The role of epigenetics in human evolution

Alexander Osborne

doi:10.1093/biohorizons/hzx007

The role of epigenetics in human evolution

Osborne, Alexander 2017-07-28 00:00:00 BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx007 ............................................................................................ ..................................................................... Review article Alexander Osborne University of Glasgow, 5 Rosemount Square, Kilwinning KA13 6LZ, UK *Corresponding author: Alexander Osborne, Email: alexander103050@hotmail.co.uk Supervisor: Christopher Finlay, University of Glasgow, Glasgow G12 8QQ, UK ............................................................................................ ..................................................................... This review aims to highlight the key areas in which changes to the epigenome have played an important role in the evolu- tion and development of our species. Firstly, there will be a brief introduction into the topic of epigenetics to outline the cur- rent understanding of the subject and inform the reader of the basic mechanisms and functions of the epigenome. This will lead on to more focussed detail on the role played by epigenetic changes in the rapid evolution of our species and emer- gence from our ancestor species, as well as the Human Accelerated Regions that played a role in this. The discussion high- lights how epigenetics has helped and hindered our species’ development via changes to the epigenome in more modern times, discussing case examples of documented instances where it is shown that epigenetics has played a role in the evolu- tion of humanity. Key words: epigenetics, evolution, human, methylation, HARs, modiﬁcation Submitted on 25 July 2016; editorial decision on 3 July 2017 ............................................................................................ ..................................................................... as they once were. However, evolution is an ongoing process, Introduction one that modern humans are not exempt from, despite the fact that the advancement of science has down played the role Human evolution is often thought of as something abstract of selection. Humans are not above the effects of evolution and distant, something that played a role in the development and recent research into epigenetics serves as a reminder of of our long forgotten ancestors but does not affect the modern that fact. state of our species. Even when we consider genetic conditions that once provided an evolutionary advantage to populations Epigenetics is a mechanism of gene control that can pro- of early humans but have now become deleterious, it is often mote or repress the expression of genes without altering the thought that modern medical care compensates and, in large genetic coding of an organism (Feinberg, 2008). In other part, negates their symptoms. These include conditions such words epigenetics represents a system by which the gene as Sickle Cell Anaemia and Diabetes Mellitus Type 1; many expression of an individual can be altered without altering of the individuals that carry these conditions live full and their genome’s sequence. Our current understanding has iden- healthy lives thanks to modern medicine. So we consider these tiﬁed some of the controlling epigenetic processes that regu- conditions via the lens of disease and not as relics of our evo- late gene expression, referred to as epigenetic ‘marks’. For lutionary history. At one time Sickle Cell Anaemia provided example, methylation of DNA, alteration of the histone mole- an important defence against Malaria (Wiesenfeld, 1967) and cules that hold together DNA super structures via methyla- there is evidence that Diabetes Mellitus Type 1 developed in tion or acetylation and various RNA and Dicer protein early Europeans as an adaptation to the colder climate dependent processes that inhibit gene expression. In combin- (Moalem et al., 2005). As technology has advanced and com- ation, the sum total of all these epigenetic marks in an individ- pensated for the evolutionary drivers of these traits, they are ual is known as the epigenome. This review will mainly focus no longer as advantageous to the individuals who carry them on studies that involve the methylation of DNA as this is the ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. most widely studied epigenetic mechanism, but other aspects represents something very important, a fundamental revalu- of the epigenome will be touched upon. Methylation of DNA ation of the theory of evolution. Acquired traits, while not is already known to be very important; for example extreme alterations of the genome, can be inherited (Jones, 2012). cases of demethylation, representing a loss of gene expression This review will examine the implications this has for the con- control, are associated with oncogenesis (Feinberg and cept of human evolution and highlight interesting examples Tycko, 2004). This review will, however, not focus on the and case studies in which these effects are notable. inﬂuence that changes to the epigenome can have on an indi- vidual’s health, instead it will discuss the role this mechanism of gene expression control has played in the evolution of our Method of inheritance species, both the emergence of the human species and the effects it has had more recently. The study of epigenetics has revealed an interesting facet of this method of gene expression control. The methylation of Before we can fully grasp the effects epigenetics has had on DNA and other epigenetic marks do not alter the genes that our species a ﬁrmer understanding of what epigenetics is and they inﬂuence at a sequence level but nonetheless alter the the way in which it can alter gene expression is needed. Gene expression of these genes. Furthermore these marks can be control is a fascinating area of genetics and this is particularly acquired throughout the lifetime of the individual and, if car- interesting to those with a fascination for human evolution. ried in their gametes, these marks are inheritable. In this sec- Epigenetic inﬂuence over gene expression possibly originated tion, the focus will be on the ways in which these marks can as a defence against Transposons, parasitic DNA that jumps be inherited. around in the genome and can disrupt genes by inserting into the middle of them (Slotkin and Martienssen, 2007). A possible The semi-conserved nature of mitosis results in two sets of mechanism of defence can be achieved via methylation of daughter chromatids, one in each set carrying the Epigenetic DNA, as illustrated in Fig. 1. Silencing these transposable ele- marks from the original chromosome (Feinberg, 2008), as ments and preventing or limiting damage to an organism’sgen- illustrated in Fig. 2. This allows the transfer of epigenetic ome provides an important advantage to those ﬁrst species to marks from mother cells to daughter cells in somatic tissue. develop this mechanism. Eventually this process evolved into a This explains how these marks can be maintained in an indi- method of promoting and repressing host genes (Feinberg, vidual, but not how they are spread to the next generation of 2008) that could not only be acquired throughout the lifetime offspring. of an individual, but also passed onto its offspring (Jones, These marks can also be conserved in their daughter chro- 2012). This mechanism of gene silencing may have also matid during meiosis, resulting in all gametes carrying the epi- allowed for the development of multicellular organisms by genetic marks of the individual of origin. However, many of allowing a single genome to tailor its expressed genes in each these marks are removed during the process of gamete forma- individual cell within the larger organism (Badyaev, 2014). tion. It is now understood that some genes are protected from While epigenetics is a relatively new understanding of the this process of demethylation, resulting in the marks being systems involved in gene control and expression it also maintained in their gametes’ epigenome (Giuliani et al., Figure 1. Methylation as a defence against Transposons. The ﬁgure illustrates how methylation can help an organism defend itself from Transposons. Over time the DNA coding vital proteins for the Transposon will become methylated and cease to be expressed, therefore trapping the Transposon in its current position in the host’s genome. This prevents the Transposon from ‘jumping’ and possibly disrupting the expression of vital genes elsewhere in the host’s genome. ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. of famine. If the affected parent is the mother the effects of deleterious epigenetic marks are more heavily expressed in the offspring’s phenotype, especially if famine occurs during the early stages of pregnancy (Tobi et al., 2009). For an example of this deleterious nature of hypomethylation one can look at the Dutch Winter of Hunger, a well-documented example of famine in the modern world that occurred from 1944 to 1945 due to a blockage preventing the movement of fuel and food in the Netherlands. This starvation resulted in the hypo- methylation of the IGF-2 gene, the gene responsible for the formation of insulin-like growth factor 2. This protein is essential in the growth and development of a foetus and so the genes’ methylation and subsequent silencing led to an increase in metabolic disease in infants (Heijmans et al., 2008). The ability of parental malnutrition to affect the epi- genome of the offspring in an overtly negative and harmful way will be examined more closely later in the review. Not all inheritable epigenetic marks inherited the digestive systems of the offspring, with many affecting the offspring’s immunological capabilities. This was very useful and advan- tageous for nomadic peoples and a case study of this can be seen in the comparison of the Oromo peoples and the Amhara peoples of Ethiopia (Alkorta-Aranburu et al., 2012). In this case it appears that epigenetic marks actual favour immunological variation within the newly arrived population. This will be examined in more depth as part of the Case stud- ies section later in the review. Another case of inherited epi- genetic marks that affect an individual’s adaptation to the environment is the strong inﬂuence that an individual’s epi- Figure 2. Preservation of epigenetic marks during mitosis. genome exerts on the homoeostatic system (Gluckman, The ﬁgure demonstrates how epigenetic marks can be maintained in Hanson, and Spencer, 2005). An individual’s adaptation to an individual cell’s epigenome during mitosis. As can be seen in (A) the original chromosome contains epigenetic marks on both chromatids, their environment is strongly inﬂuenced by their parents’ own and in (B) both daughter chromosomes contain some of the acquired traits and as generations pass by, each generation epigenetic marks of the mother chromosome due to the semi- will accumulate more and more epigenetic marks that inﬂu- conserved nature of mitosis. ence their generations’ homoeostatic systems. This will even- tually result in a population that is genetically similar to the 2015). The overall mechanics of the process do leave some original settlers but will be more adapted to their surrounding unanswered questions but histone modiﬁcation is known to environment. This process will produce a homoeostatic be key to identifying areas of the offspring’s genome for phenotype that better compensates for their native climate in methylation after fertilization of the gametes (Samson et al., a shorter timespan than if the population’s phenotype had 2014). changed under a combination of genetic mutation and evolu- tionary pressure alone. Methylation marks can be inherited from either the mater- nal (Giuliani et al., 2015) or paternal gamete (Soubry, 2015). Through the father, the offspring can inherit a wide array of Inﬂuences on the development methylation marks, with the majority of these marks in some way affecting the digestive systems of the child (Soubry, of the human species 2015). In this way, the father’s own diet can inﬂuence the development and adaptation of his child to be better suited to To understand the impact epigenetics has had on our develop- the dietary conditions he lived in. Far more inﬂuence is ment into modern humans we have to compare the areas of exerted by the maternal parent’s epigenome concerning diet- gene methylation seen in our species and our closest living ary conditions. The mother has twice as much inﬂuence on relatives. Many of the regions in the human genome that are her offspring’s epigenome, ﬁrstly by her own epigenetic adap- methylated are not genes that are unique to humans, with the tations, acquired by her in the periconceptional period of her biggest differences in methylation occurring in regions of life (Giuliani et al., 2015), and secondly, during the pregnancy DNA involved with Transcription Factors (or TFs) and gene itself (Heijmans et al., 2008). The comparably increased inﬂu- control (Hernando-Herraez et al., 2015). This is because TFs ence of the mother’s epigenome is further highlighted in cases have a wide-reaching inﬂuence on the expressed phenotype of ............................................................................................... .................................................................. 3 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. an individual due to these factors functioning as a form of mutations that made them suited to their old environment gene expression regulation, therefore promoting or suppres- until selection pressure allows new mutations to compensate sing other genes in the genome. Even small differences in the for these genetic relics. epigenome surrounding TFs can result in widely varying phe- An important idea is the way in which to consider each dif- notypes between individuals of the same species due to their ferent type of adaptation in comparison to one another. wide-reaching inﬂuences (Heyn et al., 2013). So it can only be Cultural adaptation is a catch all term that encompasses all assumed just how important these phenotypic changes are in artiﬁcial adaptations an individual can pick up to become the variation that separates us from our ancestor species. more comfortable in an environment (Cavalli-Sforza and Of note are the epigenetic changes that are known to have Feldman, 1983). Clothing and the development of new cus- occurred in Human Accelerated Regions (or HARs) (Hubisz toms are all useful tools in the face of environmental chal- and Pollard, 2014). HARs are regions of DNA that have lenges but these represent short-term adaptations that do not undergone rapid changes since the emergence of the human affect the species’ expressed phenotypes. In comparison gen- species far and above the normal rate of mutation. These etic changes, such as the prevalence of Sickle Cell Anaemia in regions stand out due to the extremely accelerated rate of regions prone to malaria outbreaks, represent much longer mutations they have undergone and are widely understood to term adaptations. These changes take longer to gain and can- be responsible for the speedy divergence of humans from not as easily be shaken off once their usefulness has run its other species (Hubisz and Pollard, 2014). The exact nature of course, such as an individual simply changing their attire to the role played by epigenetic changes in HARs is not clear but suit the weather (Laland, Odling-Smee, and Myles, 2010). the importance of their role is undoubtable, with epigenetic What do epigenetic changes represent in this model then? changes possibly predating sequential changes in DNA Firstly they exemplify medium-term adaptations, falling between (Badyaev, 2014). A suggested theory is that these marks actu- cultural changes and genetic evolution in the time it takes an ally promoted the occurrence of mutations in the genes that individual to acquire them (Giuliani et al., 2015). In this model are responsible for our species existence. of understanding human adaptation epigenetic changes also Studying the epigenomes of our related species sheds light serve as a time-keeping mechanism, helping to mitigate the nega- on the relatively large divergence that has occurred since our tive effects of genetic relics acquired by ancestor populations emergence from our distant cousins, a divergence of such stat- under different evolutionary pressures (Badyaev, 2014). By silen- ure that it cannot be solely explained by nucleotide changes cing older genes that once served a vital purpose epigenetics also (Hernando-Herraez et al., 2015). It has even been speculated helps to prevent the build-up of complexity in an organism, silen- that epigenetic changes could be more impactful on the cing older, less frequently transcribed genes (Badyaev, 2014), Darwinian evolution of a species than genomic mutations much in the same way that DNA methylation combats the dam- (Badyaev, 2014) and this area of research only adds more age caused by transposons (Slotkin and Martienssen, 2007). weight to these claims. A good way to examine this model of adaptation is to con- sider the way each of these changes would affect a hypothet- Inﬂuences on evolution of modern ical population that has suddenly become exposed to a harsh, cold climate. Very quickly, this population will adapt, ﬁrst by humans increasing their protection against the elements by wearing thicker clothes. While this is an effective method of staying Modern humans have survived and thrived in a wide array of warm their bodies have not yet adapted to the cold, and so, environments for thousands of years, from the Arctic tundra their genes controlling homoeostasis will still function in the to Saharan deserts. The key to this success has always been same way as they had in a warmer climate, something that the uniquely human ability to adapt quickly and epigenetics might be considerably wasteful and possibly deleterious. has played a role in this capacity to adapt. While cultural Where once their perspiration would help keep the heat from adaptations to environments, such as changes in clothing or damaging their bodies it now wastes water. At this stage, after ritualistic behaviour, are the most visual signs of this adapt- a considerable number of generations, epigenetic changes will ability, no less important are the more subtle genetic and epi- begin to take affect under selective pressure. DNA methyla- genetic changes that a population undergoes as they live in an tions and histone modiﬁcations will accumulate, ﬁne tuning area for generations. For example a population that has lived their homoeostatic gene expression to the colder environ- in an arid environment will carry many genetic mutations ment. This results in the silencing of genes that were better that make them more