TL;DR

  • The X chromosome shows multiple recent selective sweeps in neural genes (TENM1, NLGN4X, PCDH11X)
  • Hemizygosity in males accelerates both adaptive fixation and purging of deleterious alleles
  • Escape from X-inactivation creates sex-biased dosage effects in neural genes
  • X-linked mutations underlie many intellectual disabilities and autism cases
  • A dopaminergic VTA ↔ Broca loop links X-sweep gene TENM1 to metacognitive circuitry

X Chromosome and Cognition: Evolutionary, Genetic, and Epigenetic Perspectives

Introduction#

The human X chromosome plays an outsized role in brain development and cognitive function despite representing only ~5% of the genome. Notably, roughly 15% of genes known to cause intellectual disability (ID) are X-linked. Numerous X-chromosomal genes are crucial for neural development, synaptic function, and higher cognition. Mutations in these genes frequently lead to neurodevelopmental disorders, often with a distinctive sex bias due to the X’s unique inheritance (males are hemizygous, carrying one X, while females carry two). Females mitigate the dosage imbalance via X-chromosome inactivation (XCI), a process that transcriptionally silences one X in each cell. However, XCI is incomplete for many genes, and this mosaic expression in females can influence cognitive phenotypes. Hemizygosity in males means any deleterious or beneficial X-linked allele is immediately exposed to selection pressure, impacting the evolution of cognition-related genes. This report examines five facets of the X–cognition relationship: (1) signatures of positive selection on X-linked genes related to cognition, (2) X-linked developmental disorders of cognition, (3) X-inactivation, escape from silencing, and dosage effects on cognitive function, (4) sex-biased differences in cognitive traits and disorders, and (5) evolutionary implications of hemizygosity for cognitive gene selection.

Selective Sweeps on the X Chromosome and Cognition#

Population-genetic scans for recent positive selection (selective sweeps) have revealed that the X chromosome harbors numerous signals of adaptation in genes with neural functions. An X-wide analysis of 1000 Genomes Project data reported a global enrichment of selection signals in neural-related genes, suggesting that cognitive or brain-development traits have been important targets in human evolution. One of the strongest sweep signals on the X centers on the TENM1 gene (Teneurin-1), which spans a ~300 kb haplotype with extended linkage disequilibrium. The haplotype structure at TENM1 indicates an ancient, hard selective sweep that likely predates the out-of-Africa human population split. TENM1 encodes a transmembrane protein involved in neural development and synapse organization (particularly in the olfactory system). Intriguingly, rare mutations in TENM1 cause congenital general anosmia (loss of smell) , suggesting that olfactory neural adaptations may have driven the TENM1 sweep. Olfactory capacity is thought to have been under selection in modern humans , and TENM1’s strongly selected haplotype could reflect changes in brain circuitry related to smell or broader neural development. More generally, promoter regions of many brain-expressed genes show evidence of positive selection in humans , consistent with the idea that regulatory changes in neural genes (including those on the X) underlie cognitive evolution.

Another notable evolutionary innovation on the X is the protocadherin cluster involving PCDH11X. About 6 million years ago, a segment of Xq21 containing the PCDH11X gene was duplicated to the Y chromosome, creating a Y-linked paralog PCDH11Y unique to humans. Both PCDH11X and PCDH11Y encode cell-adhesion molecules predominantly expressed in the brain. This gene pair has undergone accelerated evolution with human-specific changes (including two amino acid substitutions in PCDH11X’s extracellular domain). Such changes may alter binding properties of the protocadherin and have been hypothesized to relate to the emergence of human language circuitry. In other words, PCDH11X/Y is posited to be critical for human-specific brain functions such as language. The rapid divergence of this X–Y gene pair underscores how selection can act on X-linked genes (and their Y counterparts) to possibly confer cognitive traits unique to our species.

