“Myosin Gene Mutations” may support “Androgens in Human Evolution”
Copyright 2004, James Michael Howard,
Hansell H. Stedman, et al., produced a paper, Nature 2004; 428: 415-418 which suggests that a “myosin gene mutation” may be connected to the formation of “Homo.” Here is the abstract:
“Powerful masticatory muscles are found in most primates, including
chimpanzees and gorillas, and were part of a prominent adaptation of Australopithecus
and Paranthropus, extinct genera of the family Hominidae. In contrast,
masticatory muscles are considerably smaller in both modern and fossil members
of Homo. The evolving hominid masticatory apparatus—traceable to a
Late Miocene, chimpanzee-like morphology—shifted towards a pattern of gracilization
nearly simultaneously with accelerated encephalization in early Homo.
Here, we show that the gene encoding the predominant myosin heavy chain (MYH)
expressed in these muscles was inactivated by a frameshifting mutation after
the lineages leading to humans and chimpanzees diverged. Loss of this protein
isoform is associated with marked size reductions in individual muscle fibres
and entire masticatory muscles. Using the coding sequence for the myosin rod
domains as a molecular clock, we estimate that this mutation appeared
approximately 2.4 million years ago, predating the appearance of modern human
body size and emigration of Homo from
In order to explain how this may support my explanation of human evolution, it will be necessary to explain my hypotheses. Firstly, I suggested mammalia evolved because of increases in production of dehydroepiandrosterone (DHEA). (Hormones in Mammalian Evolution, Rivista di Biologia / Biology Forum 2001; 94: 177-184). Subsequently, primates may have evolved from mammalia as a result of increases in testosterone. (“Mitochondrial Eve,” “Y Chromosome Adam,” Testosterone and Human Evolution, Rivista di Biologia / Biology Forum 2002; 95: 319-326). Increases in testosterone may have culminated in the evolution of humans. (Androgens in Human Evolution, Rivista di Biologia / Biology Forum 2001; 94: 345-362).
The foregoing publications are derived from my principal hypothesis that DHEA was selected by evolution because it may “optimize” replication and transcription of DNA. Therefore, all tissues are affected by DHEA. DHEA may be involved in growth and development of all tissues and subsequent maintenance of “adult” tissues. Subordinately, testosterone evolved to affect the availability of, and directs the use of, DHEA. That is, testosterone directs the use of DHEA and, therefore, testosterone also affects the growth and development and maintenance of all “testosterone-target-tissues.” In humans, DHEA naturally starts to decline around the ages of twenty to twenty-five years, reaching very low levels in old age and may explain why some elderly are positively affected by testosterone while some are not. (If DHEA is too low, testosterone cannot exert effect.)
Testosterone is higher in male and female humans compared to chimpanzee males and females, respectively. Dehydroepiandrosterone levels are much higher in chimpanzees than humans. I suggest it is the increase in testosterone which eventually separated hominids from chimpanzees. As testosterone increased within the hominids, it increased the use of DHEA for testosterone-affected tissues. This increase in testosterone positively affected the brain as well as the body. This increased the strength and massiveness of the muscles of posture by directing use of DHEA for these muscles and stimulated upright, bipedal locomotion. Increasing testosterone reduced the effects of estrogen on genital display, while, at the same time, increasing growth of the breast. (This is explained in detail in “Androgens in Human Evolution,” at http://members.cox.net/jmhoward3/evolution.html .) So, the signal of female sexual maturity was switched from genital display to breast display in an organism beginning upright locomotion, simultaneously. (DHEA is also known to be directly involved in human female breast growth. Estradiol, according to my work, also directs use of DHEA. Estradiol and testosterone both positively affected breast growth by directing use of DHEA. Hence, human female breasts are larger than those of other primates.) At this point in human evolution, hominids have begun upright locomotion and some brain enlargement.
The basis of human evolution, according to this hypothesis, is increases in testosterone in the female. Testosterone positively affects sexual activity in males and females. Females of higher testosterone will increase in percentage within a population faster than those of lower testosterone over time. The increased testosterone of these females will affect the brains of fetuses. This will stimulate larger brain formation. At some point in human evolution, this will manifest itself as an increase in female size, or a decrease in the ratio of male to female size, at the time of hominid brain enlargment. I think this is first noticed in Homo erectus. This is also a time when brain size begins to increase rapidly and the phenomenon continued. The brain is beginning to use more DHEA for growth and development.
