Beyond the Gene: Epigenetics, Lactase Persistence, and the Shifting Landscape of Evolutionary Theory

Lactase persistence (LP), the ability of adult humans to digest lactose, the primary sugar in milk, stands as one of the most compelling examples of recent human evolution. Its epidemiology reveals a striking correlation: high frequencies of LP are predominantly found in populations with long histories of pastoralism and dairy consumption, particularly in Northern Europe and certain parts of Africa and the Middle East. The conventional neo-Darwinian explanation posits that random genetic mutations conferring LP arose and were subsequently strongly selected for in environments where milk provided significant nutritional advantages (e.g., calories, protein, calcium, hydration). While specific single nucleotide polymorphisms (SNPs) within regulatory elements of the lactase (LCT) gene are linked to the LP phenotype, emerging perspectives suggest that epigenetic mechanisms play a more intricate role than previously appreciated, potentially adding nuance to the traditional gene-centric view of this evolutionary trajectory.

The Neo-Darwinian Framework for Lactase Persistence:

The modern synthesis, or neo-Darwinism, explains evolution through the interplay of random genetic variation (mutation) and natural selection. In the context of LP, specific SNPs, most notably C/T-13910 in Europeans and G/C-14010 in some African populations, located within an intron of the adjacent MCM6 gene, act as enhancers for LCT gene expression. In individuals with the ancestral, non-persistent genotype, LCT expression naturally declines significantly after weaning, leading to lactose intolerance. The mutations associated with LP prevent this downregulation, allowing continued lactase production throughout adulthood.

According to the neo-Darwinian model, these mutations arose randomly. In populations that domesticated cattle and relied on dairy, individuals carrying these mutations gained a substantial selective advantage. Milk became a reliable, nutrient-dense food source, particularly valuable in environments with seasonal food scarcity or limited sunlight for Vitamin D synthesis (calcium absorption). This positive selection led to a rapid increase in the frequency of LP alleles within just a few thousand years – consistabt with a gene-culture coevolution driven by genetic change and selective pressures. This model, emphasizing mutation and selection acting on DNA sequence, has been used in explaining the broad geographic patterns of LP. 

One immediate problem is that these mutations are thought to occur over tens of thousands of years where calculations indicate millions of years would be required.

The Involvement of Epigenetics:

Epigenetics refers to modifications to the genome that alter gene expression without changing the underlying DNA sequence. 

These modifications, including DNA methylation, histone modifications (like acetylation and methylation), and non-coding RNAs, act as regulatory layers, dictating when and where genes are turned on or off.

Crucially, the normal developmental downregulation of the LCT gene after weaning is an epigenetic process. 

In lactase non-persistent individuals, changes in the chromatin structure and methylation patterns around the LCT gene promoter and its regulatory elements (like the MCM6 enhancer region) are thought to occur, leading to gene silencing. The SNPs associated with LP likely function by interfering with this programmed epigenetic silencing. They may prevent the binding of repressor proteins or maintain an open chromatin state (euchromatin) around the LCT enhancer/promoter, thereby overriding the default silencing pathway and allowing persistent expression.

Therefore, epigenetics controls mutations of LP and is the mechanism through which the genetic variants exert their effect. The mutations prevent the establishment or maintenance of the repressive epigenetic marks that normally shut down the gene in adulthood. This interplay highlights that gene expression is inherently regulated epigenetically, and mutations often function by altering these regulatory landscapes.

Challenging 

Does the involvement of epigenetics challenge neo-Darwinism? Neo-Darwinism fundamentally relies on heritable variation upon which selection acts. This variation is conceived as changes in DNA sequence. The central question regarding epigenetics is whether epigenetic states themselves can be heritable across generations and act as a substitute for selection, independent of DNA sequence changes?

1. Mechanism vs. Inheritance: As discussed, epigenetics is clearly involved in the mechanism of LCT regulation and how LP mutations function. This challenges neo-Darwinism; it elaborates on the molecular details through which genetic variation manifests phenotypically.

2. Environmental Induction and Plasticity: Epigenetic states influenced by environmental factors (like diet). Can sustained milk consumption itself induce epigenetic changes that promote LCT expression, even in the absence of the canonical LP SNPs. Environmental factors clearly influence gene expression within an individual's lifetime via epigenetic phenotypic plasticity. If significant transgenerational epigenetic inheritance related to diet and LP occur, it would introduce a more Lamarckian element (inheritance of acquired characteristics) that sits uneasily with the purely mutation-driven variation assumed by classical neo-Darwinism.

3. Source of Variation: Neo-Darwinism emphasizes random mutation as the source of new variation. While the establishment of epigenetic marks can be influenced by the environment, the underlying DNA sequences (like the LP-associated SNPs) still occur.

Conclusion:

Many older evolutionists hold to lactase persistence as supporting neo-Darwinian principles. However younger evolutionists see epigenetics as integral to understanding the proximate molecular mechanisms – how the LCT gene is regulated and how the LP-associated mutations prevent its silencing. 

The ultimate evolutionary driver appears to be epigenetics. It can take mutations and drive them in a beneficial way. 

Epigenetics and its environmental influence on heritable epigenetic states affecting LCT expression

is an active area of research. The study of epigenetics in LP enriches our understanding of gene regulation and how genetic variation translates into phenotypic adaptation, highlighting the intricate interplay between genes, environment, and the epigenetic machinery that governs expression. In this new paradigm epigenetics can overcome mutations to still control the phenotype without Darwin. It underscores that evolution operates on phenotypes, which arise from complex interactions far beyond the DNA sequence alone.