The NLGN4X gene (Neuroligin-4, X-linked) illustrates how even subtle sequence changes on the X can have cognitive significance. NLGN4X encodes a postsynaptic cell adhesion protein essential for synapse formation, and it has a Y-linked homolog, NLGN4Y, with ~97% amino acid identity. Despite their similarity, a single amino acid difference severely impairs NLGN4Y’s function: NLGN4Y shows defective protein trafficking and synaptogenesis, meaning it cannot effectively substitute for NLGN4X in the brain. This has evolutionary and clinical implications. The likely degeneration of NLGN4Y’s function (perhaps through relaxed selection on the Y chromosome copy) leaves males functionally reliant on NLGN4X. If NLGN4X undergoes mutation in a male, there is no backup – resulting in X-linked autism or intellectual disability, as observed in many cases. Researchers have found that autism-associated mutations clustering near the critical residue in NLGN4X “phenocopy” the loss-of-function of NLGN4Y. Thus, the differentiation of the X vs. Y copies of neuroligin-4 may have been neutral or even deleterious for males, but it highlights how hemizygosity exposes cognitive genes to unique selective pressures. Any beneficial mutations improving NLGN4X’s synaptic function could spread in the population (since they immediately confer an advantage in males), whereas deleterious variants are rapidly purged in hemizygous males. Indeed, theory predicts a “faster-X” effect whereby recessive advantageous alleles on the X fix more rapidly due to full exposure in males. Consistent with this, human population analyses indicate natural selection can be a stronger force on the X than on autosomes. In sum, multiple lines of evidence – from ancient selective sweeps (TENM1) to human-specific X gene innovations (PCDH11X) to X–Y divergence in synaptic genes (NLGN4X/Y) – demonstrate that the X chromosome has been a key canvas for cognitive evolution in our species.

X-Linked Developmental Disorders Affecting Cognition#

Dozens of X-linked genes are known in which mutations give rise to developmental disorders involving intellectual disability, autism spectrum disorder (ASD), epilepsy, or other cognitive impairments. The prevalence of X-linked intellectual disability (XLID) highlights the X chromosome’s importance: it is estimated that mutations in over 140 X genes can cause ID , and roughly 1 in 600–1000 males has an ID attributable to an X-linked mutation. A striking example is Fragile X syndrome, caused by a CGG-repeat expansion silencing the FMR1 gene on Xq27. Fragile X is the single most common inherited cause of intellectual disability and autism. Affected males typically show moderate to severe cognitive impairment, behavioral abnormalities, and the syndrome accounts for a large fraction of X-linked ID cases. Females with a full mutation in one FMR1 allele can be milder due to mosaic expression (they have one normal FMR1 allele active in roughly half their cells). The high frequency and impact of Fragile X syndrome underscore how an X mutation can broadly affect cognition and why such variants are under strong negative selection in populations.

Beyond Fragile X, many monogenic X-linked syndromes highlight pathways crucial for cognition. Rett syndrome is a severe neurodevelopmental disorder (with regression of language and motor skills in early childhood) caused by de novo mutations in MECP2, an X-linked gene encoding a neuronal chromatin-binding protein. Rett primarily affects females (who are heterozygous), as MECP2 mutations in males usually cause neonatal encephalopathy and early lethality. Another X-linked gene, ATRX, when mutated causes a syndrome with intellectual disability and brain malformations, emphasizing the X’s role in fundamental neurodevelopmental processes like chromatin regulation. Mutations in chromatin modifiers on X such as KDM5C (JARID1C) and KDM6A (UTX) also lead to ID syndromes, reflecting how epigenetic regulation genes on the X are dosage-sensitive in brain development.

X-linked genes involved in synaptic function and neurotransmission frequently emerge in neurodevelopmental disorders. Neuroligin and neurexin genes are pivotal for synapse formation; as noted, NLGN4X mutations cause ASD and ID in males , and mutations in NLGN3 (also X-linked) have been found in families with ASD. IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) is another X-linked synaptic gene: deletions or mutations in IL1RAPL1 cause non-syndromic ID and ASD. Disruption of OPHN1 (oligophrenin-1, involved in Rho GTPase signaling at synapses) leads to cerebellar hypoplasia and intellectual disability. These examples illustrate a broader theme that many X-linked ID genes encode synaptic proteins, reflecting the X chromosome’s enrichment in genes for neural connectivity.

