Lactase Persistence and the Extended Evolutionary Synthesis: A Beneficial Framework for Studies of Human Evolution

by Katherine McLean

The extended evolutionary synthesis (EES) is a novel paradigm for understanding evolution (Müller, 2007). It was proposed as a more comprehensive alternative to the existing modern synthesis (MS), the early 20th-century reconciliation of Charles Darwin’s and Albert Wallace’s theories of evolution via natural selection and Gregor Mendel’s theories on genetic inheritance mechanisms (Dickins & Rahman, 2012). The EES introduced additional, more recently developed, concepts and
proposed integrating these into a holistic evolutionary theory (Pigliucci, 2007). It integrated traditional selection and genetics with concepts such as multilevel selection, inclusive inheritance, niche construction theory, evolvability, phenotypic and developmental plasticity, genomics, systems biology, and evolutionary developmental biology (Baedke, Fábregas-Tejeda, & Vergara-Silva, 2020). Some scholars have questioned the necessity and applicability of the EES within biological anthropology (Futuyma, 2017; Laland et al., 2014). However, a close analysis of human lactase persistence as a biosocial phenomenon demonstrates that these concepts have significant impact when applied to the study of human evolution. This paper compiles research on niche construction theory, epigenetic inheritance, genomics, and phenotypic plasticity to demonstrate that the application of the EES expands our field’s understanding of the evolution and implications of lactase persistence. The EES is thus shown to fundamentally alter our interpretations of historical and
ongoing evolution in the human lineage.


It is necessary to understand the nature of the EES and MS within broader evolutionary biology before narrowing focus to human evolution. The MS was a synthetic theory of evolution that emerged in the 1930s and 1940s out of the work of researchers such as Theodosius Dobzhansky, Julian Huxley, Ernst Mayr, Bernhard Rensch, George Simpson, and George Stebbins (Huxley, 1942; Mayr, 1993). It is also referred to as the evolutionary synthesis, the new synthesis, standard evolutionary theory, and the modern evolutionary synthesis (Mayr, 1993; Murray, Benitez, & O’Brien, 2021). However, as these names can be ambiguous and may also refer to later syntheses, for the sake of clarity this paper will solely use the term modern synthesis, as coined by Julian Huxley in his Evolution: The Modern Synthesis (1942).

The MS brought together research from what were at that time disparate sub-disciplines in the biological sciences (Brandon, 1986). It reconciled Mendelian genetics with natural selection and Darwinian evolutionary theory via modern population genetics (Beatty, 1986; Mayr, 1993). Whilst specific definitions may vary, the heart of the synthesis is the application of the theory of natural selection to heritable variation arising from mutation. Combining knowledge from separate fields focussed on different levels of organisation, the MS united macro- and microevolution (Darden, 1986). By the mid to late 20th century, most researchers accepted the MS as the most functional theory of evolution (Dickins & Rahman, 2012).

However, in the late 2000s, Massimo Pigliucci (2007) and Gerd B. Müller (2007) challenged the accepted paradigm. Unhappy with the incompleteness of the MS in light of modern discoveries and developments, they proposed a new, extended evolutionary synthesis. This extended synthesis integrated recent conceptual developments whilst retaining the fundamental tenets of the MS. While the MS focussed solely on mechanisms such as natural section and genetic drift, the EES explains them as simply aspects of a greater network of interacting factors (Murray et al., 2021). Novel factors introduced by the EES include: evolvability, a measure of an organism’s ability to generate genetic variation and use this genetic diversity to respond to natural selection (Colegrave & Collins, 2008; Kirschner & Gerhart, 1998); group selection mechanisms where natural selection acts at the group level, including multilevel selection and inclusive fitness theory (Goodnight, 2012); niche construction theory, where organisms’ modifications of the environment make them active participants in their own evolution; inclusive inheritance, where soft forms of inheritance such as transgenerational epigenetic effects are considered equal with traditional hard forms of inheritance (Dickins & Rahman, 2012); phenotypic plasticity, where a single genotype can be influenced by environmental variation to produce multiple phenotypes (West-Eberhard, 1989); systems biology, where mathematical and computational analyses are used to model biological systems from a holistic rather than reductionist viewpoint (Tavassoly, Goldfarb, & Iyengar, 2018); aspects of genomics such as lateral or horizontal gene transfer, where genetic material moves between organisms outside of vertical parent-offspring transmission (Dunning Hotopp, 2011; Keeling & Palmer, 2008; Ochman, Lawrence, & Groisman, 2000); and evolutionary developmental biology, where developmental processes such as growth and differentiation are studied in relation to
evolutionary change (Gilbert, Opitz, & Raff, 1996; Hall, 2012; Müller, 2007).

