's genetic code, the beneficial ones are preserved, accu-
mulated and passed on to the next generation. The result is an entirely
new organism characterized by new phenotypic and genetic char-
acteristics, a “descent with modification” (Darwin, 1859). One parti-
cular descent into the water, about 50 million years ago (mya), came
with drastic changes for a certain group of mammals. This “walk back
into the ocean” happened several times resulting in 3 separate extant
orders of polyphyletic marine mammals, all adapted in many similar
ways to the problems caused by being aquatic (Feldhamer et al., 1999).
A large body size, streamlining shape, insulation of blubber and/or fur,
reduction of the size of external appendages, and many modifications
for diving and orientation are all distinctive characteristics of the
aquatic mammals. These adaptations have evolved to a higher level in
one particular group, namely Cetacea (Berta et al., 2015). The world's
present-day cetacean fauna consists of 88 species. Ocean dolphins,
porpoises, sperm whales, beaked whales, river dolphins and mono-
dontids characterize the parvorder of the Odontoceti, the toothed ce-
taceans. Much less diverse group is represented by the parvorder of the
Mysticeti, or baleen whales, including right whales, rorquals, pygmy
right whales and grey whales. Morphological features readily distin-
guish the two groups: Odontoceti have teeth and a single blowhole and
Mysticeti have baleen and two blowholes. Another major difference is
the echolocation, used by the Odontoceti to hunt, locate prey and to
know their environment in the sea (Cranford and Amundin, 1996;
McKenna et al., 2011).
Linnaeus, the “father of modern taxonomy” used morphology evi-
dences to classify for the very first-time plants and animals in his
Systema Naturae. But, in the first edition of the book, whales and the
West Indian manatee were classified among the fishes (Linnaeus, 1758).
However, Linneus was a systematicist, not an evolutionist. In evolu-
tionary studies, when species share similar physical features is because
the feature was present in a common ancestor. To identify the common
ancestor and examine how morphology has become modified through
descent over a particular interval of time, a collection of observable or
reliably inferable information needs to be assembled: fossils from pa-
leontology studies, description of the early stage changes from devel-
opmental biology, and, last but not least, molecular comparative studies
from gene, protein and even entire genomes. A phylogenetic analysis
that combines this information might address the questions about
when, where and why certain modifications (or derived conditions)
evolved and what factors have triggered a speciation process. So we
now know that baleen whales possess teeth in the early fetal stage but
then they lose them before birth; we know that a dramatic develop-
mental shifts take place in extant fetal baleen whales that lead to skull
development, resorption of the fetal dentition and growth of baleen
(Berta et al., 2016). Integration of diverse data (molecules, fossils)
provides the most robust test of the phylogeny of cetaceans. Continued
discovery of fossils that capture transitional stages in cetacean evolu-
tion provided essential new data on how the stem lineage to Cetacea
transformed (Gingerich et al., 2001; Thewissen et al., 2007),

E-mail address: annalaura.mancia@unife.it.

https://doi.org/10.1016/j.margen.2018.08.004
Received 6 July 2018; Received in revised form 21 August 2018; Accepted 21 August 2018
Available online 25 August 2018
1874-7787/ © 2018 Elsevier B.V. All rights reserved.
A. Mancia
demonstrating an evolution from an artiodactyl ancestors thus making
artiodactyl and cetaceans a monophyletic clade, grouped in the Order
of the Cetartiodactyla (Agnarsson and May-Collado, 2008; Spaulding
et al., 2009).
At present, of the extant 88 species of cetaceans, 12 are considered
endangered (3 of which are critically endangered), 5 vulnerable and 1
threatened. The situation could be even more critical than that due to
the missing assessment data for at least 38 species (International Union
for Conservation of Nature, IUCN, Red List of Threatened Species).
Many species and populations, considered to be the most vulnerable to
human activities, are endangered or threatened, or designated as de-
pleted worldwide. The vaquita, Phocoena sinus, representing one of only
seven species of true porpoises and only found in a small area in the
extreme northern Gulf of California, in Baja California, Mexico.
Vaquitas are small cetaceans, characterized by dark eye rings and lip
patches that look like a make-up application; the most-endangered
species of marine mammal in the world, with < 30 animals in 2016 and
a 50% annual decline continued since then. Unfortunately, losing a
species also means loss of useful and valuable information, before they
are even fully understood.
This mini-review is focused on the description and significance of
newly accessible cetacean genome tools and information, and their
relevance in the study of the evolution of successful phenotypic adap-
tations associated to mammal's marine existence, and their applicability
to the unresolved disease mechanisms in humans.