Several X-linked disorders also prominently feature epilepsy alongside cognitive impairment. One remarkable case is PCDH19, encoding protocadherin-19 (an adhesion molecule in the δ2-protocadherin subfamily). PCDH19 mutations cause Epilepsy and Mental Retardation limited to Females (EFMR). Paradoxically, heterozygous females suffer childhood-onset seizures and often cognitive deficits, while hemizygous mutant males are typically unaffected or have only mild symptoms. This unique inheritance is explained by cellular mosaicism: in heterozygous females, random X-inactivation produces a mosaic brain with intermixed PCDH19-mutant and wild-type neurons, leading to defective cell–cell communication (“cellular interference”) and network epileptogenesis. Males, having no mosaicism (all neurons mutant), apparently avoid this interneuronal mismatch; in fact, transmitting males (with the mutation in all cells) show no epilepsy, but pass the mutation to daughters who then manifest the disorder. Thus, PCDH19 EFMR reveals how mosaic X expression can itself be pathogenic, and how an X-linked mutation can spare males but harm females – the inverse of the usual pattern. Other X-linked epilepsy genes include CDKL5, where heterozygous females develop early infantile epileptic encephalopathy with severe developmental delay (sometimes considered an atypical Rett syndrome variant), and ARX (Aristaless-related homeobox), a gene critical for interneuron migration. ARX mutations in males can cause X-linked infantile spasms syndrome and intellectual disability, often with cortical malformations. Females can be carriers of ARX mutations (usually without symptoms due to skewed XCI or mosaic rescue).

The example of ARX also raises the point that some X-linked genes are so vital that null mutations are male-lethal, manifesting only in females (who survive due to mosaicism). CCNA2 and RBM10 are additional such genes where male loss-of-function is embryonic lethal or perinatally lethal, but heterozygous females live with syndromic cognitive impairments. In contrast, X-linked mutations that are viable in males often present as diseases preferentially affecting males – this includes the many forms of non-syndromic X-linked intellectual disability (traditionally called “mental retardation” in older literature) caused by loci like HCFC1, AP1S2, CUL4B, MED12, ZFPM2, and others. Female heterozygotes for these mutations usually have milder effects or are asymptomatic due to the presence of a functional allele in a proportion of cells. Consequently, epidemiologically, males are disproportionately affected by developmental cognitive disorders. The male-to-female ratio is about 4:1 in autism spectrum disorder and 3:1 in attention deficit hyperactivity disorder (ADHD), and while multifactorial factors underlie these biases, X-linked risk variants are significant contributors. For instance, mutations in NLGN4X or NLGN3 can cause autism in males, with carrier females spared or showing only subtle traits. Similarly, the incidence of profound intellectual disability is higher in males, partly due to X-linked conditions like Fragile X and XLID syndromes that rarely manifest fully in females.

In summary, the X chromosome harbors a large cluster of genes where mutations disrupt cognition, spanning synaptic proteins, transcriptional regulators, and developmental morphogens. These X-linked disorders emphasize two crucial points: (a) Dosage sensitivity of X genes in neural development – loss of one functional copy in males (or functionally in females, via dominant or mosaic effects) often cannot be compensated, impairing cognition; and (b) Sex-specific manifestations – the same genetic mutation may lead to different outcomes in males and females due to differences in X dosage, XCI mosaicism, or Y-chromosome homologs, as illustrated by PCDH19 and other cases. Studying these disorders not only informs medical genetics but also highlights pathways essential for normal human cognitive development.

X-Inactivation, Escape from Silencing, and Cognitive Impacts#

Mammalian females achieve dosage parity for X-linked genes by inactivating one X chromosome in each cell early in embryogenesis. However, X-inactivation is far from absolute – an estimated 15–25% of X-linked genes “escape” inactivation to some degree, being expressed from both alleles in females. These escapee genes create a dosage difference: females have roughly double the expression of such genes compared to males (who have only one active copy). Notably, the X chromosome is enriched in genes with roles in the brain , and the dosage of certain escape genes has been linked to sex-biased phenotypes in cognition. For example, higher expression of some escape genes in females may contribute to cognitive resilience or enhanced performance on certain tasks, whereas loss of that “double dose” can be deleterious (as seen in Turner syndrome, discussed below).