suitable to a dry climate. If a cata- suited to the hotter climate and promotes the expression of strophic climate shift occurs and their ancestral lands sud- other genes that confer an advantage in this colder one. denly become cold and damp they can adapt to wear thicker Finally, after even more generations new alleles will take hold clothing (Cavalli-Sforza and Feldman, 1983) to protect in the populations that represent novel genes. These novel against the cold and may even take on new customs and genes will encode new proteins that in some way will provide rituals around hygienic behaviour to protect against new dis- a selective advantage that is near permanent in expression, if eases that have taken root in the region (Wiesenfeld, 1967). not in providing an advantage. This population will however still carry many of the genetic ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. In the short- to long-term adaptation model discussed tolerance to lactose can only be expected to increase, at least above, the longer the period of time taken to acquire and until the lactose tolerance mutation proliferates into the glo- adapt the more signiﬁcant the changes will be to an indivi- bal gene pool. dual’s physiology and expressed phenotype. Another point Various genetic conditions affect red blood cells and their highlighted by this model is that the longer an adaptation ability to uptake oxygen. These include Sickle Cell Anaemia takes to be acquired the less likely it is to ever be lost. After and Thalassaemia, both of which only occur once the switch all, it is much easier to take a jacket off than to spontaneously to adult haemoglobin is complete in an individual (Sripichai lose a gene responsible for increasing metabolic activity. et al., 2009). In the case of Sickle Cell Anaemia it is known Epigenetics comes in yet again at this point as not only does it that the condition confers a resistance to Malaria. With anti- silence older genes that are no longer required, under the Malaria treatments becoming more and more efﬁcient and inﬂuence of selective pressure, it also introduces more plasti- mosquito culling beginning to keep infection rates under city into the expression of genes (Giuliani et al., 2015)by control it has become a condition that now mostly serves to allowing individuals that carry the same, or incredibly similar burden ﬂedgling health services around the world. As the genome, to have altered gene expression. Through this mech- selective pressure on these populations has changed, the epi- anism epigenetics allows the variability of phenotypes that are genome of these populations has also reacted. Two different required for adaptation and selection (Tobi et al., 2009). studies have discovered epigenetic markers that can produce Persistence of Foetal Haemoglobin (or POFH) (Sripichai et al., 2009; Sankaran, Xu, and Orkin, 2010). POFH is a Case studies condition where an individual never undergoes the switch to adult haemoglobin, and thus avoids expressing the An interesting examination of epigenetics that provides an Sickle Cell Anaemia and Thalassaemia mutations. While example of its role in human evolution is a study into the dif- they still carry these mutations these individuals do not ferent epigenetic markers between the Oromo and Amhara express the deleterious phenotypes due to epigenetic mar- peoples of the Ethiopian highlands, which revealed something kers that inhibit the associated genes. This is illustrated in surprising: researchers expected to ﬁnd that individuals of the Fig. 3. Oromo peoples, who are migrants to the highlands, would have an increase in epigenetic marks around genes associated with oxygen uptake or red blood cell production. These are adaptations that the Amhara peoples already had, allowing them to live successfully in their elevated homeland. Instead many of the epigenetic markers the researchers found in the Oromo population were around genes associated with the immune system (Alkorta-Aranburu et al., 2012). More inter- esting was that these marks were not uniform throughout the population and instead varied widely from person to person (Alkorta-Aranburu et al., 2012). This appears to show epi- genetic marks acting as a catalyst for the introduction of variation in gene expression, resulting in a wide range of phenotypes and responses to combat the new microbio- logical threats that the migrating population were exposed to upon arriving in the region. Here, these epigenetic marks are compensating for the lack of immunological adaptation the Oromo peoples have for this new climate compared to the native Amhara people, miti- gating the damage done to the Oromo populations in the interim before a genetic mutation could occur that provides stronger protection. As discussed earlier epigenetics plays a key role in the diet- ary adaptation individuals carry, producing an individual Figure 3. Epigenetic prevention of Sickle Cell Anaemia. who carries epigenetic marks that make them more suited to the ﬁgure shows how epigenetic marks can prevent the expression of the Sickle Cell Mutation. (A) shows what occurs in an individual who the diet of their parents. Lactose tolerance is one of the ways carries the mutations but does not have any epigenetic marks this epigenetic digestive adaptation manifests (Ingram et al., silencing the Adult Haemoglobin Switch Gene. These individuals will 2009). Phenotypes of ‘patchy’ lactose tolerance have been eventually develop Sickle Cell Anaemia. In (B) the Adult Haemoglobin witnessed in populations lacking the lactose tolerance muta- Switch Gene is silenced by epigenetic marks, and as such the Sickle tion. With the increasing availability of dairy products world- Cell Anaemia gene is never expressed as the individual maintains wide, the epigenetic modiﬁcation that produces a weaker production of Foetal Haemoglobin. ............................................................................................... .................................................................. 5 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. positive ability to act as a response to selective pressures and Vulnerabilities of epigenetics as a way of mitigating deleterious mutations can be advanta- geous. However its signiﬁcant control over gene expression Throughout this review changes to the epigenome of an indi- can also lead to harmful consequences, e.g. as an avenue for vidual have been discussed in an overly positive light. Such oncogenesis or as a mechanism for accumulating traits that changes can be a mechanism that provides a quicker form of lower ﬁtness and adaptability. The most important thing to adaptation than genetic mutations (Giuliani et al., 2015). It can understand about the epigenome is that it is not always about also act as a time-keeping mechanism in older and now dele- positive or negative inﬂuences on our species’ development, terious genes (Badyaev, 2014). Lastly it can be an inﬂuential but rather that it has given our genome plasticity (Giuliani response to Darwinian pressures on an individual or popula- et al., 2015). By encouraging the variations and adaptability tion (Alkorta-Aranburu et al., 2012). As with any process of of our species, epigenetic mechanisms for controlling gene adaptation, there does exist a negative side and, like genetic expression have ensured that humanity could survive and mutations, epigenetic marks are often damaging to an indivi- thrive in any number of environments. Epigenetics is a signiﬁ- dual’s health. For example, there is a known link between cant part of the reason our species has become so adaptable, a hyper-demethylation and oncogenesis (Feinberg and Tycko, trait that is often thought to distinguish us from what we 2004), but this review will consider the negative aspects of epi- often think of as lesser-evolved and developed animals that genome changes in terms of its impact on human evolution. we inhabit this earth with. Indeed, it can be argued that epi- Epigenetics can act as a time-keeping mechanism by silencing genetics is responsible for, and provided our species with, the genes that have outlived their purpose. However it is worth not- tools that truly made us unique in our ability to conquer any ing that this function of epigenetic marks has limits, as in many habitat and adapt to almost any climate. The study of epigen- cases the gene in question is not entirely silenced (Badyaev, etics has also made the evolution of our species less abstract 2014), but instead is expressed at a lower rate. From a Darwinian and distant; we can now better understand the effects of dif- perspective this is an undesirable consequence as the individual ferent traits at a generational level and better observe the driv- will survive but their offspring will instead now possess a trait ing factors behind changes to our species. More importantly, that reduces their adaptability. In this way many traits that lower this provides the evidence that humanity is not above or the overall ﬁtness of the species may accumulate. untouched by the effects of selective pressure. Finally, a dee- per understanding of epigenetics has altered how we think of The role epigenetics plays in digestive adaptation also evolution, constituting a fundamental re-understanding of the comes as a double-edged sword. This has been demonstrated topic and how this mechanism allows us to acquire traits in a by the research into numerous cases of