2. About the past 50 million years
The common bottlenose dolphins (Tursiops truncatus) are un-
questionably the most well-known of all the cetaceans. Their smiling
faces, their intelligence and charisma, make them the most popular
marine mammals in marine parks and dolphinaria, and also the most
represented in movies and television programs where they are trained
to complex performance. They are distributed in temperate and tropical
oceans around the globe and while some populations live further out to
sea, there are also many others populations living closer to the shore,
are residents of harbors, bays, lagoons and estuaries, are parts of the
2
Marine Genomics 41 (2018) 1–5
Fig. 1. The fall of dinosaurs and the rise of mam-
mals, in the oceans and on land.
After dinosaur extinctions 65 mya, mammals ra-
diated dramatically filling all niches of the dinosaurs
and invading new ones. The diversity of these
mammals included the first fully aquatic mammals
and primates. Above the arrow, on land, from left to
right: Aegyptopithecus (early monkeys, 35–33 mya);
Proconsul (first ape, 23–17 mya); Australopithecus
(early homininis, 4 mya); Homo (first humans) 2.5–3
mya; Homo sapiens sapiens (150,000 ya). Below the
arrow, into the water, from left to right: Pakicetus
(terrestrial ‘Pakistan whale’, amphibious cetacean)
48.5 mya; Ambulocetus (‘walking whale’, early ce-
tacean) 47–41 mya; Durodon (basilosaurid ancient
whale) 41–30 mya; Mysticetes (baleen whales) and
Odontocetes (toothed whales), modern whales.
coastal fauna, and are easy to recognize and fun to watch in the wild.
But the bottlenose dolphin hasn't always had the friendly face we
smile at today. Pakicetus, the first whale living 48.5 mya along the
margins of the large shallow Tethys Ocean (and in what we know as
Pakistan today), didn't look like a whale at all. It was a typical land
animal with large carnivorous teeth but its head had the distinctive long
skull shape of a whale; he had an ear bone with a feature unique to
whales and an ankle bone that linked it to artiodactyls (Gingerich et al.,
1983; Thewissen et al., 2009). Ambulocetus (47–41 mya) lived a more
aquatic lifestyle with its shorter legs, enlarged hands and feet and a
longer, more muscular tail. Whales that evolved after Ambulocetus
evolved nostrils positioned further and further back along the snout,
with a pelvis that is much reduced in size separate from the backbone,
for the use of the whole vertebral column in locomotion, a trait showing
their ancient terrestrial heritage (Thewissen et al., 2009). Dorudon
(41–30 mya) evolved other changes in the skeleton and had almost no
hindlimbs (Thewissen et al., 2009; Uhen, 2007). There is a remarkable
fossil record of Cetacea that has made them an exemplar of macro-
evolution, but while the adaptive transition from terrestrial to fully
aquatic mammals is well known, this is not true for the radiation of
modern whales and dolphins. Modern Cetacea consists of two evolu-
tionary lineages supported by morphological (Geisler and Sanders,
2003; Messenger and McGuire, 1998) and molecular data (Arnason
et al., 2004; Nikaido et al., 2001). The Odontoceti share a common
ancestor with the Mysticeti that lived about 30–35 mya (Cunha et al.,
2011). Within the Odontoceti, the Delphinida originated about 26 mya
(Steeman et al., 2009). High levels of phenotypic and genotypic poly-
morphisms made the genus Tursiops one of the most taxonomically
controversial among delphinid cetaceans. Currently two species, T.
truncatus, and T. aduncus are widely accepted based on morphological
and genetic evidence, and a third (T. australis) has been recently pro-
posed (Moura et al., 2013). Much of the divergence within Tursiops
occurred within the Pleistocene (2.58 mya - 117,000 ya), indicating a
rapid radiation within the species group probably correlated with a
period of a fast climatic change during the Holocene (Moura et al.,
2013). About the same time, around 200,000 ya, early modern Homo
sapiens with an anatomy similar to that of humans today were
A. Mancia
wondering the African lands (Brown et al., 2012). The hominoid/cer-
copithecoid divergence has an estimate of 30 mya, similar to that of the
Odontoceti and Mysticeti (Eizirik et al., 2004). Consistent estimates
place the basal Hominoidea divergence at 20 mya, the Hominidae di-
vergence at 18 mya and the human–chimpanzee split at about 7 mya
with a population split between Neanderthals and modern humans
400,000–800,000 ya (Langergraber et al., 2012; Schrago and Voloch,
2013) (Fig. 1).
