Evolution of Homeothermy in Mammals

     All mammals and birds are endothermic, by generating and retaining heat internally they can achieve core body temperatures higher than the ambient temperature. This contrasts with other vertebrate classes where at most only a few species have this ability.  All mammals are at least sometimes homeothermic, maintaining body temperature within a narrow range of a few degrees.  Some mammals are temporarily heterothermic, letting their body temperature decrease towards the ambient temperature by a regulated process, called (daily) torpor if it lasts less than 24 hours, and hibernation for longer periods.

     My interest in homeothermy grew out of two observations which likely seemed to be connected, but for which the connection remains obscure.  One is the association in humans of fetal and neo-natal deaths with a minor anatomical anomaly, small ribs on the 7th cervical vertebrae.  The other that nearly all mammalian species have exactly 7 cervical vertebrae (the 7 cv constraint), in contrast to birds where the number is highly variable.

      A small rib on the last cervical vertebrae would seem to be a minor, even trivial, shift in anterior/posterior patterning, with no evidence connecting it directly to lethality.   That this minor shift was even noticed may be because it occurs at the position of a dramatic change in the structure of the vertebrae, between the ribless neck and rib-bearing thoracic segments. Freitsen Galis and her colleagues have examined this possible connection extensively (Backgrounds 1, 2, and 3), and have suggested the events resulting in lethality occur during the period of development with the most interaction of signaling pathways originating in distant regions of the embryo, roughly from the period from gasrulation through early organogenesis, a stage often considered the phylotypic stage. 

     At the time of their divergence from the cephalochordates, the ancestors of vertebrates are thought to have to have diploid sets of 13 distinct Hox genes.  Prior to the first vertebrates, it is thought that the whole genome underwent two rounds of duplication.  Some of the redundant genes were lost, but in all extant vertebrates each of the original 13 is present in from 2 to 4 somewhat different sequences (each with two possibly different alleles).  This increased number of Hox genes gave the possibility of complex A/P patterning among vertebrates.

        Among each of the classes of vertebrates, there is considerable variability in the number of vertebrae within each of the major groups (cervical, thoracic, etc,) with the exception of the mammals, where almost all have exactly 7 cervical vertebrae with some, but limited variability more posteriorly.  These constraints likely are related to the evolution of endothermy and later homeothermy in the lineage from which mammals arose.   

    Prior to the advent of endothermy, embryonic development had to cope with variability of the environmental temperature, which may have even increased with the advent of the amniote egg that allowed development to occur in a terrestrial rather than aqueous environment.  This situation may have begun to change in the therapsid lineage when larger size produced a stabler maternal temperature.  Possible evolutionary benefits were then made possible by brooding behavior or progressively longer retention in the embryo, ultimately leading to full term gestation in eutherian mammals.

       The constraint limiting to cervical vertebral number to seven among the ancestors of mammals appears to have taken place around 250 million years ago (mya) around the time of the Permian/Triassic boundary (Background 6).  Around this time there was a very large rise in average global temperatures, followed by a slow decrease.  Lovegrove (2019) argued that this and subsequent increases in internal temperatures were selective for faster growth rates, mobility and increased parental care. Since tissues arising in the neck region are involved in head and forelimb movement and oxygen supply (heart and diaphragm), increasing restrictions were likely placed on developmental process in this region. 

      Anterior/posterior vertebral patterns are determined during gastrulation and show little variability among members of a given species, even in the case of ectotherms in which development can occur over a wide range of environmental temperatures (van Oostrum et al. 2025, see also Exploration 3 and Background 9).   

      Dawkins (1988) suggested that groups of animals that are highly segmented, the annelids, arthropods, and vertebrates, may be more "evolvable" than other groups.  In vertebrates, each vertebra differs little structurally and functionally from its neighbors, except at a few positions where there are large changes.  The Hox genes play an important role in anterior/posterior (A/P) patterning in diploblastic animals.  Two features of the Hox genes are especially notable in vertebrates.  Unlike in the case of arthropods, where Hox genes controlling adjacent segments are located in different parts of the genome, in vertebrates the Hox genes are located contiguously and exactly matches their order of expression along the A/P axis.    Also, in vertebrates, the timing of the initial expression of Hox genes occurs in the same order.

      Construction of this site was also inspired by two other groups of investigators.  The late Barry Lovegrove in his book "Fires of Life: Endothermy in Birds and Mammals (2019)" presented the hypothesis that evolution of endothermy occurred due to a series of changes starting about 250mya, during a period of worldwide higher termperatures.  He and his colleagues have been among the leaders in documenting changes in internal temperature during gestation in mammals.  A minority of extant mammals at times abandon homeothermy, allowing their internal temperatures to temporarily to decrease towards the ambient temperature through the controlled processes of torpor and hibernation, some of which this has been observed to occur during gestation.  They had proposed that heterothermy is the ancestral state and that the adaptation to strict homeothermy (and loss of facultative heterothermy) has occurred piecemeal in various lineages.

    Levesque and Lovegrove (2014) proposed that one advantage of adapting endothermy/homeothermy is greater energy output during reproduction (parental care model).  They examined this in tenrecs of Madagascar, which have among the lowest basal metabolic rates and largest temperature variability among mammals, and suggest that they are remnants of the original eutherian basoendotherms.