Genes that escape XCI tend to fall into two categories: those in the pseudoautosomal regions (PAR1 and PAR2) which are present on both X and Y and need to be biallelic in both sexes, and a select subset in the non-PAR X that somehow avoid silencing. Many escapees have functional Y-homologs, and evolutionary studies show these genes are under strong purifying selection, likely because both copies are crucial. For instance, DDX3X (a DEAD-box RNA helicase) escapes inactivation and has a Y homolog (DDX3Y); loss-of-function mutations in DDX3X cause intellectual disability and often congenital brain anomalies in females, indicating that halving its dosage (in mosaic fashion) is pathogenic. KDM6A, a histone demethylase gene, is another escapee with no Y counterpart; KDM6A mutations cause Kabuki syndrome with cognitive impairment in both males and females, but female heterozygotes are affected because the active X still expresses the mutant allele in many cells (since it’s not fully silenced on the inactive X). Female heterozygous mutations in escape genes often produce disease, unlike typical X-linked mutations where a normal copy on the second X can compensate in a majority of cells. This is because even cells where the wild-type allele is on the active X may still express the mutant from the inactive X if the gene escapes. Thus, escape from XCI blunts the protective effect of heterozygosity and can render X-linked disorders semi-dominant in females. This phenomenon is seen with KDM6A, DDX3X, SMC1A, and others where females manifest clinical syndromes albeit sometimes milder than males.

Beyond rare mutations, natural variation in XCI escape could contribute to sex differences in brain and behavior. The set of genes escaping XCI is somewhat tissue-specific and variable between individuals. Notably, a recent integrative analysis found ~23% of X-linked genes show some degree of escape when surveying multiple human tissues. Some escapees are highly expressed in the brain, such as IFI44L and PKM2 (identified in fibroblasts/lymphoblasts studies ), though the brain-specific escape profile is still being elucidated. Intriguingly, aging may reactivate silenced X genes in the brain: a study reported that in older female mice, some normally inactivated genes began to be expressed from the inactive X in the hippocampus (dentate gyrus), potentially impacting cognitive aging. This suggests XCI escape is dynamic and can respond to physiological or environmental factors, introducing another layer of complexity in how X-linked gene dosage affects neural function over the lifespan.

The consequences of abnormal X dosage are clearly seen in sex chromosome aneuploidy syndromes. In Turner syndrome (45,X), females have only one X (no homologous X to inactivate), meaning they lack the second copy of all X genes, including escapees that would normally be biallelic. Turner individuals often have specific cognitive profile differences: despite generally normal intelligence, they commonly show deficits in spatial reasoning and executive function, and a subset have social cognition difficulties. Notably, the parent-of-origin of the single X matters: Turner patients who inherited an X from their mother (Xm) show greater cognitive and social deficits than those with a paternal X. Skuse et al. first demonstrated this imprinting effect, suggesting that a gene (or genes) on the X is imprinted (silenced) when maternal and expressed only from the paternal copy, influencing social brain development. The existence of such an imprinted locus was supported by the finding that 45,X girls with maternal X have impaired social communication compared to 45,X girls with paternal X. Although the exact gene remains uncertain, candidates have been proposed (e.g. XIST region genes, or factors like NAP1L2 or FTX). Recent work in mice provides further evidence: enforcing maternal-X-only expression in female mice (by deleting Xist on the maternal X to make it the sole active chromosome) led to impaired spatial memory and accelerated cognitive aging, relative to normal mosaic females. This implies that paternal X-linked alleles active in a proportion of cells normally contribute to optimal cognitive function and brain maintenance. In other words, a balance of Xm and Xp expression (X-mosaicism) in females may be neuroprotective, whereas skewing toward a single-parent X can be detrimental.

