Neurodivergence, Ancestry Genomics and the Glycan Landscape: What Retained Biological Constellations Reveal About Human Bio-Evolutionary Progression

Preface

This is a highly technical and complex subject, and making it accessible without losing the scientific significance is challenging. I have deliberately kept the article concise and structured it in a report-style format to make the complexity easier to follow.

This forms part of the broader Divergent Genomics research, which takes a transdisciplinary approach to understanding human evolution and biological variation. This work brings together findings from different scientific fields to explore relationships that are not made explicit when examined separately.

The article presents the key evidence, mechanisms and hypotheses within that wider research framework.

1. The fundamentals

This article analyses the biological implications of the glycogenomic / extracellular developmental systems environment: the sugars, proteoglycans, Glycosaminoglycans (GAGs) and extracellular matrix that cells live in and signal through. That environment affects how developmental signals move, where cells migrate, how tissues organise, and what structures emerge. The underlying chain is: genome + epigenome → glycosylation/GAG biology → extracellular environment → signalling + cell behaviour → anatomy + nervous system + immunity.

2. Why GAGs are relevant

Glycosaminoglycans (GAGs) such as heparan sulphate and chondroitin sulphate influence SHH, FGF, WNT, BMP/TGF-β and other signalling systems.

They affect:

Morphogen gradients

Morphogens are signalling molecules that guide how cells develop, organise and form structures during embryonic development.

Cell migration

The movement of cells from one location to another. This is essential during development, allowing cells to reach the correct places to form tissues, organs and body structures.

Neural crest behaviour

Neural crest cells are specialised embryonic cells that travel throughout the developing body. They contribute to the formation of facial structures, parts of the skull, peripheral nerves, pigment cells and other tissues.

Tissue hydration and mechanics

The ability of tissues to retain water, maintain their shape and respond to physical forces. GAGs are particularly important because they attract and hold water, influencing tissue flexibility, cushioning and structural resilience.

Receptor interactions

Cells have receptors that detect chemical signals from their surroundings. Glycans can influence how these signals reach receptors, how receptors interact with other molecules and how cells respond.

Neural development & synaptic organisation

The formation and organisation of the nervous system, including how neurons grow, connect and communicate. Glycans help regulate the environment in which neural connections form, develop and change.

So changing GAG biology can change multiple systems at once.

3. How this also connects to midline development

Midline development depends heavily on tightly controlled signalling. Sonic Hedgehog (SHH) and related pathways are involved in:

• forebrain patterning

• neural tube development

• craniofacial formation

• palate development

• nasal/midfacial structures

GAGs determine how these signals are distributed. That gives us a plausible bridge between: midline differences ↔ connective tissue ↔ craniofacial differences ↔ sensory structures ↔ nervous-system development.

4. The existing science

Congenital Disorders of Glycosylation (CDG) demonstrate what happens when glycosylation biology is different enough for medicine to notice.

Glycosylation differences - framed as disorders - can produce combinations of:

Corpus-callosum differences

The corpus callosum is a thick bundle of approximately 200 million nerve fibres connecting the brain’s left and right cerebral hemispheres. It acts as a communication bridge, allowing both hemispheres to exchange and coordinate information involved in movement,sensory processing, cognition and other functions potentially influencing how information is exchanged and coordinated.

Neurological differences

Variations in how the brain and nervous system develop, process information and communicate.

Craniofacial differences

Variations in the development and structure of the skull, face and jaw, including their shape, proportions and alignment.

Palate and midline differences

Variations in how structures along the body’s central dividing line form and join together, including the roof of the mouth, face, certain brain structures, pelvis, spine and reproductive anatomy, including the uterus .

Connective-tissue features

Differences in the tissues that support and connect the body, affecting skin, joints, ligaments, blood vessels and tissue flexibility.

Skeletal differences

Variations in bone growth, shape, density and proportions, influencing the structure and development of the skeleton.

Immune differences

Variations in how the immune system develops, recognises threats, regulates inflammation and responds to the environment.

Autism research already implicates glycan-related biology, proteoglycans and glycosylated synaptic molecules. Neurexin itself is a heparan-sulphate proteoglycan, putting glycobiology directly inside a major autism-associated synaptic system. Ancient-human methylation work has already highlighted ACAN, XYLT1, SOX9, COL2A1 and NFIX. Divergent Genomics has been connecting archaic ancestry, connective-tissue divergence, sensory biology and neurodivergence. The constellation framework, identifies glycosylation (like collagen/connective tissue) as also on a non-linear spectrum. Subsequently, different glycan configurations produce different biological outcomes across multiple dimensions.