famine, including lifetime, and pass these traits on to our offspring. Of course, modern examples such as the Dutch Winter of Hunger (Tobi survival of the ﬁttest remains the golden rule of evolution but et al., 2009; Giuliani et al., 2015; Soubry, 2015). The research by delving ever deeper into the epigenome we understand that shows that parental exposure to famine resulted in the accu- the traits that govern ﬁtness, and therefore an individual’s ﬁt- mulation of negative traits in the offspring due to dysregula- ness, are more ﬂuid and malleable than when thought of tion of methylation marks, including a pertinacity towards purely through the lens of genetic mutation and inherited diabetes and obesity and increased rates of cardiovascular dis- traits. ease (Heijmans et al., 2008). The most important lesson learned from studying the epi- Finally, and perhaps the most chilling aspect of the epigen- genome of our species is that it has provided an understand- ome is the ability for individuals who have survived trauma- ing of the factors that have separated us from our closest tizing experiences that put their mind and body under living relations within the animal kingdom that cannot be extreme stress to acquire, and then pass on, the resulting epi- explained by genetic mutations alone. genetic marks and traits from this time in their lives. The most poignant example of this is the accumulation of epigenetic marks in the descendants of Holocaust survivors that result in Outlook a marked increase of PTSD, depression and obesity, all result- ing from differential methylation of the FKBP5 gene (Yehuda The central theorem that has driven this review is understand- et al., 2015). While these effects are less severe than genetic ing epigenetics from the perspective of it serving a role in allow- mutations the effects of epigenome changes, by virtue of being ing for medium-term adaptation. To further this hypothesis, less powerful in their effect on phenotype, allow for the accu- and support the evidence provided in this review, deeper mulation of traits that, if they were expressed at the sequence research must be conducted on the emergence of epigenetic level, would not be carried on to the next generation. marks in populations facing changing selective pressure. The work done in studying and comparing the epigenome of the native and newly migrated populations in the Ethiopian high- Conclusion lands is a strong example of the way in which this research can Throughout this review the different effects the epigenome be conducted (Alkorta-Aranburu et al., 2012). Moreover, exerts on the evolution of our species has been discussed. Its an ideal area that might shed even more insight into the role ............................................................................................... .................................................................. 6 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. Feinberg, A. P. (2008) Epigenetics at the epicenter of modern medicine, epigenetics plays in the evolution of humans is a comparison Journal of the American Medical Association, 299 (11), 1345–1350. of the populations of the Upper and Lower Nile. These areas historically faced similar threats in the form of Malaria but Feinberg, A. P. and Tycko, B. (2004) The history of cancer Epigenetics, development along the Lower Nile, backed up by investment Nature Reviews. Cancer, 4 (2), 143–153. in prevention by the Egyptian Government, has in recent dec- ades lowered the transition rates by mosquitos of Malaria Giuliani, C., Bacalini, M. G., Sazzini, M. et al. (2015) The Epigenetic side drastically. Furthermore, both these areas have had signiﬁcant of human adaptation: hypotheses, evidences and theories, Annals levels of Sickle Cell Anaemia (El-Hazmi, Al-Hazmi and of Human Biology, 42 (1), 1–9. Warsy, 2011). Both these factors in combination make this Gluckman, P. D., Hanson, M. A. and Spencer, H. G. (2005) Predictive region ideal for research into emerging epigenomic changes in adaptive responses and human evolution, Trends in Ecology and the face of changing selective pressure. It could be predicted Evolution, 20 (10), 527–533. that epigenetic marks that silence the effects of Sickle Cell Anaemia (Sripichai et al., 2009), as discussed earlier, would Heijmans,B.T., Tobi,E.W., Stein, A. D. et al.(2008) Persistent Epigenetic dif- become more prevalent in these areas but that cannot be ferences associated with prenatal exposure to famine in humans, known for certain, as was the case with the predicted epigen- Proceedings of the National Academy of Sciences, 105 (44), 17046–17049. ome changes in the Ethiopian highlands (Alkorta-Aranburu Hernando-Herraez, I., Heyn, H., Fernandez-Callejo, M. et al. (2015) The et al., 2012). interplay between DNA methylation and sequence divergence in recent human evolution, Nuclear Acids Research,43(17), 8204–8214. Author biography Heyn, H., Moran, S., Hernando-Herraez, I. et al. (2013) DNA methylation con- tributes to natural human variation, Genomic Research, 23, 1363–1372. As a genetics graduate from the University of Glasgow my interests began to focus on the ﬁeld of epigenetics quite late in Hubisz, M. J. and Pollard, K. S. (2014) Exploring the genesis and functions my academic career. However, after delving into epigenetics of Human Accelerated Regions sheds light on their role in human and the sheer number of questions and theories raised by the evolution, Current Opinion in Genetics & Development,29, 15–21. topic that turn genetics on its head, epigenetics has captivated Ingram, C. J. E., Mulcare, C. A., Itan, Y. et al. (2009) Lactose digestion and me. I hope to one day either conduct research into the inﬂu- the evolutionary genetics of lactase persistence, Human Genetics, ence of epigenetics on human evolution or become a journal- 124 (6), 579–591. ist focused on the subject. Jones, P. A. (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond, Nature reviews Genetics, 13 (7), 484–492. Acknowledgements Laland, K. N., Odling-Smee, J. and Myles, S. (2010) How culture shaped I would like to thank my advisor Dr Chris Finlay for his sup- the human genome: bringing genetics and the human sciences port throughout my research and pointing me towards the together, Nature reviews Genetics, 11 (2), 137–148. ﬁnal aim of my study into epigenetics. He provided the initial Moalem, S., Storey, K. B., Percy, M. E. et al. (2005) The sweet thing about papers that gave me a deeper insight into the work research- Type 1 diabetes: a cryoprotective evolutionary adaptation, Medical ing the role of the epigenome in the development of the Hypotheses, 65 (1), 8–16. human species. Samson, M., Jow, M. M., Wong, C. C. et al. (2014) The speciﬁcation and global reprogramming of histone Epigenetic marks during gamete References formation and early embryo development in C. elegans, PLoS Genetics, 10 (10), e1004588. Alkorta-Aranburu, G., Beall, C. M., Witonsky, D. B. et al. (2012) The gen- etic architecture of adaptations to high altitude in Ethiopia, PLoS Sankaran, V. G., Xu, J. and Orkin, S. H. (2010) Advances in the under- Genetics, 8 (12), e1003110. standing of haemoglobin switching, British Journal of Haematology, 149 (2), 181–194. Badyaev, A. V. (2014) Epigenetic resolution of the ‘curse of complexity’ in adaptive evolution of complex traits, The Journal of Physiology, Slotkin, R. K. and Martienssen, R. (2007) Transposable elements and the 592, 2251–2260. Epigenetic regulation of the genome, Nature reviews Genetics, 8 (4), 272–285. Cavalli-Sforza, L. L. and Feldman, M. W. (1983) Cultural versus genetic adaptation, Proceedings of the National Academy of Sciences,80 Soubry, A. (2015) Epigenetic inheritance and evolution: a paternal per- (16), 4993–4996. spective on dietary inﬂuences, Progress in Biophysics and Molecular Biology, 118 (1–2), 79–85. El-Hazmi, M. A. F., Al-Hazmi, A. M. and Warsy, A. S. (2011) Sickle cell dis- ease in Middle East Arab countries, Indian Journal of Medical Sripichai, O., Kiefer, C. M., Bhanu, N. V. et al. (2009) Cytokine-mediated Research, 134 (5), 597–610. increases in fetal hemoglobin are associated with globin gene ............................................................................................... .................................................................. 7 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. histone modiﬁcation and Transcription Factor reprogramming, Wiesenfeld, S. L. (1967) Sickle-cell trait in human biological and cultural Blood, 114 (11), 2299–2306. evolution, Science (New York, N.Y.), 157 (3793), 1134–1140. Tobi, E. W., Lumey, L. H., Talens Rudolf, P. et al. (2009) DNA methylation Yehuda, R., Daskalakis, N. P., Bierer, L. M. et al. (2015) Holocaust differences after exposure to prenatal famine are common and tim- exposure induced intergenerational effects on FKBP5 methylation, ing- and sex-speciﬁc, Human Molecular Genetics,18(21), 4046–4053. Biological Psychiatry, 80, 652–656. ............................................................................................... .................................................................. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press http://www.deepdyve.com/lp/oxford-university-press/the-role-of-epigenetics-in-human-evolution-cAPBV4lAM5

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Publisher: Oxford University Press
Copyright: © The Author 2017. Published by Oxford University Press.