By contrast, in Klinefelter syndrome (47,XXY males), an extra X leads to over-expression of escape genes (since one X is inactivated, but escapees remain active from both the inactive X and the active X). XXY males often have mild learning disabilities, delayed speech/language development, and relatively lower verbal IQ, which could stem from that excess dosage of some X genes (along with endocrine factors). Notably, PPP2R3B and STS are examples of escape genes whose overexpression might contribute to Klinefelter cognitive profiles, though the exact mechanisms are still under study.

Finally, XCI mosaicism in females can sometimes mitigate the impact of X-linked mutations, but also create variability. As mentioned, females heterozygous for mutations in X-linked synaptic genes (like NLGN4X or DCX) may range from unaffected (if favorable skewing or sufficient compensation occurs) to manifesting mild cognitive or neurological issues. This female mosaic advantage is one proposed reason for the lower incidence of autism and severe ID in females: deleterious X alleles are buffered by the mosaic presence of normal cells. However, when a female does manifest an X-linked disorder, skewed X-inactivation is often observed (the body preferentially uses the “healthier” X in a higher fraction of cells). For instance, in Rett syndrome female patients, cells often skew towards the X with the normal MECP2 to compensate, and the degree of skewing can correlate with severity. In the case of PCDH19 epilepsy, skewing does not rescue because the pathology arises specifically from the mosaic state itself, a unique scenario.

In summary, X-inactivation and escape from X-inactivation represent a delicate equilibrium with significant cognitive ramifications. Escapee genes provide a dosage boost in females, which can be beneficial (and perhaps evolutionarily favored) but also creates vulnerabilities if dosage is imbalanced (too low in Turner, too high in Klinefelter, or disrupted by mutation in heterozygotes). Many escape genes are implicated in brain function, and their sex-biased expression may underlie subtle cognitive differences between males and females. Moreover, the mosaic expression of X genes in females is a form of natural brain “mosaicism” that might increase cellular diversity and resilience, though it can also generate unique pathology (as with PCDH19). Understanding which X genes escape and how they influence neural cells is key to deciphering sex differences in neurobiology.

Sex-Biased Effects in Cognitive Traits and Disorders#

The X chromosome’s special characteristics contribute to sex differences in both normal cognitive traits and the prevalence or presentation of brain disorders. Many cognitive or neuropsychiatric disorders exhibit sex biases in incidence or severity, and in several cases X-linked genes are partially responsible. The clearest example is the male bias in intellectual disability and autism, largely due to X-linked mutations that are fully penetrant in males but only variably so in females (who must have two mutant alleles or adverse X-skewing to be equivalently affected). This creates a “female protective effect” in disorders like ASD: female brains, with two Xs, often require a higher mutational burden (including possibly two hits at an X locus or hits on both Xs and autosomes) to reach the same threshold of impairment as a hemizygous male. Conversely, when females do meet that threshold (e.g. a de novo dominant X mutation such as MECP2 or CDKL5), the phenotype can be severe or even lethal for males.

Autism spectrum disorder (ASD) is ~4 times more common in males. While many factors contribute (including hormonal and autosomal genetic differences), X-linked genes have been repeatedly implicated. Besides NLGN3 and NLGN4X mentioned earlier, other X genes like PTCHD1, MAOA, and AFF2 (FMR2) have been associated with ASD or related neurodevelopmental conditions. The neuroligin findings are particularly illustrative: male-specific mutations in NLGN4X lead to autism or ASD with intellectual disability, whereas heterozygous females are typically unaffected carriers. The underlying reason is that males cannot compensate for loss of NLGN4X (NLGN4Y is non-functional), whereas females still have one working NLGN4X in roughly 50% of synapses, often sufficient for near-normal function. Thus, male vulnerability in ASD is partly rooted in the X – a single detrimental allele can manifest in males, whereas females enjoy a protective redundancy for many risk variants.

On the other hand, certain X-linked disorders show female biases, revealing interesting biology. We discussed PCDH19 epilepsy where heterozygous females are ill while males are spared due to the requirement of mosaic expression for pathogenesis. Another example is autoimmune disorders and mood disorders – some have hypothesized that XX vs. XY differences (including X-linked immune genes or brain-expressed escapees) may contribute to females’ higher rates of conditions like depression or autoimmune encephalitides, though conclusive genes are not yet identified.