For example:

Immune function: Configurations may protect against organic pathogens while increasing susceptibility to synthetic exposures.

Development: Different glycan structures can alter morphogen signalling, tissue organisation and cellular migration.

Connective tissue: Variations in GAG composition can influence tissue mechanics, hydration and structural properties.

Neurological function: Glycosylation differences can influence synaptic organisation, receptor interactions and neural development.

Environmental compatibility: The same configuration may have different functional consequences depending on microbial, nutritional and chemical exposures.

These dimensions need not change together, or in the same direction. Greater activity in one glycosylation pathway does not necessarily mean better overall biological function.

CDG demonstrates that one glycosylation system can influence all of these clinically separated system phenotypes at once. CDG therefore acts almost like a high-effect natural experiment exposing what the glycogenomic system controls.

Significant CDG would represent one extreme phenotype of divergent pathway function. This phenotype would theoretically be at disproportionately high risk of modern living/ environments. Heterozygous variants, hypomorphic alleles, and regulatory variants may sit elsewhere on the same biological continuum.

Those states may reflect:

• retained older configurations

• alternative configurations

• environment-dependent configurations

• or remnants of previously adaptive biology

Are glycosylation-pathway variants enriched in particular neurodivergent/connective-tissue phenotypes? Are you neurodivergent, and do you have any glycosylation genetic variants?

5. The new Yan et al. 2026 research article

This new research connects valuable missing evolutionary evidence. The paper shows coordinated human-lineage regulatory change affecting GAG biosynthesis:

• Human cartilage had markedly lower GAG content

• Multiple GAG-related genes were downregulated

• CSGALNACT1 showed strong regulatory divergence

• ACAN, which encodes aggrecan, also showed major evolutionary change

The point is that the machinery constructing the extracellular sugar environment itself changed substantially during human evolution.

6. Archaic ancestry and the Neanderthal/Denisovan comparison

Some ECM/GAG-related changes pre-date the split between modern humans and archaic humans. There were also later modern-human-specific regulatory changes. ACAN and CSGALNACT1 appear to have undergone further regulatory suppression after modern humans separated from Neanderthals and Denisovans. Earlier methylation research also found modern-human divergence involving XYLT1, which sits right at the beginning of proteoglycan GAG-chain construction. So there appears to be layers of change, not one event: older Homo state → archaic/modern divergence → additional modern-human regulatory change.

There is extensive evidence linking Neanderthal-derived variants with autism/ADHD-associated genomic variation.

Therefore, do archaic-derived haplotypes preserve divergent glycan/ECM regulatory states? And do those states correlate with connective-tissue, sensory, midline and neurodevelopmental phenotypes?

7. Significance for Divergent Genomics and progressive evolution

Evolutionary theory frames human evolution as a neutral act. The derived modern state is not automatically better, or improved in comparison to our ancestors. The Divergent Genomics framework moves beyond neutrality and seeks to distinguish contemporary ‘evolution’ from maladaptation and/or degeneration. In the recent Yan et al. findings, one major trajectory is towards less GAG production, not more. That reduced state brings increased vulnerability to cartilage degeneration. Therefore, that evolutionary change was demonstrably: loss / suppression / trade-off / compensation, and not improvement. This fits a wider concern that modern biological states may represent reduction from earlier capacities, while some present-day divergent states naturally retain inherent aspects of older biology.

8. The crucial reframing of “disorder”

A biochemical loss-of-function sounds negative but it does not necessarily mean evolutionary inferiority. It tells us that one molecular activity is reduced relative to a reference state. It does not tell us whether that state was: beneficial, harmful, neutral, or entirely context-dependent in another environment. That distinction is central to everything herein.

MOGS-CDG is a perfect example, divergent N-glycosylation can make cells less usable by some enveloped viruses. So a glycosylation state classified clinically as a ‘disorder’ can paradoxically confer viral resistance. Researchers have observed particular physiological and developmental characteristics in individuals with substantially reduced MOGS activity.

Specifically:

Neurological development

Delayed acquisition of motor and other developmental skills, sometimes accompanied by significant neurological impairment.