The adaptive evolution leading to cetaceans and humans as we
know them today is happening at the same time under and above the
water. In the early Cenozoic era, after the non-avian dinosaurs became
extinct, the number and diversity of mammals that carried a low-profile
existence for 150 my before that, exploded. Without the once-dominant
group of competitors, mammals could occupy new environmental zones
and step into new ecological roles. But it took several million years for
the mammals to evolve larger body sizes with the best outcome in the
water leading to the largest living animal (30 m, 173 t), the blue whale.
The ability to socially interact and cultivate relationships allowed hu-
mans to colonize almost every terrestrial ecosystem. But just like hu-
mans, whales and dolphins live in tightly knit social groups, engage in
hunting, cooperate with other species, talk to each other and even have
regional dialects; some even have signature whistles which are believed
to represent names, so they can call to individuals. With an ex-
ceptionally large and anatomically sophisticated brains they have cre-
ated a human-like, marine based culture. The co-evolution of brains,
social structure, and behavioral richness of cetaceans provides a unique
and striking parallel to the large brains and sociality of humans and
other primates on land (Fox et al., 2017).
3. Cetaceans today: the post-genomic era
Linneus would say that cetaceans and humans are really different.
Luckily, we live in the post-genomic era where most of the organism's
genome sequences are available to test, confirm or reject hypotheses
based on observations. The focus of the post-genomic era is, in fact, on
the discovery and explanation of all the functional elements encoded
within the genome sequence and the comparison of related genomes
which have emerged as a powerful instrument for genome interpreta-
tion. At present, the final number of true protein coding genes listed in
the human reference genome in the manual curated database run by the
US National Center for Biotechnology Information (NCBI) is 20,203,
accounting for a 1.5% of the 3 billion base pairs representing the entire
genome. Similarly, the protein coding genes in the 7 cetacean reference
genomes fully sequenced, annotated and released by the NCBI
Eukaryotic Genome Annotation Pipeline so far account for 1.2% - 1.3%
of the entire genome (1. Common bottlenose dolphin, Tursiops trun-
catus; 2. Minke whale, Balaenoptera acutorostrata scammoni; 3. Yangtze
River dolphin, Lipotes vexillifer; 4. Killer whale, Orcinus orca; 5. Sperm
whale, Physeter catodon; 6. Beluga whale, Delphinapterus leucas; 7,
Yangtze finless porpoise, Neophocaena asiaeorientalis asiaeorientalis).
The comparison of genome sequences at nucleotide and protein
levels does not seem to show high degrees of dissimilarities: there is no
big difference when we compare sequences of cetacean to humans or to
the Cetartiodactyla, cetacean's closest relatives (Fig. 2). The identity is
always near 90% and 80% in transcripts and protein sequence com-
parisons, respectively (Fig. 2). But comparative genomic analyses are
showing interesting insight. For example, evolutionary analyses de-
monstrated that the overall synonymous substitution rate in dolphins
has slowed down when compared with other studied mammals, and is
within the range of primates (McGowen et al., 2012). A comparison of
10,025 protein-coding sequences from the bottlenose dolphin genome
with nine other amniotes genomes, documented the positive selection
of multiple genes in the dolphin lineage associated with the nervous
system (related to human intellectual disabilities, synaptic plasticity
and sleep), energy metabolism (metabolic processes, glycemic regula-
tion and mitochondrion activity), and other specializations such as deep
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Marine Genomics 41 (2018) 1–5
diving, blubber and fat storage which are specific to cetaceans
(McGowen et al., 2012).