eISSN: 1754-7431
DOI: 10.1093/biohorizons/hzx007
Publisher site: See Article on Publisher Site

Abstract

BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx007 ............................................................................................ ..................................................................... Review article Alexander Osborne University of Glasgow, 5 Rosemount Square, Kilwinning KA13 6LZ, UK *Corresponding author: Alexander Osborne, Email: alexander103050@hotmail.co.uk Supervisor: Christopher Finlay, University of Glasgow, Glasgow G12 8QQ, UK ............................................................................................ ..................................................................... This review aims to highlight the key areas in which changes to the epigenome have played an important role in the evolu- tion and development of our species. Firstly, there will be a brief introduction into the topic of epigenetics to outline the cur- rent understanding of the subject and inform the reader of the basic mechanisms and functions of the epigenome. This will lead on to more focussed detail on the role played by epigenetic changes in the rapid evolution of our species and emer- gence from our ancestor species, as well as the Human Accelerated Regions that played a role in this. The discussion high- lights how epigenetics has helped and hindered our species’ development via changes to the epigenome in more modern times, discussing case examples of documented instances where it is shown that epigenetics has played a role in the evolu- tion of humanity. Key words: epigenetics, evolution, human, methylation, HARs, modiﬁcation Submitted on 25 July 2016; editorial decision on 3 July 2017 ............................................................................................ ..................................................................... as they once were. However, evolution is an ongoing process, Introduction one that modern humans are not exempt from, despite the fact that the advancement of science has down played the role Human evolution is often thought of as something abstract of selection. Humans are not above the effects of evolution and distant, something that played a role in the development and recent research into epigenetics serves as a reminder of of our long forgotten ancestors but does not affect the modern that fact. state of our species. Even when we consider genetic conditions that once provided an evolutionary advantage to populations Epigenetics is a mechanism of gene control that can pro- of early humans but have now become deleterious, it is often mote or repress the expression of genes without altering the thought that modern medical care compensates and, in large genetic coding of an organism (Feinberg, 2008). In other part, negates their symptoms. These include conditions such words epigenetics represents a system by which the gene as Sickle Cell Anaemia and Diabetes Mellitus Type 1; many expression of an individual can be altered without altering of the individuals that carry these conditions live full and their genome’s sequence. Our current understanding has iden- healthy lives thanks to modern medicine. So we consider these tiﬁed some of the controlling epigenetic processes that regu- conditions via the lens of disease and not as relics of our evo- late gene expression, referred to as epigenetic ‘marks’. For lutionary history. At one time Sickle Cell Anaemia provided example, methylation of DNA, alteration of the histone mole- an important defence against Malaria (Wiesenfeld, 1967) and cules that hold together DNA super structures via methyla- there is evidence that Diabetes Mellitus Type 1 developed in tion or acetylation and various RNA and Dicer protein early Europeans as an adaptation to the colder climate dependent processes that inhibit gene expression. In combin- (Moalem et al., 2005). As technology has advanced and com- ation, the sum total of all these epigenetic marks in an individ- pensated for the evolutionary drivers of these traits, they are ual is known as the epigenome. This review will mainly focus no longer as advantageous to the individuals who carry them on studies that involve the methylation of DNA as this is the ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. most widely studied epigenetic mechanism, but other aspects represents something very important, a fundamental revalu- of the epigenome will be touched upon. Methylation of DNA ation of the theory of evolution. Acquired traits, while not is already known to be very important; for example extreme alterations of the genome, can be inherited (Jones, 2012). cases of demethylation, representing a loss of gene expression This review will examine the implications this has for the con- control, are associated with oncogenesis (Feinberg and cept of human evolution and highlight interesting examples Tycko, 2004). This review will, however, not focus on the and case studies in which these effects are notable. inﬂuence that changes to the epigenome can have on an indi- vidual’s health, instead it will discuss the role this mechanism of gene expression control has played in the evolution of our Method of inheritance species, both the emergence of the human species and the effects it has had more recently. The study of epigenetics has revealed an interesting facet of this method of gene expression control. The methylation of Before we can fully grasp the effects epigenetics has had on DNA and other epigenetic marks do not alter the genes that our species a ﬁrmer understanding of what epigenetics is and they inﬂuence at a sequence level but nonetheless alter the the way in which it can alter gene expression is needed. Gene expression of these genes. Furthermore these marks can be control is a fascinating area of genetics and this is particularly acquired throughout the lifetime of the individual and, if car- interesting to those with a fascination for human evolution. ried in their gametes, these marks are inheritable. In this sec- Epigenetic inﬂuence over gene expression possibly originated tion, the focus will be on the ways in which these marks can as a defence against Transposons, parasitic DNA that jumps be inherited. around in the genome and can disrupt genes by inserting into the middle of them (Slotkin and Martienssen, 2007). A possible The semi-conserved nature of mitosis results in two sets of mechanism of defence can be achieved via methylation of daughter chromatids, one in each set carrying the Epigenetic DNA, as illustrated in Fig. 1. Silencing these transposable ele- marks from the original chromosome (Feinberg, 2008), as ments and preventing or limiting damage to an organism’sgen- illustrated in Fig. 2. This allows the transfer of epigenetic ome provides an important advantage to those ﬁrst species to marks from mother cells to daughter cells in somatic tissue. develop this mechanism. Eventually this process evolved into a This explains how these marks can be maintained in an indi- method of promoting and repressing host genes (Feinberg, vidual, but not how they are spread to the next generation of 2008) that could not only be acquired throughout the lifetime offspring. of an individual, but also passed onto its offspring (Jones, These marks can also be conserved in their daughter chro- 2012). This mechanism of gene silencing may have also matid during meiosis, resulting in all gametes carrying the epi- allowed for the development of multicellular organisms by genetic marks of the individual of origin. However, many of allowing a single genome to tailor its expressed genes in each these marks are removed during the process of gamete forma- individual cell within the larger organism (Badyaev, 2014). tion. It is now understood that some genes are protected from While epigenetics is a relatively new understanding of the this process of demethylation, resulting in the marks being systems involved in gene control and expression it also maintained in their gametes’ epigenome (Giuliani et al., Figure 1. Methylation as a defence against Transposons. The ﬁgure illustrates how methylation can help an organism defend itself from Transposons. Over time the DNA coding vital proteins for the Transposon will become methylated and cease to be expressed, therefore trapping the Transposon in its current position in the host’s genome. This prevents the Transposon from ‘jumping’ and possibly disrupting the expression of vital genes elsewhere in the host’s genome. ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. of famine. If the affected parent is the mother the effects of deleterious epigenetic marks are more heavily expressed in the offspring’s phenotype, especially if famine occurs during the early stages of pregnancy (Tobi et al., 2009). For an example of this deleterious nature of hypomethylation one can look at the Dutch Winter of Hunger, a well-documented example of famine in the modern world that occurred from 1944 to 1945 due to a blockage preventing the movement of fuel and food in the Netherlands. This starvation resulted in the hypo- methylation of the IGF-2 gene, the gene responsible for the formation of insulin-like growth factor 2. This protein is essential in the growth and development of a foetus and so the genes’ methylation and subsequent silencing led to an increase in metabolic disease in infants (Heijmans et al., 2008). The ability of parental malnutrition to affect the epi- genome of the offspring in an overtly negative and harmful way will be examined more closely later in the review. Not all inheritable epigenetic marks inherited the digestive systems of the offspring, with many affecting the offspring’s immunological capabilities. This was very useful and advan- tageous for nomadic peoples and a case study of this can be seen in the comparison of the Oromo peoples and the Amhara peoples of Ethiopia (Alkorta-Aranburu et al., 2012). In this case it appears that epigenetic marks actual favour immunological variation within the newly arrived population. This will be examined in more depth as part of the Case stud- ies section later in the review. Another case of inherited epi- genetic marks that affect an individual’s adaptation to the environment is the strong inﬂuence that an individual’s epi- Figure 2. Preservation of epigenetic marks during mitosis. genome exerts on the homoeostatic system (Gluckman, The ﬁgure demonstrates how epigenetic marks can be maintained in Hanson, and Spencer, 2005). An individual’s adaptation to an individual cell’s epigenome during mitosis. As can be seen in (A) the original chromosome contains epigenetic marks on both chromatids, their environment is strongly inﬂuenced by their parents’ own and in (B) both daughter chromosomes contain some of the acquired traits and as generations pass by, each generation epigenetic marks of the mother chromosome due to the semi- will accumulate more and more epigenetic marks that inﬂu- conserved nature of mitosis. ence their generations’ homoeostatic systems. This will even- tually result in a population that is genetically similar to the 2015). The overall mechanics of the process do leave some original settlers but will be more adapted to their surrounding unanswered questions but histone modiﬁcation is known to environment. This process will produce a homoeostatic be key to identifying areas of the offspring’s genome for phenotype that better compensates for their native climate in methylation after fertilization of the gametes (Samson et al., a shorter timespan than if the population’s phenotype had 2014). changed under a combination of genetic mutation and evolu- tionary pressure alone. Methylation marks can be inherited from either the mater- nal (Giuliani et al., 2015) or paternal gamete (Soubry, 2015). Through the father, the offspring can inherit a wide array of Inﬂuences on the development methylation marks, with the majority of these marks in some way affecting the digestive systems of the child (Soubry, of the human species 2015). In this way, the father’s own diet can inﬂuence the development and adaptation of his child to be better suited to To understand the impact epigenetics has had on our develop- the dietary conditions he lived in. Far more inﬂuence is ment into modern humans we have to compare the areas of exerted by the maternal parent’s epigenome concerning diet- gene methylation seen in our species and our closest living ary conditions. The mother has twice as much inﬂuence on relatives. Many of the regions in the human genome that are her offspring’s epigenome, ﬁrstly by her own epigenetic adap- methylated are not genes that are unique to humans, with the tations, acquired by her in the periconceptional period of her biggest differences in methylation occurring in regions of life (Giuliani et al., 2015), and secondly, during the pregnancy DNA involved with Transcription Factors (or TFs) and gene itself (Heijmans et al., 2008). The comparably increased inﬂu- control (Hernando-Herraez et al., 2015). This is because TFs ence of the mother’s epigenome is further highlighted in cases have a wide-reaching inﬂuence on the expressed phenotype of ............................................................................................... .................................................................. 3 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. an individual due to these factors functioning as a form of mutations that made them suited to their old environment gene expression regulation, therefore promoting or suppres- until selection pressure allows new mutations to compensate sing other genes in the genome. Even small differences in the for these genetic relics. epigenome surrounding TFs can result in widely varying phe- An important idea is the way in which to consider each dif- notypes between individuals of the same species due to their ferent type of adaptation in comparison to one another. wide-reaching inﬂuences (Heyn et al., 2013). So it can only be Cultural adaptation is a catch all term that encompasses all assumed just how important these phenotypic changes are in artiﬁcial adaptations an individual can pick up to become the variation that separates us from our ancestor species. more comfortable in an environment (Cavalli-Sforza and Of note are the epigenetic changes that are known to have Feldman, 1983). Clothing and the development of new cus- occurred in Human Accelerated Regions (or HARs) (Hubisz toms are all useful tools in the face of environmental chal- and Pollard, 2014). HARs are regions of DNA that have lenges but these represent short-term adaptations that do not undergone rapid changes since the emergence of the human affect the species’ expressed phenotypes. In comparison gen- species far and above the normal rate of mutation. These etic changes, such as the prevalence of Sickle Cell Anaemia in regions stand out due to the extremely accelerated rate of regions prone to malaria outbreaks, represent much longer mutations they have undergone and are widely understood to term adaptations. These changes take longer to gain and can- be responsible for the speedy divergence of humans from not as easily be shaken off once their usefulness has run its other species (Hubisz and Pollard, 2014). The exact nature of course, such as an individual simply changing their attire to the role played by epigenetic changes in HARs is not clear but suit the weather (Laland, Odling-Smee, and Myles, 2010). the importance of their role is undoubtable, with epigenetic What do epigenetic changes represent in this model then? changes possibly predating sequential changes in DNA Firstly they exemplify medium-term adaptations, falling between (Badyaev, 2014). A suggested theory is that these marks actu- cultural changes and genetic evolution in the time it takes an ally promoted the occurrence of mutations in the genes that individual to acquire them (Giuliani et al., 2015). In this model are responsible for our species existence. of understanding human adaptation epigenetic changes also Studying the epigenomes of our related species sheds light serve as a time-keeping mechanism, helping to mitigate the nega- on the relatively large divergence that has occurred since our tive effects of genetic relics acquired by ancestor populations emergence from our distant cousins, a divergence of such stat- under different evolutionary pressures (Badyaev, 2014). By silen- ure that it cannot be solely explained by nucleotide changes cing older genes that once served a vital purpose epigenetics also (Hernando-Herraez et al., 2015). It has even been speculated helps to prevent the build-up of complexity in an organism, silen- that epigenetic changes could be more impactful on the cing older, less frequently transcribed genes (Badyaev, 2014), Darwinian evolution of a species than genomic mutations much in the same way that DNA methylation combats the dam- (Badyaev, 2014) and this area of research only adds more age caused by transposons (Slotkin and Martienssen, 2007). weight to these claims. A good way to examine this model of adaptation is to con- sider the way each of these changes would affect a hypothet- Inﬂuences on evolution of modern ical population that has suddenly become exposed to a harsh, cold climate. Very quickly, this population will adapt, ﬁrst by humans increasing their protection against the elements by wearing thicker clothes. While this is an effective method of staying Modern humans have survived and thrived in a wide array of warm their bodies have not yet adapted to the cold, and so, environments for thousands of years, from the Arctic tundra their genes controlling homoeostasis will still function in the to Saharan deserts. The key to this success has always been same way as they had in a warmer climate, something that the uniquely human ability to adapt quickly and epigenetics might be considerably wasteful and possibly deleterious. has played a role in this capacity to adapt. While cultural Where once their perspiration would help keep the heat from adaptations to environments, such as changes in clothing or damaging their bodies it now wastes water. At this stage, after ritualistic behaviour, are the most visual signs of this adapt- a considerable number of generations, epigenetic changes will ability, no less important are the more subtle genetic and epi- begin to take affect under selective pressure. DNA methyla- genetic changes that a population undergoes as they live in an tions and histone modiﬁcations will accumulate, ﬁne tuning area for generations. For example a population that has lived their homoeostatic gene expression to the colder environ- in an arid environment will carry many genetic mutations ment. This results in the silencing of genes that were better that make them more suitable to a dry