These additional elements are intended to work in conjunction with classical mechanisms of evolution (Odling-Smee, Laland, & Feldman, 1996). Supporters of the EES, such as Fuentes (2016) and Müller (2017), make clear that it is not a replacement for the MS. Pigliucci (2007) describes his ideal of the EES as an organic incorporation of the new concepts into the old framework of the MS. Succinctly, it is an addition and not a replacement (Kissel & Fuentes, 2021; Pigliucci, 2007). Supporters believe that the need for this change is dire, and that research will be inhibited and restricted without an extended synthesis (Laland et al., 2014; Noble, 2015).

The necessity of the EES is, however, debated. The majority of criticism stems from claims that the EES is an unnecessary complication to evolutionary theory (Craig, 2010; Murray et al., 2021). Opponents such as Wray, Hoekstra, and colleagues (Laland et al., 2014) argue that the key concepts of the EES, despite not being formally included in the MS, are already in use alongside it. Consequently, a formal extension is unnecessary, as they believe that there is no need to explicitly include these concepts in the evolutionary synthesis for them to be considered, accepted, and utilised in research (Lewens, 2019; Whitfield, 2008). In their opinion, research has not yet demonstrated the practical necessity of the EES over the MS (Futuyma, 2017; Pigliucci, 2008). However, the definitions we use affect how we approach problems and answer questions (Murray et al., 2021). Our theoretical frameworks are delineated by the definitions we use to create them.
These frameworks, in turn, then dictate what issues are selected for research and what solutions are drawn from the data (Murray et al., 2021). Even if sceptics are correct in claiming that these concepts are technically able to be used outside the EES, that does not mean that they are utilised in practice. For example, the exclusion of soft forms of inheritance such as epigenetic inheritance from the MS has led to research that tends to assume that only changes in the DNA sequence are inherited across generations (Danchin et al., 2011). This is problematic and clearly demonstrates that the unintentional omission of a concept from a working paradigm inevitably leads to its accidental exclusion from practical research. Critical elements of the EES cannot and are not being adequately utilized, as those working within the framework of the existing MS are neglecting critical evolutionary processes (Laland et al., 2014).

The question then turns to exactly how critical these elements are. Suppose a meaningful number of the concepts introduced by the EES can be shown to fundamentally alter our understandings of human evolution. If so, then it can be confidently claimed that the EES is of significant benefit to evolutionary anthropology. Such tangible examples of the benefits of the EES will hopefully persuade skeptics of its relevance and necessity (Murray et al., 2021).

The Impact of the EES on Understandings of Human Lactase Persistence

Lactose is a disaccharide sugar present in milk, composed of galactose and glucose monomer subunits joined by a glycosidic linkage (Reece et al., 2015). As with other sugars, the human body produces a genetically-controlled enzyme to catalyse the hydrolysis of dietary lactose (Mantei et al.,1988). The lactose-specific enzyme is lactase-phlorizin hydrolase, or simply lactase (Vesa, Marteau, & Korpela, 2000). If lactase levels in the digestive tract are low, then the unhydrolysed lactose becomes available to Escherichia coli and other colonic bacteria when the human host consumes dairy (Gerbault, 2013; Reece et al., 2015). Carbon dioxide (CO2) is a by-product of this bacterial breakdown of lactose, and its consequent presence in the gastrointestinal tract can result in gastric bloating, abdominal pain, nausea, and diarrhoea (Gerbault, 2013). This digestive disorder is known as lactose intolerance.