A comprehensive analysis using 11,838 high-quality orthologous
gene alignments selected from the dolphin and four other terrestrial
mammalian genomes identified genes that have undergone positive
selection resulting in significant enrichment of categories of lipid
transport and localization, ATPase activity, sense perception of sound,
and muscle contraction, all areas that are potentially related to cetacean
adaptations (Nery et al., 2013; Sun et al., 2013). The dolphin genome
has been used to obtain information on the independent evolution of
echolocation in bats and cetaceans (Parker et al., 2013). Comparative
genomics analysis of the bottlenose dolphin, killer whale, walrus and
manatee genome revealed that parallel substitutions are widespread in
marine mammals (Foote et al., 2015). The precise phenotypic effects of
these parallel substitutions in the genes described are not specifically
determined in the paper, but there are functional associations sug-
gesting a role in the convergent phenotypic evolution of the marine
mammal lineages. For example, S100A9 and MGP encode calcium-
binding proteins that have a role in bone formation, suggesting con-
vergent phenotypic changes in bone density, high in shallow-diving
species (manatee and walrus) but low in deep-diving cetacean species
that collapse their lungs to overcome neutral buoyancy. However, when
searching the published minke whale genome (Yim et al., 2014), not all
the putatively adaptive convergent substitutions where found, sug-
gesting that they were either derived in the toothed whales or lost in the
baleen whales after the of the Odontoceti/Mysticeti divergence. Sur-
prisingly, the Authors found an unexpectedly high level of convergence
along the combined branches of the terrestrial sister taxa to the marine
mammals for which there is no obvious phenotypic convergence, con-
cluding that evolution doesn't often uses convergent molecular evolu-
tion to reach convergent phenotypic evolution (Foote et al., 2015; Zhou
et al., 2015). In the whale lineage, a comparative genomic analysis
identified the expansion in the whale lineage of gene families associated
with stress-responsive proteins and anaerobic metabolism, whereas
gene families related to body hair and sensory receptors were con-
tracted (Yim et al., 2014). Further insights into the genomic basis of
aquatic adaptations in marine mammals that can be linked to their
physiology and health, may rely on functional or genomic analyses of
non-coding regions which have the potential to be uncovered due to the
better coverage of genomes.
All the new genome information is unraveling many unanswered
questions on similarity and differences between human and cetaceans
whilst focusing on the discovery and explanation of all the functional
elements within the genome sequence.
4. Understanding resemblance
Humans are complex and intricate organisms. Scientists untangle
human complexity using in vivo models called model organisms, which
are simpler organisms: easy to maintain, breed and manipulate in a
laboratory, with similar genes and genomes to humans. A few such
examples are the yeast (Saccharomyces cerevisiae), the fruit fly
(Drosophila melanogaster), the nematode worm (Caenorhabditis elegans),
the Western clawed frog (Xenopus tropicalis), the Zebrafish (Danio rerio),
the Mouse (Mus musculus). Despite obvious differences, these organisms
all share key biochemical and physiological functions with humans that
have been conserved by evolution and they can be very informative to
study and understand human diseases and treatments. Cetaceans are
the antithesis of model organisms: they are even more complicated to
study in a laboratory setting than any other organism, too big to keep
and maintain only for research purpose, and unethical to manipulate,
with generation times longer than humans. But they are the closest
oceanic relatives of humans, long-term resident, long-lived top pre-
dators, which make them perfect sentinels. Sentinel organism can be
very informative to detect risks posed by environmental conditions.
Cetaceans in particular evolved a thick layer of blubber under the skin
A. Mancia
Fig. 2. Average percentage identity in transcript and protein alignment among cetaceans, human and cetartiodactyla.
Transcripts and proteins alignments were performed using genome information retrieved from the Eukaryotic genomes annotated at NCBI (https://www.ncbi.nlm.
nih.gov/genome/annotation_euk/all/). Schematic representation of the organisms genome sequence information used in the comparisons; on the top, from left to
right: Tursiops truncatus, Orcinus orca, Physeter catodon, Lipotes vexilifer, Balenoptera acutorostrata scammoni; on the first column to the left, from top to bottom: Homo
sapiens, Cetartiodactyla. T, transcripts. P, protein.
which not only functions as insulation, but also functions as a re-
pository for lipophilic contaminants. And so, they are sentinel organ-
isms able to provide an early warning on the cumulative effects of
different environmental stressors and the extent to which these stressors
can affect ecosystems and human health (Wells et al., 2004). Over the
years studies on wild dolphins have shown the impact of multiple stress
factors stemming from the bioaccumulation of anthropogenic con-
taminants combined with infectious diseases, food depletion, and cli-
mate change on dolphin immunity and health both at cellular and at
molecular level (Mancia et al., 2015) (Mancia et al., 2014) (Reif et al.,
2015) (Schwacke et al., 2012). Several studies have shown that in-
creasing environmental pressure can cause more frequent and severe
zoonosis and marine mammals can be infected with pathogens of both
marine and terrestrial origin (Bossart, 2011). The list comprises bac-
terial, viral and fungal infections producing seal finger, brucellosis,
leptospirosis, mycobacteriosis, mycoplasmosis, influenza, lobomycosis
and blastomycosis. As the number of zoonotic diseases rises, the iden-
tification of pathogens in cetaceans is becoming robust indicator of
environmental health (Waltzek et al., 2012). Cetaceans cannot escape
the legacy of contamination of the areas in which they live, as their
philopatric nature, for the most part, precludes occupation of new and
less contaminated areas making them suitable sentinels of the ocean
health and valuable indicators of the aquatic pollution, pathogens and
water quality and all the hazards posed to humans.