Normal cognitive trait distributions also show subtle sex differences. Males on average perform better on certain spatial navigation or mathematical reasoning tasks, while females tend to excel in verbal memory and social cognition. While cultural factors and hormones (e.g. organizational effects of androgens) largely explain these trends, an intriguing contributor could be X-linked gene effects. For instance, the imprinted X hypothesis (by Skuse and colleagues) posits that a gene on the X is expressed only when paternally inherited and enhances social cognitive abilities. Females normally receive one paternal X in half their cells, potentially giving them an advantage in social skills, whereas males receive their single X maternally (and thus lack the putative paternally-expressed factor entirely). This model was proposed to explain why Turner syndrome patients with a maternal single X had marked social impairments (more autism-like features) compared to those with a paternal X. If a similar effect exists in the general population, it could mean that on average females benefit from having some fraction of cells expressing certain paternal X alleles that promote, say, empathy or communication, whereas males do not. Supporting this, a specific gene (XLr3b in mice) was identified in 2005 as a strong candidate for such parent-of-origin effects on cognitive function. Moreover, the recent study in mice enforcing maternal X-active across all cells found not only memory deficits but also exacerbated brain aging, suggesting that the mosaic expression of a paternal X normally has beneficial effects in the female brain. While direct evidence in humans is still limited, these findings point to the possibility of imprinted X-linked loci influencing human cognition in a sex-specific manner.

Sex-biased gene expression is another avenue by which the X can create cognitive differences. By virtue of XCI escape or sex-specific regulation, some X genes may be expressed at higher levels in one sex’s brain. For example, the AMPA receptor subunit gene GRIA3 is X-linked and escapes inactivation in some individuals. Elevated GRIA3 expression has been correlated with cognitive resilience in women , possibly contributing to their lower susceptibility to cognitive decline. Additionally, a recent large-scale study (X-WAS) on Alzheimer’s disease (AD) risk found a variant in NLGN4X that was associated with AD in women but not men. Since NLGN4X escapes XCI (and thus women have two active copies) , a risk allele could have a larger effect in females (influencing synaptic maintenance with age) whereas males, with only one allele, might be less affected or the effect masked by other factors. This example underscores how an X-linked gene variant can contribute to sex differences in a cognitive disorder (in this case, AD). Likewise, the AD study noted several other escape genes (e.g. MID1, ADGRG4) with female-specific association signals , reinforcing that escape from XCI can lead to differential disease susceptibility.

Another contributor to sex-biased cognitive outcomes is the interaction between sex hormones and X-linked genes. The androgen receptor gene AR is on the X chromosome and contains a polymorphic CAG repeat that modulates receptor activity. Longer CAG repeats (lower AR activity) have been linked to differences in male cognitive profiles and even disorders like Kennedy’s disease (spinobulbar muscular atrophy) where some cognitive changes occur. While AR’s effect is more hormonal, it is an example of an X gene variant influencing male neural phenotype directly. Additionally, sex hormones can differentially regulate X-linked genes: for instance, estrogen upregulates PGK1 (an X gene encoding an enzyme) in brain cells, which might afford metabolic advantages to females under certain conditions.

In psychiatric disorders such as schizophrenia and bipolar disorder, the sex ratios are closer to equal, but some studies have suggested X-linked factors play a role in specific endophenotypes. For example, OPA1 (an X-linked synaptic gene) variants were once investigated for link to schizophrenia, and a disproportionate number of schizophrenia susceptibility loci have shown different effect sizes by sex in GWAS (with a few hits on X, though results have been inconsistent). The overall contribution of the X to these complex traits likely exists but is difficult to disentangle from autosomal influences.

In summary, the X chromosome contributes to sex differences in cognition on multiple levels: biasing who is affected by certain disorders (X-linked conditions often affecting males more, except in special mosaic cases); imprinting effects and escapee dosage leading to differences in normal cognitive strengths; and sex-specific associations in complex disorders due to differential gene expression or gene–hormone interactions. The net effect is that some cognitive phenotypes cannot be fully understood without accounting for sex chromosome effects. Females’ mosaic, double-dose X biology and males’ hemizygous exposure create alternate “substrates” on which neurodevelopment unfolds, with neither being strictly better or worse, but each giving rise to certain vulnerabilities and advantages. Modern research leveraging large cohorts and single-cell expression data is now starting to pinpoint which X genes drive these sex-biased cognitive outcomes , which will deepen our understanding of brain dimorphism and could inform sex-tailored approaches to treating developmental disorders.