Muscle function

Hypotonia (reduced muscle tone), which can affect movement and physical functioning.

Immune physiology

Reduced circulating immunoglobulin concentrations, partly associated with unusually rapid antibody clearance.

Differential glycoprotein processing

Reduced removal of glucose residues from N-linked glycans, altering the processing of proteins throughout the body.

Processed through a normative clinical lens, this would usually mean:

• greater susceptibility to certain infections, and cancers, depending on which antibodies are affected and how well other immune mechanisms compensate

• a need for clinical monitoring or immunoglobulin replacement in some affected individuals

However, here’s the contradiction: the original MOGS research identified low antibody concentrations alongside unexpectedly limited infections in the individuals studied. That prompted researchers to investigate whether divergent glycosylation was interfering with the viruses themselves. So the immune system may show fewer circulating antibodies while certain viruses simultaneously have greater difficulty exploiting the body’s cells. Those are two different mechanisms operating within the same biological system.

Notably, the functional impact of a MOGS variant on an individual cannot be understood independently of the wider biological system and the environment in which it operates.

9. Glycosylation

Glycosylation is an enzyme-mediated biological process in which carbohydrates are attached to proteins, lipids or other molecules, forming or modifying glycan structures that influence their biological functions.

Glycosylation influences:

• Cell signalling: How receptors recognise and respond to molecular signals.

• Development: How cells communicate, migrate and organise into tissues.

• Immunity: How immune cells recognise other cells and pathogens.

• Nervous-system function: How synaptic proteins interact and organise connections.

• Extracellular organisation: How proteoglycans and their GAG chains influence tissue structure and developmental signalling.

It is one of the ways cells modify molecules and influence how they function. Glycosylation is one of the primary interfaces between organism and environment. Pathogens bind glycans. Immune cells use glycans. Microbes metabolise glycans. Diet provides substrates affecting glycosylation. Inflammation alters glycosylation. Nutrient/cofactor availability alters glycosylation. The glycogenome is where genome and environment meet; an evolutionary handshake.

10. PMM2 and the relationship between glycosylation and viral replication

PMM2 participates in mannose metabolism, supplying a precursor required for N-glycan synthesis.

The Divergent Genomics framework has identified compatibility as an evolutionary signature. This is how biological systems recognise, interact and function together. Glycosylation helps determine this compatibility by shaping the glycan structures found on cell surfaces.

Pascoal et al. (2024) examined how changes in glycosylation associated with the PMM2 gene affect immune function and interactions with microorganisms.

Key findings:

Molecular recognition: Glycan structures influence how microorganisms recognise and attach to cells.

Genetic variation: PMM2 genotypes are associated with differences in immune function.

Development: Immune-related effects vary across developmental stages.

Biological interaction: Changes in glycosylation alter the molecular conditions governing interactions between organisms.

This is relevant for evolutionary biology because:

• Glycan structures evolve alongside genetic and developmental systems

• Evolutionary changes in glycosylation alter how biological systems recognise and interact with one another

• Comparing ancestral and derived glycan configurations offers a way to investigate which biological recognition mechanisms have been retained, modified or lost

In their review, Revisiting the immunopathology of congenital disorders of glycosylation, Pascoal et al. explicitly identify a relationship between altered glycosylation patterns in host cells and potentially favoured interactions with microorganisms, interpreting this primarily through increased susceptibility to infection. Yet this observation also supports a much broader evolutionary question, one that aligns directly with the theory of biological compatibility as an evolutionary signature. Glycosylation influences which organisms can recognise, attach to and interact with one another. Why, then, should increased microbial compatibility automatically be interpreted as biological disadvantage? The evolutionary history of mitochondria offers a remarkable perspective: these essential components of our cells originated from bacteria that entered into an ancient endosymbiotic relationship, ultimately becoming integral to complex life. Imagine if an advanced civilisation had existed at that evolutionary crossroads, equipped with technologies designed to eliminate every unfamiliar microorganism before such relationships could develop. What evolutionary possibilities might have been lost? Of course, microbial compatibility does not guarantee beneficial integration, but neither does it exclude it. Evolution is a history of interaction, accommodation and integration. The findings therein raise a question extending beyond immunopathology: could some biological configurations currently characterised predominantly by their disadvantages also represent forms of compatibility whose evolutionary significance depends on the organisms and environments they encounter?