5. Learning from divergence
Human medical research has greatly improved in the last decades
thanks to the advancement of technology but there are still unresolved
underlying mechanisms in human disease and the exploitation of ce-
taceans unique adaptations can give valuable insights into uncertain
human conditions. How? Cetaceans can develop metabolic syndrome,
just like humans, characterized by elevated insulin, glucose, triglycer-
ides and ferritin (Venn-Watson et al., 2011; Venn-Watson et al., 2015).
A comprehensive study into these animal's diet as a possible risk factor
for longer life and metabolic disease, highlighted the potential benefits
of the saturated heptadecanoic acid on erythrocyte membranes or
plasma phospholipids in dolphins (Venn-Watson et al., 2015). A diet
rich in this specific type of saturated fatty acid results in increased
serum levels of adiponectin (an insulin sensitizing hormone) and
sphingosines coherent with an insulin-sensitizing phenotype (Sobolesky
et al., 2016). A better understanding of the networks activated by the
mechanisms regulating insulin sensitivity could aid research for
therapies of metabolic syndrome and diabetes affecting human popu-
lations. The first lesson we learned from cetaceans is that fats are
4
Marine Genomics 41 (2018) 1–5
important. Another lesson from cetaceans comes from their extra-
ordinary way of regeneration when wounded. Despite the analogies
between cetaceans immune system and that of terrestrial mammals
(Beineke et al., 2010; Mancia et al., 2007), the process of wound
healing in cetaceans is much faster and less subject to infections due to
stem cells high in activity and the accumulation of specific components
and antimicrobial function in blubber (Zasloff, 2011). Stem cells pre-
sent in the blubber probably have a critical role in the healing process
as well as the fats. For example, the composition of dolphin's blubber
has a high concentration (2–5% of total fatty acid) of isovaleric acid,
which accumulates in the blubber but doesn't get burned for fuel during
times of starvation (Koopman et al., 2003). A genomic approach de-
scribing transcripts, proteins and metabolites present in the blubber
after a serious injury could unravel the mechanisms involved in the
healing process and those involved in the protection from infection,
which can be used for the discovery of new therapies in regenerative
medicine. The second lesson we learned is that fats are very important.
Cetaceans need their blubber and their fats. Lipid-rich, collagen fiber-
laced blubber can comprise up to 50% of the body mass of some ce-
taceans ranging from 2 in. thick in dolphins to > 12 in. thick in right
whales. It stores energy, insulates heat, and increases buoyancy. Be-
cause blubber is a large deposit of fats, cetaceans are particularly sus-
ceptible to persistent organic pollutants (POPs) (Bachman et al., 2014;
Yordy et al., 2010). Their accumulation in the blubber affects the an-
imal health, whilst keeping the POPs away from the bloodstream. If an
animal is immunodepressed, for any reason, the blubber thins and the
POPs are released into bloodstream. The lipophilic nature of blubber
that makes it a reservoir for anthropogenic pollutants, also contributes
to keep them contained, far from where they can harm the most. The
third lesson we learned is that fats are extremely important. Blubber is
essential for the ocean top predators providing valuable information
about body condition, health and life history of individual animals.
6. Conclusions
In the last few years, a great deal of information about cetacean's
genome has been collected and insights into the mechanisms under-
lying the variety and diversity of cetaceans, revealing novel functions,
connections of molecular and physiological mechanisms related to their
adaptations, health and disease, are continuously being discovered.
But now, after 15 years the completion of the Human Genome
Project and 7 years after the sequencing of the first marine mammal
genome, it is clear that the sequencing of a genome and the information
encoded within will not unlock the code of life by itself. The DNA se-
quence is not the only responsible source for the final physical makeup
A. Mancia
of the organism. Certainly, there is a better understanding of the roles of
the coding part of the DNA, namely messangerRNA (mRNA), but all the
information encrypted in the non-coding RNA (such as micro RNA,
short interfering RNA, piwi-interacting RNA and long non-coding RNA)
as well as in DNA modifications (such as the DNA methylation, histone
modifications, nucleosome positioning and three-dimensional archi-
tecture) are still missing or in their infancy, above all in non-human
species. What about the epigenome? What about the heritable mod-
ifications of the DNA that do not change its sequence, while changing
the way the DNA sequence gives its instructions? What about the in-
tegration of genome and epigenome?
We are still far from understanding how environment and genetic
inclinations can intertwine in the complexity of cell biology but we
know that the network and pathways observed in cetaceans can identify
and be predictive of potential risks for our health and for the health of
the environment and, most importantly, for the health of cetaceans.
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