       From around 200 mya to around 50mya (and up to the present in Madagascar) global climate was consistently warm, and the ancestors of mammals are thought to have been nocturnal and insectivorous and used non-shivering thermogenesis to recover from torpor, as do tenrecs, and this may have been a factor in surviving the K/Pg boundary impact. 

       Previous studies of tenrecs had suggested that tenrecs utilize torpor less frequently during gestation and lactation.  Levesque and Lovegrove found that in the tenrec Setifer setosus females during gestation and lactation (with one exception) did not enter torpor when exposed to temperatures below 25C, but non-reproductive females did with the same frequency as males.  The exception appeared to have entered torpor earlier than gastrulation.

        In Exploration 1 I surveyed all examples I could find of mammals entering torpor during gestation.  In many cases developmental stage at time of torpor could only roughly inferred.  However, in all cases it appeared to occur well before gastrulation or after early organogenesis, which appears to be a critical period with regard to developmental abnormalities. Around the critical period many showed the smallest daily temperature fluctuation.  Exploration 1 also contains a (less extensive) survey of species that have never been observed to enter torpor during gestation.  In these, the time of maximum daily temperature also appears to occur around this period.  This led to what I call the Goldilocks hypothesis, that in mammals during this period the temperature has to be just right, or close to it. ​​

       Universal homeothermy likely arose much earlier in the mammalian lineage than in the bird lineage.  The embryonic temperature in mammals is also likely to be closer to that of the mother than would be case of birds where it depends on external transfer of heat from the homeothermic parent to the egg.  Thy possible implications of this led to the main hypothesis examined in this site.

          Lovegrove (2019) has also proposed that endothermy is this lineage arose through a series of steps either in response to changes in environmental temperatures or to take advantage of benefits of increased metabolic rate, faster speed, or increased parental care.  Some of these changes may have involved interactions between the neck and thoracic regions that were selected for despite being associated initially with deleterious effects (Background 5).  (Buchholz 2012) proposed that the origin of the diaphragm in mammals was an important factor in the 7 cv constraint, although currently it is not associated with lethality.  Here it is proposed that other homeothermic innovations ameliorated some deleterious effects, but not completely due to the increased complexity that homeothermy permitted during the critical period.

     That the constraint is connected to increased complexity is examined in Exploration 2, which was influenced by the work of Sethna and colleagues.  They took proposed mathematical models of various biological systems and first set criteria for the system to perform successfully.  For example, success might be for an initial concentration of some substrate(s) that the system produced a product within some range of rates.  They then ran simulations with a wide variety and range of model parameters and asked for which sets were successful.  They imagined that these parameters exist in what they called chemotype space, intermediate between the genotype and higher levels of structure and behavior underlying differences in phenotype.  Contrary to what might be believed, systems in living beings are most often very imprecise and, instead, display what they called "sloppiness."  For proper functioning, some parameters are limited to a fairly narrow range, but generally the ranges of other parameters can be larger, even orders of magnitude.  This seems to be because if every parameter was required to be precise, the system would be too vulnerable to disruptions by mutations.

     To my knowledge, there has only been one system for which successsful performance over a range of temperature has been analyzed by the sloppy modeling techniques.   This is for the protein KaiC, whose cycles of self-phosphorylation and dephosphorylation is central to circadian gene expression in a blue-green algae.   In vitro time course of levels of phosphorylation when this protein is incubated with ATP is independent of temperature from 25 to 35C.  The analysis suggests that if this system were only required to be succesful at a single or small range of temperatures it could "afford" to be sloppier.  This suggests that this could allow more changes of the gene without compromising the basic function, such as interacting with other cellular components in a beneficial way.

      There are at least two caveats in the interpretation of the KaiC results, explained in more detail in Exploration 2.  The model Sethna used had studied had been a simplification at the time it was proposed, in that it assumed that it had only a single phosphorylation site when in fact there were two.  Even with this simplification the model had 36 parameters. In the twenty years since, the system is now known to be even more complicated.
​​​      Did the more stable internal temperatures of homeothermy allow more refined(precise) and complex phenotypes?  If so, precision may have made development more prone to production of non-viable progeny by a variety of causes, such as mutations (heritable or somatic), stochastic processes, and excessive temperature fluctuations.  This may have placed further restrictions on or prompt evolutionary changes the organization of developmental systems, such as increased modularity of the neck, and preventing changes to reduce lethality.   The hypothesis is that association of cervical ribs with developmental lethality in humans and some other mammals likely happened as the result.

        Determining whether this actually is the case would require more studies of the effect of temperature on development systems using sloppy modeling and other yet to be devised methods for dealing with much more complicated, but more realistic, models.  There are reasons to believe that this could be achievable.

        With the recent advent of in vitro systems that mimic various aspects of development, and in which temperature can be controlled and changes in the components directly measured, it may be able to understand on molecular and organizational levels how and why homeothermy evolved.

        Computing power increases and AI may allow more refined studies of cellular systems.  One problem in sloppy modeling is that that requires some apriori knowledge of reasonable rate     

​​        I started the site mainly as a tool to organize what I was learning and to test out new ideas, but I hope others may find it interesting and/or useful.  The explorations contain some "trails with dead ends" either because I found further information that seemed to contradict the idea in question or it didn't seem that any more progress was possible.  I have included them (with a forewarning) because more than once I learned further information that revived an idea.