climate. If a cata- suited to the hotter climate and promotes the expression of strophic climate shift occurs and their ancestral lands sud- other genes that confer an advantage in this colder one. denly become cold and damp they can adapt to wear thicker Finally, after even more generations new alleles will take hold clothing (Cavalli-Sforza and Feldman, 1983) to protect in the populations that represent novel genes. These novel against the cold and may even take on new customs and genes will encode new proteins that in some way will provide rituals around hygienic behaviour to protect against new dis- a selective advantage that is near permanent in expression, if eases that have taken root in the region (Wiesenfeld, 1967). not in providing an advantage. This population will however still carry many of the genetic ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. In the short- to long-term adaptation model discussed tolerance to lactose can only be expected to increase, at least above, the longer the period of time taken to acquire and until the lactose tolerance mutation proliferates into the glo- adapt the more signiﬁcant the changes will be to an indivi- bal gene pool. dual’s physiology and expressed phenotype. Another point Various genetic conditions affect red blood cells and their highlighted by this model is that the longer an adaptation ability to uptake oxygen. These include Sickle Cell Anaemia takes to be acquired the less likely it is to ever be lost. After and Thalassaemia, both of which only occur once the switch all, it is much easier to take a jacket off than to spontaneously to adult haemoglobin is complete in an individual (Sripichai lose a gene responsible for increasing metabolic activity. et al., 2009). In the case of Sickle Cell Anaemia it is known Epigenetics comes in yet again at this point as not only does it that the condition confers a resistance to Malaria. With anti- silence older genes that are no longer required, under the Malaria treatments becoming more and more efﬁcient and inﬂuence of selective pressure, it also introduces more plasti- mosquito culling beginning to keep infection rates under city into the expression of genes (Giuliani et al., 2015)by control it has become a condition that now mostly serves to allowing individuals that carry the same, or incredibly similar burden ﬂedgling health services around the world. As the genome, to have altered gene expression. Through this mech- selective pressure on these populations has changed, the epi- anism epigenetics allows the variability of phenotypes that are genome of these populations has also reacted. Two different required for adaptation and selection (Tobi et al., 2009). studies have discovered epigenetic markers that can produce Persistence of Foetal Haemoglobin (or POFH) (Sripichai et al., 2009; Sankaran, Xu, and Orkin, 2010). POFH is a Case studies condition where an individual never undergoes the switch to adult haemoglobin, and thus avoids expressing the An interesting examination of epigenetics that provides an Sickle Cell Anaemia and Thalassaemia mutations. While example of its role in human evolution is a study into the dif- they still carry these mutations these individuals do not ferent epigenetic markers between the Oromo and Amhara express the deleterious phenotypes due to epigenetic mar- peoples of the Ethiopian highlands, which revealed something kers that inhibit the associated genes. This is illustrated in surprising: researchers expected to ﬁnd that individuals of the Fig. 3. Oromo peoples, who are migrants to the highlands, would have an increase in epigenetic marks around genes associated with oxygen uptake or red blood cell production. These are adaptations that the Amhara peoples already had, allowing them to live successfully in their elevated homeland. Instead many of the epigenetic markers the researchers found in the Oromo population were around genes associated with the immune system (Alkorta-Aranburu et al., 2012). More inter- esting was that these marks were not uniform throughout the population and instead varied widely from person to person (Alkorta-Aranburu et al., 2012). This appears to show epi- genetic marks acting as a catalyst for the introduction of variation in gene expression, resulting in a wide range of phenotypes and responses to combat the new microbio- logical threats that the migrating population were exposed to upon arriving in the region. Here, these epigenetic marks are compensating for the lack of immunological adaptation the Oromo peoples have for this new climate compared to the native Amhara people, miti- gating the damage done to the Oromo populations in the interim before a genetic mutation could occur that provides stronger protection. As discussed earlier epigenetics plays a key role in the diet- ary adaptation individuals carry, producing an individual Figure 3. Epigenetic prevention of Sickle Cell Anaemia. who carries epigenetic marks that make them more suited to the ﬁgure shows how epigenetic marks can prevent the expression of the Sickle Cell Mutation. (A) shows what occurs in an individual who the diet of their parents. Lactose tolerance is one of the ways carries the mutations but does not have any epigenetic marks this epigenetic digestive adaptation manifests (Ingram et al., silencing the Adult Haemoglobin Switch Gene. These individuals will 2009). Phenotypes of ‘patchy’ lactose tolerance have been eventually develop Sickle Cell Anaemia. In (B) the Adult Haemoglobin witnessed in populations lacking the lactose tolerance muta- Switch Gene is silenced by epigenetic marks, and as such the Sickle tion. With the increasing availability of dairy products world- Cell Anaemia gene is never expressed as the individual maintains wide, the epigenetic modiﬁcation that produces a weaker production of Foetal Haemoglobin. ............................................................................................... .................................................................. 5 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. positive ability to act as a response to selective pressures and Vulnerabilities of epigenetics as a way of mitigating deleterious mutations can be advanta- geous. However its signiﬁcant control over gene expression Throughout this review changes to the epigenome of an indi- can also lead to harmful consequences, e.g. as an avenue for vidual have been discussed in an overly positive light. Such oncogenesis or as a mechanism for accumulating traits that changes can be a mechanism that provides a quicker form of lower ﬁtness and adaptability. The most important thing to adaptation than genetic mutations (Giuliani et al., 2015). It can understand about the epigenome is that it is not always about also act as a time-keeping mechanism in older and now dele- positive or negative inﬂuences on our species’ development, terious genes (Badyaev, 2014). Lastly it can be an inﬂuential but rather that it has given our genome plasticity (Giuliani response to Darwinian pressures on an individual or popula- et al., 2015). By encouraging the variations and adaptability tion (Alkorta-Aranburu et al., 2012). As with any process of of our species, epigenetic mechanisms for controlling gene adaptation, there does exist a negative side and, like genetic expression have ensured that humanity could survive and mutations, epigenetic marks are often damaging to an indivi- thrive in any number of environments. Epigenetics is a signiﬁ- dual’s health. For example, there is a known link between cant part of the reason our species has become so adaptable, a hyper-demethylation and oncogenesis (Feinberg and Tycko, trait that is often thought to distinguish us from what we 2004), but this review will consider the negative aspects of epi- often think of as lesser-evolved and developed animals that genome changes in terms of its impact on human evolution. we inhabit this earth with. Indeed, it can be argued that epi- Epigenetics can act as a time-keeping mechanism by silencing genetics is responsible for, and provided our species with, the genes that have outlived their purpose. However it is worth not- tools that truly made us unique in our ability to conquer any ing that this function of epigenetic marks has limits, as in many habitat and adapt to almost any climate. The study of epigen- cases the gene in question is not entirely silenced (Badyaev, etics has also made the evolution of our species less abstract 2014), but instead is expressed at a lower rate. From a Darwinian and distant; we can now better understand the effects of dif- perspective this is an undesirable consequence as the individual ferent traits at a generational level and better observe the driv- will survive but their offspring will instead now possess a trait ing factors behind changes to our species. More importantly, that reduces their adaptability. In this way many traits that lower this provides the evidence that humanity is not above or the overall ﬁtness of the species may accumulate. untouched by the effects of selective pressure. Finally, a dee- per understanding of epigenetics has altered how we think of The role epigenetics plays in digestive adaptation also evolution, constituting a fundamental re-understanding of the comes as a double-edged sword. This has been demonstrated topic and how this mechanism allows us to acquire traits in a by the research into numerous cases