Last of the MTHFRs: Biological Compatibility as an Evolutionary Signature
The article proposes that some older, evolutionarily heterogeneous human genomic architectures may be more biologically compatible because they represent deeply retained combinations of successfully integrated variation, yet may now be declining under modern environmental and reproductive pressures.
EVOLUTIONSYSTEMSBIOLOGY
Alexandra Chambers
8/9/20266 min read
Image: Ernst Haeckel, Tree of Life, 1866. Public domain.
Evolution depends not only upon variation, but upon the capacity of that variation to remain integrated within a continuing lineage.
Genetic diversity provides the variation through which populations respond to changing environments, pathogens and ecological pressures. Yet diversity is evolutionarily consequential only while it remains sufficiently compatible to participate in reproduction, development and biological function.
The deeper principle is therefore:
Diversity within compatibility is essential for the continuation of a species. Too little diversity reduces biological possibility and too little compatibility prevents diversity from remaining integrated within the lineage.
Evolutionary continuity depends upon both. This principle also leads to a further proposition.
Variation that has persisted across deep evolutionary time has not merely existed for longer. It has repeatedly survived reproduction, recombination, development and interaction with other genetic backgrounds.
Deep evolutionary genomic retention therefore represents a signature of successful biological integration.
Within the Divergent Genomics framework, I propose that some contemporary human genomic architectures preserve unusually old and heterogeneous combinations of human variation, and that some neurodivergent populations may disproportionately carry these older evolutionary blueprints.
More specifically, I propose that:
Older, more evolutionarily heterogeneous genomic architectures may exhibit greater biological compatibility because they represent deeply retained configurations of successfully integrated variation.
At the same time, some of these deeply retained architectures may now be becoming less reproductively represented.
The hypothesis is that older, deeply integrated genomic architectures may be more biologically and organically compatible, while toxic modern environmental conditions may nevertheless be progressively removing them from the human lineage.
Variation is often treated as inherently evolutionarily valuable, but variation alone does not guarantee continuity.
A novel genetic configuration can arise and disappear. Divergent populations can encounter one another without successfully exchanging genetic material. Genetic material entering a new population through admixture can persist or be progressively removed.
The variation represented in later generations is variation that has remained sufficiently viable, transmissible and integrated to continue.
Human evolution illustrates this clearly; contemporary Homo sapiens carry genomic material inherited through admixture with other hominin populations, including Neanderthals and Denisovans.
Those inherited sequences were not retained uniformly; some persisted, and others were depleted. The contemporary human genome is therefore a filtered inheritance. It contains evidence of diversity that successfully entered, interacted with and remained within later human genomic backgrounds.
This suggests a simple evolutionary relationship:
Divergence + compatibility → integration → retained diversity → continuity
Where sufficient compatibility remains, divergent genetic material can recombine and enter subsequent generations.
Difference survives as diversity. Where compatibility is insufficient, the opposite can occur:
Divergence + incompatibility → failed integration → reproductive loss → disappearance
At the level of individual variants, this can mean removal from the gene pool. At the level of populations or lineages, sustained reproductive failure can ultimately contribute to extinction.
Loss of compatibility should not be confused with the successful formation of a new species (speciation).
For an independent species to emerge, reproductive separation must be accompanied by continuing viability and successful reproduction across generations.
A population does not become a new species merely because its reproductive compatibility deteriorates. Without the emergence of a viable independent lineage, incompatibility can simply produce loss.
The more fundamental evolutionary distinction is therefore:
Integration versus loss, and ultimately: Continuity versus extinction.
Human evolution is frequently represented as a branching history in which populations separate and progressively diverge, but human evolution also involved reconnection.
Populations separated, changed, encountered one another again and exchanged genetic material. Their evolutionary histories were recombined. Some of those combinations persisted into contemporary humans.
Human evolution therefore involved repeated episodes of:
Divergence → encounter → admixture → integration → retention
The modern human genome partly records the successful outcomes of those integrations.
This leads to a central proposition: Compatibility determines whether divergence can survive as diversity.
Human genomic diversity is not only accumulated difference, it is difference that remained compatible enough to continue.
If evolutionary retention reflects successful integration, then the depth of retained variation becomes biologically significant. Different individuals and populations contain different combinations of ancient and more recent variation. Some genomic architectures may preserve broader or older combinations of the heterogeneous genetic material from which humanity emerged.
Within Divergent Genomics, I propose that (neuro)divergent genomic architectures may fall into this category.
Research identifying associations between archaic-derived variation and autism or other neurodivergent traits provides one reason to investigate this possibility, but isolated archaic variants are not the central hypothesis.
The question concerns the wider architecture:
Do some neurodivergent populations disproportionately retain older and more evolutionarily heterogeneous genomic configurations?
They do, therefore, a second question immediately follows:
Does the depth of that evolutionary retention predict biological compatibility?
This is the central prediction.