Liang et al. (2024) demonstrated that altering mannose metabolism and glycosylation can change both viral susceptibility and the body’s response to infection. Reducing phosphomannose isomerase (PMI) activity interfered with replication of several viruses, including influenza, SARS-CoV-2 and Zika, while the physiological effects of mannose depended on the metabolic pathways available to process it. This demonstrates why glycogenomic variation cannot be understood through isolated genes or clinical classifications alone. Could some inherited glycan configurations preserve biological capacities that have been reduced or lost during human evolution, while changes in environmental conditions alter how those same capacities are expressed? The Liang et al. study provides experimental evidence for the relationship between glycogenomic configuration, environmental conditions and biological function.

11. FUT2 non-secretor status

FUT2 non-secretor status comes from loss-of-functional FUT2 activity in relevant tissues. That changes which glycans appear on mucosal surfaces. Several norovirus and rotavirus strains depend on those glycans. Therefore, remove the glycan target and infection risk can fall dramatically. The non-secretor allele has undergone positive selection in human populations. This is a very real example of: “loss of function” → altered glycosylation → protection from pathogen → evolutionary advantage.

Therefore, this particular loss of biochemical function can be considered evolutionary progressive. The advantage demonstrated above is innate, however, the disadvantages are not: altered microbial balance or increased susceptibility to inflammatory conditions, are not intrinsic defects. They are consequences, arising through interactions with anthropogenic environmental exposures, diet, and microbial ecology. The protective capacity is built into the biology, while the disadvantages depend on the environment in which that biology operates. In the current climate, that is significant.

12. An environmental-mismatch

An older glycogenomic state was highly compatible with an earlier environment. Environmental and/or pathogen pressure changed. Biochemical pressures altered the relative consequences of different glycan configurations. That state then becomes more common. An older, organic retained state will now present as pathological because it’s inheritance is less compatible with the dominant synthetic environment. The result is anthropogenic selection, and is wholly separate from natural selection. What is termed neurological “disorder” becomes genotype × present environment mismatch, rather than an intrinsically inferior/defective organism.

Evolutionary advantage becomes modern disadvantage

The MTHFR C677T variant provides a compelling example of why reduced enzyme activity should not automatically be equated with biological inferiority.

Smulders et al. (2007) investigated folate distribution in healthy adults and found striking differences associated with MTHFR genotype. Among individuals with the 677TT genotype, non-methylated folates represented a median 30.3% of total red-cell folate, compared with just 0.58% among those with the CC genotype. This demonstrates that reduced MTHFR activity can substantially alter the distribution and accumulation of different folate forms within red blood cells. The TT individual is distributing folate differently, therefore a greater proportion of folate remains in non-methylated forms, in order to participate in other processes, such as nucleotide synthesis (DNA repair, replication and development).

Consider the potential evolutionary significance of retained folate during periods of food scarcity. In ancestral environments characterised by harsh winters and seasonal shortages of folate-rich foods, the ability to retain or redirect available folate compounds towards essential cellular processes likely influenced survival and reproductive success.

The evolutionary question becomes particularly interesting when examining seasonal selection. Lucock et al. (2007) investigated MTHFR C677T genotype frequencies in populations exposed to differing seasonal patterns of dietary folate availability. They identified significant seasonal differences in the UK population that were absent in their Australian comparison population, proposing that natural fluctuations in dietary folate availability may have influenced genetic selection through embryonic viability.

A genetic configuration associated with advantages under one set of nutritional and environmental conditions may produce very different outcomes under another. This raises a broader evolutionary question: have the presentations of some inherited biological configurations been pathologized because they are being evaluated within the anthropogenic environmental context that caused the epigenetic stress, without sufficient consideration of the conditions under which they have actually evolved?

There is a profound irony in the modern pathologization of inherited biological variation. Individuals carrying variants such as MTHFR C677T frequently attribute migraines, raised homocysteine, B12 insufficiency, fatigue and other clinical symptoms to supposedly defective genes. Yet these inherited configurations represent evolutionary advantages whose expression has been inverted by industrial and environmental conditions. Rather than questioning the compatibility of contemporary nutritional, chemical and metabolic environments with our inherited biology, the genetic variation itself becomes the presumed problem. The underlying genes are not defective, but rather evolutionary beneficial - being naturally retained and selected for - but being disproportionately disadvantaged in the current climate. This should fundamentally change how we interpret health risk, shifting the investigation from assumed genetic inferiority towards the current conditions that are causing epigenetically-derived chronic functional illnesses.