of famine, including lifetime, and pass these traits on to our offspring. Of course, modern examples such as the Dutch Winter of Hunger (Tobi survival of the ﬁttest remains the golden rule of evolution but et al., 2009; Giuliani et al., 2015; Soubry, 2015). The research by delving ever deeper into the epigenome we understand that shows that parental exposure to famine resulted in the accu- the traits that govern ﬁtness, and therefore an individual’s ﬁt- mulation of negative traits in the offspring due to dysregula- ness, are more ﬂuid and malleable than when thought of tion of methylation marks, including a pertinacity towards purely through the lens of genetic mutation and inherited diabetes and obesity and increased rates of cardiovascular dis- traits. ease (Heijmans et al., 2008). The most important lesson learned from studying the epi- Finally, and perhaps the most chilling aspect of the epigen- genome of our species is that it has provided an understand- ome is the ability for individuals who have survived trauma- ing of the factors that have separated us from our closest tizing experiences that put their mind and body under living relations within the animal kingdom that cannot be extreme stress to acquire, and then pass on, the resulting epi- explained by genetic mutations alone. genetic marks and traits from this time in their lives. The most poignant example of this is the accumulation of epigenetic marks in the descendants of Holocaust survivors that result in Outlook a marked increase of PTSD, depression and obesity, all result- ing from differential methylation of the FKBP5 gene (Yehuda The central theorem that has driven this review is understand- et al., 2015). While these effects are less severe than genetic ing epigenetics from the perspective of it serving a role in allow- mutations the effects of epigenome changes, by virtue of being ing for medium-term adaptation. To further this hypothesis, less powerful in their effect on phenotype, allow for the accu- and support the evidence provided in this review, deeper mulation of traits that, if they were expressed at the sequence research must be conducted on the emergence of epigenetic level, would not be carried on to the next generation. marks in populations facing changing selective pressure. The work done in studying and comparing the epigenome of the native and newly migrated populations in the Ethiopian high- Conclusion lands is a strong example of the way in which this research can Throughout this review the different effects the epigenome be conducted (Alkorta-Aranburu et al., 2012). Moreover, exerts on the evolution of our species has been discussed. Its an ideal area that might shed even more insight into the role ............................................................................................... .................................................................. 6 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. Feinberg, A. P. (2008) Epigenetics at the epicenter of modern medicine, epigenetics plays in the evolution of humans is a comparison Journal of the American Medical Association, 299 (11), 1345–1350. of the populations of the Upper and Lower Nile. These areas historically faced similar threats in the form of Malaria but Feinberg, A. P. and Tycko, B. (2004) The history of cancer Epigenetics, development along the Lower Nile, backed up by investment Nature Reviews. Cancer, 4 (2), 143–153. in prevention by the Egyptian Government, has in recent dec- ades lowered the transition rates by mosquitos of Malaria Giuliani, C., Bacalini, M. G., Sazzini, M. et al. (2015) The Epigenetic side drastically. Furthermore, both these areas have had signiﬁcant of human adaptation: hypotheses, evidences and theories, Annals levels of Sickle Cell Anaemia (El-Hazmi, Al-Hazmi and of Human Biology, 42 (1), 1–9. Warsy, 2011). Both these factors in combination make this Gluckman, P. D., Hanson, M. A. and Spencer, H. G. (2005) Predictive region ideal for research into emerging epigenomic changes in adaptive responses and human evolution, Trends in Ecology and the face of changing selective pressure. It could be predicted Evolution, 20 (10), 527–533. that epigenetic marks that silence the effects of Sickle Cell Anaemia (Sripichai et al., 2009), as discussed earlier, would Heijmans,B.T., Tobi,E.W., Stein, A. D. et al.(2008) Persistent Epigenetic dif- become more prevalent in these areas but that cannot be ferences associated with prenatal exposure to famine in humans, known for certain, as was the case with the predicted epigen- Proceedings of the National Academy of Sciences, 105 (44), 17046–17049. ome changes in the Ethiopian highlands (Alkorta-Aranburu Hernando-Herraez, I., Heyn, H., Fernandez-Callejo, M. et al. (2015) The et al., 2012). interplay between DNA methylation and sequence divergence in recent human evolution, Nuclear Acids Research,43(17), 8204–8214. Author biography Heyn, H., Moran, S., Hernando-Herraez, I. et al. (2013) DNA methylation con- tributes to natural human variation, Genomic Research, 23, 1363–1372. As a genetics graduate from the University of Glasgow my interests began to focus on the ﬁeld of epigenetics quite late in Hubisz, M. J. and Pollard, K. S. (2014) Exploring the genesis and functions my academic career. However, after delving into epigenetics of Human Accelerated Regions sheds light on their role in human and the sheer number of questions and theories raised by the evolution, Current Opinion in Genetics & Development,29, 15–21. topic that turn genetics on its head, epigenetics has captivated Ingram, C. J. E., Mulcare, C. A., Itan, Y. et al. (2009) Lactose digestion and me. I hope to one day either conduct research into the inﬂu- the evolutionary genetics of lactase persistence, Human Genetics, ence of epigenetics on human evolution or become a journal- 124 (6), 579–591. ist focused on the subject. Jones, P. A. (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond, Nature reviews Genetics, 13 (7), 484–492. Acknowledgements Laland, K. N., Odling-Smee, J. and Myles, S. (2010) How culture shaped I would like to thank my advisor Dr Chris Finlay for his sup- the human genome: bringing genetics and the human sciences port throughout my research and pointing me towards the together, Nature reviews Genetics, 11 (2), 137–148. ﬁnal aim of my study into epigenetics. He provided the initial Moalem, S., Storey, K. B., Percy, M. E. et al. (2005) The sweet thing about papers that gave me a deeper insight into the work research- Type 1 diabetes: a cryoprotective evolutionary adaptation, Medical ing the role of the epigenome in the development of the Hypotheses, 65 (1), 8–16. human species. Samson, M., Jow, M. M., Wong, C. C. et al. (2014) The speciﬁcation and global reprogramming of histone Epigenetic marks during gamete References formation and early embryo development in C. elegans, PLoS Genetics, 10 (10), e1004588. Alkorta-Aranburu, G., Beall, C. M., Witonsky, D. B. et al. (2012) The gen- etic architecture of adaptations to high altitude in Ethiopia, PLoS Sankaran, V. G., Xu, J. and Orkin, S. H. (2010) Advances in the under- Genetics, 8 (12), e1003110. standing of haemoglobin switching, British Journal of Haematology, 149 (2), 181–194. Badyaev, A. V. (2014) Epigenetic resolution of the ‘curse of complexity’ in adaptive evolution of complex traits, The Journal of Physiology, Slotkin, R. K. and Martienssen, R. (2007) Transposable elements and the 592, 2251–2260. Epigenetic regulation of the genome, Nature reviews Genetics, 8 (4), 272–285. Cavalli-Sforza, L. L. and Feldman, M. W. (1983) Cultural versus genetic adaptation, Proceedings of the National Academy of Sciences,80 Soubry, A. (2015) Epigenetic inheritance and evolution: a paternal per- (16), 4993–4996. spective on dietary inﬂuences, Progress in Biophysics and Molecular Biology, 118 (1–2), 79–85. El-Hazmi, M. A. F., Al-Hazmi, A. M. and Warsy, A. S. (2011) Sickle cell dis- ease in Middle East Arab countries, Indian Journal of Medical Sripichai, O., Kiefer, C. M., Bhanu, N. V. et al. (2009) Cytokine-mediated Research, 134 (5), 597–610. increases in fetal hemoglobin are associated with globin gene ............................................................................................... .................................................................. 7 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. histone modiﬁcation and Transcription Factor reprogramming, Wiesenfeld, S. L. (1967) Sickle-cell trait in human biological and cultural Blood, 114 (11), 2299–2306. evolution, Science (New York, N.Y.), 157 (3793), 1134–1140. Tobi, E. W., Lumey, L. H., Talens Rudolf, P. et al. (2009) DNA methylation Yehuda, R., Daskalakis, N. P., Bierer, L. M. et al. (2015) Holocaust differences after exposure to prenatal famine are common and tim- exposure induced intergenerational effects on FKBP5 methylation, ing- and sex-speciﬁc, Human Molecular Genetics,18(21), 4046–4053. Biological Psychiatry, 80, 652–656. ............................................................................................... ..................................................................

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The role of epigenetics in human evolution

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The role of epigenetics in human evolution

The role of epigenetics in human evolution

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