From an evolutionary standpoint, the hemizygous state of X-linked genes in males profoundly influences how mutations in cognitive genes are selected for or against. In males, any X-linked allele is immediately exposed to natural selection (since there is no second copy to mask recessive effects). This has two major consequences: advantageous mutations, even if recessive in nature, can spread more rapidly on the X (the “faster-X effect”), and deleterious mutations are purged more efficiently from the population, at least in males. For cognitive-related genes, which often harbor recessive loss-of-function variants causing ID or ASD in males, this means such severe alleles are usually kept at very low frequency in humans. Carrier females can propagate these alleles without strong fitness penalties, but each generation they produce affected male offspring who face negative selection. This dynamic establishes a mutation-selection balance for many XLID genes – high new mutation rates (some X genes like MECP2 and AFF2 have mutation hotspots) balanced by purifying selection against affected males.

Indeed, genetic analysis of human polymorphism shows that X-linked genes overall tend to have reduced genetic diversity relative to autosomes, consistent with a history of more effective purifying selection (and also the lower effective population size of the X). However, when looking specifically at genes that escape X-inactivation, an interesting twist appears: these genes show even stronger evolutionary constraint (lower divergence between species, lower tolerance of variation) than fully inactivated X genes. The likely reason is that escape genes are effectively dosage-sensitive – they function with two active copies in females and one in males, and many also have a Y homolog, so natural selection maintains their function stringently across both sexes. Cognitive escape genes like DDX3X or EIF2S3X (involved in neural progenitor proliferation) fall in this category; any deleterious change might upset dosage balance or male-female expression equilibrium and thus is selected against. In contrast, genes subject to XCI can tolerate slightly more divergence since female heterozygotes can buffer recessive changes and the gene is only fully active in one copy per cell in both sexes.

The flip side is the role of hemizygosity in facilitating adaptive evolution of cognition-related genes. If a new mutation in an X-linked gene confers a cognitive advantage (for example, improves neural processing or social communication), a male possessing it would immediately benefit and could have higher reproductive success, spreading that allele without needing a female to ever be homozygous for it. This mechanism has been proposed to explain the disproportionate number of positively selected loci found on the X in some scans. For instance, the rapid evolution of speech and language faculties in humans may have involved X-linked changes: while the famous FOXP2 gene is autosomal, the X chromosome harbors candidates like PCDH11X/Y for lateralized brain function and perhaps other loci influencing neural connectivity. Population genetic analysis confirms that positive selection signals are enriched among X-linked neural genes , and intriguingly, many of these are escape genes with female-biased expression. One study found that escapees had a higher probability of showing selective sweep signatures than non-escape X genes. This suggests that some sex-biased adaptive traits – potentially cognitive or behavioral dimorphisms – have been evolving via changes in escape gene loci. If an escape gene variant confers a benefit primarily in females (due to higher expression), it could be selected in that sex while males tolerate it if it’s not highly detrimental. Conversely, an allele beneficial in males (even if slightly harmful in females) could spread via male advantage, given the nuances of X inheritance (men pass X only to daughters). The X’s inheritance pattern (father-to-daughter transmission, mother-to-son expression) creates unique scenarios for sexual selection and conflict. For example, an X-linked allele that improves male cognitive performance would increase a mother’s sons’ fitness, but that allele will on average be in half her daughters (who might experience any deleterious effect if heterozygous). This can lead to complex trade-offs in selection, sometimes maintaining polymorphisms.