13. This changes how neurodivergence should be conceptualised

The same glycosylation machinery influences both immune function and nervous-system development. This underlies the relationship between inherited glycogenomic variation, changing environmental and infectious pressures, and neurodevelopmental outcomes. An inherited glycan configuration may remain unchanged while the environment in which it operates changes substantially. Environmental mismatch influences multiple biological systems without requiring genetic selection and/or the emergence of a new glycan configuration.

Rather than: Clinical neurological ‘disorder’, the model becomes: ancestry + genomic regulation + glycosylation divergence + collagen/connective tissue divergence/ extracellular environment + neuroimmune development → whole-body phenotype. That is aligned with the pattern of neurodivergence appearing alongside connective-tissue, sensory, immune, craniofacial and autonomic differences (on a constellation spectrum).

14. The concept

The glycome is the mediator between environmental selection and developmental evolution. The environment does not need to directly alter developmental genes. It can select for a glycan state because of natural immunity or pathogen resistance. Because glycans also regulate morphogens and ECM, developmental anatomy changes alongside it. This produces a vast and diverse spectrum of divergence in the aforementioned core functional domains.

The concept model

Inherited glycogenomic architecture and historical regulatory divergence

↓

Glycan composition and extracellular-matrix organisation

↓

Regulation of SHH/FGF/WNT/BMP signalling

↓

Neural-crest migration and midline development

↓

Connective-tissue, craniofacial, sensory and nervous-system organisation

↓

Individual developmental phenotype

Alongside this developmental pathway:

Changing nutritional, microbial, biochemical and infectious environments

↓

Altered interactions with existing glycan configurations

↓

Changes in immune recognition, microbial ecology, metabolic signalling and physiological function

↓

Environmental epigenetic mismatch

↓

functional consequences of an existing glycogenomic state, without requiring genetic change or natural selection.

15. The question of evolutionary progress

What have we retained from our ancestral glycogenomic architecture, what have we gained, and what have we lost through human evolution so far? How have these changes shaped human development, physiology and neurodevelopmental diversity, and how might rapidly developing anthropogenic influences affect the expression and function of what remains?

16. The prediction

If the relevant research is done and this framework is proven correct, we will eventually find:

• patterns of enrichment in glycosylation/GAG-pathway variants present in subsets of neurodivergent people

• strong overlap with connective-tissue and midline phenotypes

• archaic ancestry signals within some of those pathways

• environmental-dependent flourishing

• Unique innate protective effects, including neuroimmunological and ancestral metabolic advantages, in combination with a disproportionate modern environmental risk phenotype. This would likely result in a paradoxical individual presentation, such as coexisting gifts and disabilities and/or asynchronous developmental profiles, with increased risk of chronic ill health via the exposome.

In sum:

• the environment selects the glycan landscape

• the glycan landscape shapes development

• development shapes the body and brain

• when the environment changes, the meaning of that biological state changes too

Final Note: The Exposome and Biological Compatibility

The glycan landscape represents an evolutionary handshake between our biology and the environment, mediating how our bodies interact with substances we consume, inhale, absorb or introduce. Modern environmental pressures, including frequent exposure to rapidly absorbed refined sugars, can disrupt glycosylation, cellular signalling and the extracellular environment, creating a mismatch between our evolved biological regulatory mechanisms and the conditions in which they now operate. This relationship is also relevant to viral interactions, including the role of glycosylation in spike protein processing - which is, itself, a glycoprotein.

This is particularly relevant when we consider that human glycan structures and glycoprotein-processing systems are genomically diverse. If the biological machinery through which we interact with our environment differs between individuals, it should not be assumed that standardised exposures produce uniform biological outcomes.

Understanding health through an evolutionary lens requires examination of the compatibility between human biology and the environment we inhabit today. This also requires consideration of the conditions that shaped our ancestors - the evolutionary progress they made - and how this compares with our anticipated trajectory.

Image: Dijo Moonnukandathil Joseph, Nazlican Yurekli and Leonhard Möckl, from Glycan atlassing enables functional tracing of cell state, Nature Nanotechnology (2026), Figure 3a(ii). Licensed under CC BY 4.0

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© Alexandra Chambers 2026. All rights reserved.