Lactase levels are high in young mammals but decline dramatically after weaning when milk consumption ends (Gerbault, 2013; Wells, 2021). The inability to digest lactose is thus the natural condition of human populations (Lewens, 2017; Newitz, 2021), although the severity of the condition is variable—it can be reduced by factors such as the simultaneous presence of glucose, as E. coli preferentially utilizes glucose (Reece et al., 2015). However, with the origin of dairying and
pastoralism, dairy products started to become incorporated into the diets of modern human populations and adult lactose intolerance suddenly became problematic (Jeong & Di Renzo, 2014). Continued production of lactase became a desirable trait, as the prolonged ability to digest lactose would provide a positive selective advantage in a diary-consuming population. This led to the development of lactase persistence, the continued production of the enzyme after the completion of weaning. The gene that codes for lactase production, LCT, developed two distinct genetically-programmed phenotypes—lactase nonpersistent, or hypolactasia, and lactase persistent, the derived phenotype (Harvey et al., 1993). At least five separate alleles governing this trait have been discovered in various human populations, suggesting convergent evolution with multiple episodes of selection (Liebert et al., 2017; Tishkoff et al., 2006; Wells & Stock, 2011). Significant frequencies of lactase persistence are now found in populations with histories of dairying and dairy product consumption, from Northern Europe to East Africa, the Middle East, and Central Asia (Jeong & Di Renzo, 2014). The mechanisms behind the development of lactase persistence are a recurrent topic of studies on human evolution, as it is an ideal illustration of the ongoing evolution of anatomically modern humans (Campbell & Ranciaro, 2021). To expand our understandings of this phenomenon, researchers are now framing their work through the lens of EES concepts such as epigenetic inheritance, niche construction theory, genomics, and phenotypic plasticity. In other words, the application of the EES significantly affects research on this topic.

Niche Construction Theory

Lactase persistence is now understood to be a product of human niche construction. Niche construction theory (NCT) posits that organisms can influence natural selection by modifying their own and other species’ niches (Odling-Smee et al., 1996). Organisms are thus active participants in evolution and not simply passive recipients of evolutionary change (Müller, 2017). Whilst the MS does recognise the concept of niche construction, it views it as a product of selection and not a cause of evolutionary change (O’Brien & Bentley, 2021).

If an organism significantly modifies its environment, then, like in other instances of environmental change, resource type and availability will be altered (Laland & Boogert, 2010). With this modulation of resource availability, novel selective pressures arise. These, in turn, cause evolutionary responses and alter the evolutionary trajectories of organisms (Matthews et al., 2014). Feedback loops are created between organisms and environments (Laland & Boogert, 2010). Niche construction is often beneficial to the constructor, but the effects can be either positive or negative, and the recipient population can vary from the original species to any others sharing its environment. (Matthews et al., 2014; Odling-Smee et al., 1996). The interacting layers of feedback loops arising from multiple episodes of niche construction link species closer together and thus drive episodes of co-evolution (Laland & Boogert, 2010). Co-evolution of traits and organisms is a cornerstone of NCT.

Human lactose tolerance co-evolved with the development and spread of agriculture and pastoralism (Gerbault et al., 2011; Lewens, 2017). The adoption of dairying and increased consumption of dairy products slowly modified the human niche by supplying a novel form of calories. The ability to utilise these calories would provide fitness benefits and an evolutionary advantage; this led to natural selection favouring genes that continued lactase production after weaning. In this way, human dairy farming created the selective pressures that led to lactase persistence (Laland, Toyokawa, & Oudman, 2019), i.e., a novel cultural trait led to selection for a novel genetic trait. This co-evolution of dairying and lactase was a complex process, with both aspects constantly increasing the spread, necessity, and benefit of the other in an ever-growing feedback loop (Gerbault et al., 2011).

Phenotypic Plasticity

Microbiota-driven phenotypic plasticity has guided the evolution of lactase persistence. Phenotypic plasticity refers to the ability of a single genotype to produce a range of morphological and behavioural responses to differing environmental and developmental conditions (West-Eberhard, 1989). The ability to produce different phenotypes in different environments helps organisms cope with environmental variation (Price, Qvarnström, & Irwin, 2003). While most variation between populations is attributable to evolutionary mechanisms such as natural selection, variation can also be rooted in phenotypic plasticity, which is not recognised by the MS (Price et al., 2003). Gut microbiota can affect a host’s phenotype and increase their phenotypic plasticity by amplifying external environmental signals (Moeller & Sanders, 2020).

The gut microbiome is intimately connected with lactase persistence. Specific microbiota, such as E. coli and Bifidobacterium, can reduce lactose intolerance in individuals lacking the genes for lactase persistence by processing the lactose in place of the host (Lewens, 2017). When these bacteria process and ferment lactose, they make beneficial by-products available for use by the human host. Moeller and Sanders (2020) believe that this mediated the initial transition to dairying by making the consumption of dairy products of enough immediate calorific benefit to justify the behaviour. Gut-microbiota mediated metabolism of lactose may thus have played a critical intermediate role in the evolution of lactose tolerance and lactase persistence in humans. The presence of these bacteria in the gut microbiome essentially increased the phenotypic plasticity of the host and enabled them to consume lactose in the short term, buying time for selection to act and potentiating the adaptation of lactase persistence.