Prior to the increase in bran size, the bodies of hominids would be increasing in size. Testosterone directs the use of DHEA for this growth. With the advent of increasing brain size, use of DHEA is increased by the brain. (I think growth and development of the brain requires more DHEA than body size. That is, the brain competes for available DHEA at the expense of other tissues.) Therefore, at this stage in human evolution, DHEA is being used for growth and development of the brain, again, at the expense of the body. I suggest this is the cause of a switch from “robust” hominids to “gracile” hominids. The brain grows bigger at the expense of the face, teeth, and jaws. Stedman, et al., suggest the change in myosin is involved in this change. I suggest Stedman, et al., are correct that this may have occurred at the critical time, that is, a time when masseter muscle size was declining approximately at the same time brain enlargement was increasing. However, I suggest the change in myosin may be due to the changing ratio of DHEA to testosterone that was driving human evolution.
Testosterone is directly involved in sex differences in masseter muscle. “Thus, a brief exposure to testosterone during postnatal maturation [in castrated rabbits] is able to produce a long lasting myosin heavy chain isoform switch that is similar in magnitude to that found during normal development.” (Cells Tissues Organs. 2001;169(3):210-7). I suggest this was ongoing in the robust hominids which exhibited very large masseter muscles. (These hominids were the construction of increasing testosterone which, because their brains were not using as much DHEA at the time, directed their DHEA for their bodies.) This effect of testosterone may be teased apart from the real effect of DHEA levels. In castrated rats, myosin heavy chain (MHC) expression in the soleus and extensor digitorum longus muscles is positively affected by nandrolone (nortestosterone decanoate) and exercise but not by nandrolone, alone. “In conclusion, it appears that endogenous anabolic steroids are not essential for the maintenance of the MHC expression of fast- and slow-twitch muscles in the young adult male rat. In addition, nandrolone combined with endurance exercise induced a shift from a fast to a slower MHC phenotype of the slow-twitch muscle.” (Eur J Appl Physiol. 2000 Jan;81(1-2):155-8). In “early postmenopausal women,” a group beginning to experience loss of DHEA, DHEA was increased for two hours and testosterone was only momentarily increased by exercise. (Eur J Appl Physiol. 2003 Sep;90(1-2):199-209). In the castrated rats, nandrolone, alone did not increase myosin heavy chain but nandrolone and exercise did increase MHC. I suggest the exercise increased DHEA which, then, nandrolone could direct for use in increasing MHC.
Myosin heavy chain declines with ageing. “Reductions in myosin heavy chain and mitochondrial protein synthesis rates have been correlated with age-associated decrements in muscle strength and aerobic exercise tolerance, respectively.” (J Nutr. 1998 Feb;128(2 Suppl):351S-355S). In elderly compared to young human skeletal muscle, myosin declines and myosin isoforms change (J Physiol. 2003 Oct 15;552(Pt 2):499-511). (Remember, from above that DHEA begins to decline around age twenty.) One form of myosin heavy chain mutation increases with age (Neurology. 2002 Mar 12;58(5):780-6). I suggest these changes in myosin levels, types, and mutation rates may be the result of the decline of DHEA. In fact, research has suggested that DHEA may inhibit mutagenesis. “The results strongly prove that DHEA is a potent cancer chemoprophylaxis agent, which exhibits inhibitory potential on mutation and chemical carcinogen in vivo and in vitro.” (Zhonghua Zhong Liu Za Zhi. 2002 Mar;24(2):137-40).
The loss of DHEA negatively affects myosin heavy chain levels and types and may increase the probability of mutation. Herein lies the possible support of Stedman, et al., of “Androgens in Human Evolution.” As humans increased in testosterone and subsequently experienced a decline in DHEA, I suggest the pertinent hominids also experienced changes in myosin heavy chain levels and types. I also suggest these hominids may also have experienced an increase in mutation of the isoforms of myosin heavy chain because of loss of DHEA. Perhaps, the mutation in myosin heavy chain that resulted in changes in human isoform expression may not be a “cause” of changing human evolution, but may have been a coincidental consequence of the multitude of changes caused by increasing testosterone and decreasing DHEA.