A genomic architecture assembled from heterogeneous evolutionary material can persist only if that material remains sufficiently capable of functioning together.
If some contemporary genomes preserve unusually deep records of such integration, their biological properties may still reflect it.
I therefore propose that:
Greater retention of evolutionarily deep genomic variation may be associated with greater biological compatibility. Compatibility here is not restricted to reproduction. Different biological systems have their own mechanisms of compatibility and interaction.
ABO blood-group compatibility, HLA matching, immune recognition, receptor–ligand interaction, metabolic integration and structural biology are mechanistically distinct phenomena.
The hypothesis does not require them to share a single mechanism. It predicts instead that an underlying genomic architecture characterised by unusually deep evolutionary integration may produce detectable patterns across multiple biological systems in which genetically variable components must successfully interact.
Relevant areas of investigation include:
- blood-group phenotype and compatibility;
- HLA architecture;
- immune recognition;
- transplantation compatibility;
- receptor–ligand interactions;
- metabolic systems;
- connective-tissue biology;
- developmental regulation;
- and other molecular networks dependent upon interactions between genetically variable components.
The important evidence would be the co-occurrence of compatibility-related characteristics with genomic evidence of unusually deep evolutionary retention.
If such patterns increase alongside the degree of retained ancient variation, that would support the hypothesis that biological compatibility itself can carry an evolutionary signature.
Neurodivergence is usually conceptualised primarily through the nervous system.
Divergent Genomics exposes this framing as too narrow. If some (neuro)divergent genomic architectures represent unusually old and heterogeneous biological configurations, their effects should therefore not be confined to cognition or behaviour.
Patterns across apparently unrelated physiological systems may instead reflect different expressions of the same underlying architecture.
What evolutionary history does the underlying genomic architecture preserve? Does that evolutionary history predict wider biological properties?
The hypothesis has a further implication. A genomic architecture can demonstrate deep historical persistence without being guaranteed future persistence.
The environmental, reproductive and social conditions affecting modern human populations differ substantially from those operating across much of human evolutionary history.
If some neurodivergent populations disproportionately carry deeply retained genomic architectures, and those populations experience reduced reproductive transmission, humanity may be progressively losing part of its oldest surviving reservoir of integrated genetic diversity.
This creates the evolutionary paradox:
Some of the older and potentially more biologically compatible human genomic architectures may now be being removed from the lineage.
The result would represent the loss of genomic configurations whose evolutionary persistence may itself contain information about biological integration.
The hypothesis can be separated into three stages.
Observed:
Contemporary humans retain genetic material originating from divergent ancestral populations, including archaic hominins, and some archaic-derived variants have been associated with neurodivergent traits.
Hypothesised:
Some neurodivergent genomic architectures disproportionately preserve older and more heterogeneous components of human evolutionary inheritance.
Predicted:
Greater evolutionary retention will be associated with measurable signatures of greater biological compatibility across multiple systems.
A further prediction follows:
If these architectures are currently being lost from the population, their reproductive transmission should be declining across generations.
These propositions can be tested.
Genomic analysis can quantify deep and archaic-derived variation and determine whether particular configurations cluster within defined (neuro)divergent populations.
Those genomic patterns can then be compared with biological measures involving compatibility, recognition and interaction.
The central analysis would ask whether increasing evolutionary depth or heterogeneity predicts increasing compatibility-related characteristics.
Population and intergenerational studies could separately examine whether the same genomic architectures are becoming less reproductively represented over time.
Alternative explanations - including population structure, shared ancestry, linkage and pleiotropy -would need to be tested against any observed relationships.
If no reproducible relationship exists between deep evolutionary retention and biological compatibility, the hypothesis would require revision or rejection.
If such a relationship does exist, it would suggest that evolutionary history remains visible not only in the sequence of the human genome, but in the way that genome functions as an integrated biological system.
Evolutionary continuity requires diversity, but diversity cannot continue without sufficient compatibility.
Humanity itself emerged through the divergence, reconnection and integration of heterogeneous populations.
The genetic variation surviving in contemporary humans is evidence of successful retention.
Divergent Genomics proposes that some contemporary genomic architectures preserve more of this deep evolutionary inheritance than others, and that some neurodivergent populations may disproportionately carry these older configurations.
The central hypothesis is explicit:
Genomic architectures retaining greater amounts of evolutionarily deep, heterogeneous variation may exhibit greater biological compatibility across multiple systems.
If some neurodivergent genomic architectures preserve these older blueprints, biological signatures of that compatibility are measurable.
If those same architectures are now becoming less reproductively represented, humanity may be losing part of the very evolutionary diversity that has demonstrated the greatest depth of biological integration.
If diversity within compatibility is essential for the continuation of a species, then the concern is whether some of humanity's oldest surviving genomic architectures carrying the biological signature of that compatibility are now being lost, and what that loss could mean for the future of humanity.