Genomic Analysis

The study of the human genome has broadened our understanding of the LCT gene. Genomics is an interdisciplinary field of biology that differs significantly from the genetics of the MS (Lockhart & Winzeler, 2000; Roth, 2019). The genome refers to the entirety of an organism’s genes and other genetic material, including non-coding DNA and mitochondrial DNA (Roth, 2019). Instead of simply studying the role of individual genes in inheritance, genomics examines the entire genome— including its interactions with the environment and influence upon the organism. This field of study has only become possible in recent decades due to advances in bioinformatics and DNA sequencing (Lockhart & Winzeler, 2000).

Genome-wide analysis has become a key tool in the arsenal of those studying human lactase persistence (Gerbault, 2013; Vicente et al., 2019). It enables researchers to trace the origins of different adaptations to the LCT gene and accordingly better understand patterns of convergent evolution and human migration (Breton et al., 2014). If the LCT gene was studied in isolation, lactase persistence would not be so striking. It is only once the entire genomic region surrounding the LCT gene was able to be analysed that the extent of the positive directional selection on this area was realised, as additional genes in the same genomic region have been shown to possess variants designed to enhance lactase expression and help facilitate its persistence (Gerbault, 2013). In other words, genomics shows us that selection for this trait is not limited to selection upon a single gene in isolation.

Genomic sequencing abilities have also enabled mutations surrounding the LCT gene to be used to trace and track the migrations of human populations (Schlebusch, Sjödin, Skoglund, & Jakobsson, 2013; Vicente et al., 2019). As lactase persistence reflects a dietary and behavioural shift to dairying and pastoralism, this means that the behaviours of ancient hunter-gatherer groups can be more accurately reconstructed. For example, Breton et al. (2014) utilised genomic analysis to trace the movements of lactase persistence through Africa and thus were able to infer from which direction pastoralism practises were introduced to specific populations.

Epigenetic Inheritance

Epigenetic inheritance has been discovered to play a significant role in the development of the lactase persistent phenotype. Transgenerational epigenetic inheritance occurs when epigenetic markers influence offspring phenotypes despite the DNA sequence remaining unchanged (Dickins &Rahman, 2012). This epigenetic inheritance can be as vital a component of phenotypes as genetic variance, sometimes even more so (Jablonka & Lamb, 2008). DNA methylation is an epigenetic mechanism in which methyl groups are added to the DNA molecule (Dickins & Rahman, 2012). These groups can alter the function and expression of a gene without changing the DNA sequence. Previously, differences in the LCT gene have been attributed solely to differences in the DNA sequence, such as the C to T single nucleotide polymorphism that affects the initiation codon of the LCT gene in many people of European descent (Lewinsky et al., 2005; Schultheis & Bowling, 2011).

However, recent research has expanded the picture and shown that DNA methylation plays an essential role in regulating the LCT gene (Labrie et al., 2016; Leseva et al., 2018). Differential methylation at specific promotor sites in the LCT gene enhancer has been shown to have an even higher power to predict actual levels of lactase phenotypes than simply the genotype alone (Leseva et al., 2018). Epigenetic mechanisms are also at the root of the gene’s original natural silencing:
lactase downregulation has been shown to be due to an age-related accumulation of DNA methylation, with individuals from populations with higher lactase persistence having a slowed rate of these accumulations (Labrie et al., 2016; Swallow & Troelsen, 2016).


The application of niche construction theory, genomics, epigenetics, and phenotypic plasticity has had a meaningful impact on the study of the evolution of human lactase persistence. These sub-fields have helped reframe lactase persistence from a simple genetic variant to a complex case of co-evolution, plasticity, and multiple modes of inheritance. As it has already been shown that these concepts cannot be adequately and consistently utilised outside the formal framework of the EES, lactase persistence thus forms a robust case study in favour of the benefits of an extended synthesis. The study of human evolution is fundamentally altered and expanded by the EES, and it appears clear that its acceptance and utilisation will result in valuable future research in this field. This paper demonstrates the benefits of adopting this synthesis as the next discipline standard. Hopefully, continued research on this subject will cumulatively demonstrate to skeptics the practical benefits of the EES in evolutionary anthropology.