Some researchers have speculated that the X chromosome is a hotspot for genes underlying specifically human cognitive traits because of these adaptive dynamics. The emergence of X–Y gene pairs like PCDH11X/Y and the acceleration of certain X-linked genes (relative to their conserved autosomal counterparts) during primate evolution lend credence to this idea. Another intriguing observation is the frequent origin of brain-expressed gene duplicates on the X. Numerous retrogenes (genes duplicated via mRNA intermediates) that are expressed in testis and brain have accumulated on the X in some species, possibly because expression in the male germline and brain gave them a selective edge (this is seen in Drosophila fast-X evolution as well). While humans have a smaller repertoire of such retrogenes, a few exist (e.g. HUWE1 duplications affecting brain size).

Hemizygosity also means the effective population size (Ne) of X-linked loci is 3/4 that of autosomes (since males have one X, females two). A smaller Ne can reduce the efficacy of selection relative to drift, potentially allowing slightly deleterious alleles to persist on the X a bit more than on autosomes. There is some evidence that protein evolution on the X is a product of both enhanced positive selection and less effective purifying selection for very mild deleterious mutations. However, for the kinds of mutations that severely affect cognition, selection is very effective (they don’t last long in populations). What might persist are sex-specific alleles with nuanced effects – for example, an allele that subtly shifts cognitive style (imagine an allele that makes carriers more risk-taking or analytical). If it slightly benefits males but slightly harms females, it could reach an equilibrium frequency where those opposing effects balance out. The X’s transmission (mothers to both sons and daughters, fathers only to daughters) creates asymmetry that can favor alleles with maternal or paternal sex-specific advantages.

An illustrative case might be the evolution of social cognition: If a paternal X allele improves social cognition (benefiting daughters who inherit that X from their father, as posited by the imprinting theory), that could drive selection for such alleles in fathers (who benefit via their daughters’ success). But that allele in a son (inherited from mother) might not help, yet it doesn’t impede its spread because the selection happened via daughters. Over time, this could engrain sexual dimorphism in social cognitive processing, perhaps contributing to the often observed female advantage in certain social cognition tasks. While this scenario is somewhat speculative, it demonstrates how hemizygous inheritance opens pathways for selection that have no analog on autosomes.

In conclusion, hemizygosity of X-linked cognition genes accelerates evolutionary responses: beneficial changes accumulate faster and detrimental changes are more starkly removed, sculpting the landscape of X-linked functions in the brain. This likely underlies why the X chromosome today is a mosaic of highly conserved genes critical for basic brain function (due to strong purifying selection) and genes that show signs of rapid change or positive selection related to reproductive or neural phenotypes (due to efficient adaptive evolution). The legacy of hemizygosity is evident in our genomes: the disproportionate share of X-linked disorders of cognition suggests that any loss of function on the X has largely been cleared of common variation (only new or rare mutations cause disease), whereas beneficial alleles like those potentially involved in human cognitive specializations have been swept to fixation. As we continue to decode the evolutionary story of the human brain, the X chromosome stands out as both a guardian of neural development (maintaining vital genes) and a driver of innovation (enabling quick adoption of new advantageous traits). It is a testament to the unique evolutionary forces at play when half the population carries two copies of a gene and the other half carries only one.

FAQ#

Q 1. Why does the X chromosome carry so many intelligence-related disorders?
A. Any harmful recessive mutation on the X is fully expressed in hemizygous males, so critical neural genes are over-represented in X-linked disease catalogs; females partially escape via mosaicism.

Q 2. Did FOXP2 undergo stronger selection than TENM1?
A. No—haplotype statistics show TENM1’s LRH score (>15) dwarfs FOXP2’s |iHS| (~2); FOXP2’s fixed substitutions are ancient, whereas TENM1’s sweep is <50 kya and still incomplete.

Q 3. What is X-inactivation escape and why does it matter for cognition?
A. Roughly 15–25 % of X genes remain active on the “inactive” X in females, doubling expression relative to males; many escapees (e.g., DDX3X) regulate neural progenitors, influencing sex-biased traits and disorders.

Q 4. How can an X-linked mutation harm females but spare males (PCDH19 epilepsy)?
A. Heterozygous females are cellular mosaics—wild-type and mutant neurons intermingle, disrupting network formation; males, with uniform mutant or wild-type neurons, avoid this “cellular interference.”

Sources#

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