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Thread: Estimating the role of the Y Chromosome in brain function

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    Satyavrata Maciamo's Avatar
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    Question Estimating the role of the Y Chromosome in brain function

    IronSide posted a link this fascinating study in another thread: The Role of the Y Chromosome in Brain Function, by Kopsida et al. (2009)

    I have selected some interesting excerpts and commented on them below.


    "In humans the X chromosome is ~155Mb in size and houses ~1500 genes, whereas the Y chromosome is just ~60Mb in size and houses ~350 genes, many of which are pseudogenes."

    This is the highest estimate of Y-DNA genes I have seen so far.

    "The human Y chromosome, like the autosomes and the X chromosome, consists of a short (Yp) and a long (Yq) arm (~11.5Mb and ~48.5Mb respectively) separated by a centromere. At either end of the chromosome are regions which can recombine during meiosis with their equivalents on the X chromosome; as this recombinatory behaviour is reminiscent of that of the autosomes, these terminal domains are designated pseudoautosomal regions (or PARs). PAR1 is located on Yp, and contains ~10 genes. PAR2 is located on Yq and contains ~15 genes. Together, the PARs comprise ~5% of the basepair content of the chromosome. The remaining 95% of the chromosome constitutes the non-recombining region (NRY) referred to earlier (also known as the male-specific region or MSY). Currently, 156 transcription units (distinct regions of DNA which are transcribed into RNA) have been found on human NRY, 78 of which are protein-coding (27 distinct proteins or protein families). Genes on NRY fall into two categories: those that are expressed throughout the body (including the brain) and those that are expressed mainly, or exclusively, in testes and are likely to affect testis development and/or spermatogenesis. Microarray analysis comparing gene expression in post mortem male and female brains has suggested that ~20% of NRY-linked genes are expressed in this tissue, though this figure is probably an underestimate given sensitivity issues and the possibility of cross-hybridisation with closely related X-linked sequences. The human NRY comprises three different types of euchromatic sequences (i.e. those which are likely to be transcribed) X-transposed sequences which have ~99% homology to equivalent regions on the X chromosome (although importantly they do not recombine) and are characterised by low gene and high repeat density ii) ampliconic sequences which exhibit a high degree of similarity (99.9%) to other NRY sequences and include genes mainly expressed in testes; these regions are usually large allowing for gene conversion, a phenomenon of non-reciprocal recombination between Y chromosome sequences that has resulted in eight large palindromes in the ampliconic sequences iii) X-degenerate sequences, which include single-copy genes and pseudogenes with an X chromosome homologue. X-degenerate genes are generally ubiquitously expressed - indeed, it is noteworthy that no ubiquitously expressed gene has yet been found amongst the other two types of sequence."

    So 5% of Y-DNA genes do recombine with X-DNA, while among the 95% of DNA in the non-recombining region, the euchromatic sequences have 99% homology on the X chromosome. In other words, most of the genes on the Y chromosome are not related to male fertility as they either recombine with the X chromosome or are homologous to the functions on X chromosome.
    Out of 350 Y-DNA genes identified to date, only about a dozen are known to be involved in testis development and parthenogenesis. Most genes have yet unknown functions, probably because researchers assumed that the Y chromosome was primarily involved in male fertility, and they failed to investigate deeply enough other parts of sexual differentiation, notably in the brain.


    "Although SRY is chiefly expressed in the testes, it is also expressed to some extent in other tissues including heart, liver and kidney, and certain brain regions. Hence, besides influencing male-specific traits indirectly, theoretically it could influence neurodevelopment and brain function in a direct cell-autonomous manner. In humans, SRY expression has been described in the medial rostral hypothalamus, frontal and temporal cortex."

    SRY is only one of the 350 Y-DNA genes, and even though it is heavily involved in testes development, it also affects brain masculinisation in crucial brain regions and
    adrenal tissue involved in the production of sex hormones.

    "The expression of Sry in brain and adrenal tissue rich in catecholaminergic cells led Milsted and colleagues to test whether the protein might be influencing the expression of genes important in catecholamine biosynthesis. Their in vitro assays showed that Sry appeared to bind at the promoter region of the gene encoding tyrosine hydroxylase (the rate-limiting enzyme in dopamine biosythesis) to enhance its transcription. These data suggest that one way in which Sry acts to confer maleness is through affecting development of the dopaminergic system; they further imply that SRY (dys)function may contribute towards the male bias in certain conditions with a known catecholaminergic basis e.g. ADHD, addiction and hypertension."

    If SRY plays a role in ADHD, addictions and hypertension, it may be worthwhile investigating if men belonged to haplogroups with SRY mutations (E, R1a1, R1b-SRY2627) have higher or lower risks for those conditions.


    "A second sex-linked gene that has relatively well-defined effects on brain and behaviour is Sts, encoding the enzyme steroid sulfatase. Steroid sulfatase is responsible for the desulfation of various neuroactive steroids, notably of the GABAergic modulator dehydroepiandrosterone sulphate (DHEAS) to DHEA. The enzyme is expressed most highly during embryogenesis in the placenta and the liver and in the cortex, thalamus and hindbrain. In mice, Sts is the only known PAR gene, and is therefore expressed from both the X and Y chromosomes.

    Aggression in mice is highly sexually dimorphic, with males exhibiting a far greater tendency to attack their conspecifics. A genetic study aiming to identify and characterise the Y chromosomal correlates of this sexual dimorphism localised the underlying region to the Y-PAR. As the only known PAR gene, Sts immediately became an excellent genetic candidate for these effects on aggression. Follow-up pharmacological studies targeting the steroid sulfatase axis seem to confirm a role for the enzyme in the brain processes underlying aggression. Besides influencing aggression, parallel genetic and pharmacological studies have demonstrated that steroid sulfatase may influence attention and impulsivity in mice.
    [...]

    In man, subjects with deletions of the STS gene, or inactivating mutations within it, and thus presenting with the disorder X-linked ichthyosis, appear to display heightened vulnerability to autism and to predominantly-inattentive subtype ADHD. Moreover, the STS gene has been associated with ADHD, suggesting that steroid sulfatase may underlie attentional processes in both rodents and humans.
    "

    There we go. We already have two genes on the Y chromosome with confirmed cognitive and behavioural effects: SRY and STS. STS is associated with male aggression. Mutations in STS are linked to heightened vulnerability to autism and to predominantly-inattentive subtype ADHD.


    "SRY and STS are perhaps the best characterised genes resident on the Y chromosome in terms of their brain and behavioural functions, although it must be acknowledged that in many respects our knowledge about the role of these two genes is lacking. However, there are several other Y-linked genes in NRY, which, in that they are expressed in the brain, could also potentially contribute towards neural sexual differentiation. Xu and colleagues described six NRY genes (Dby (now Ddx3y) Ube1y, Smcy (now Kdm5d), Eif2s3y, Uty, and Usp9y) which were expressed at one or more developmental stages in male and 40,XY female mouse brain (the latter indicating a lack of requirement for testicular secretions). Of the genes analysed, all had an X-linked homologue, which was definitively known to escape X-inactivation in three cases (Smcx/Kdm5c, Utx and Eif2s3x)."

    A mutation in the USP9Y gene defines haplogroups R1b-M222, the most common Irish subclade of R1b, which expanded only in the last 2000 years and managed to replace about 30% of other lineages in the country. The only other haplogroups or subclade which has a mutation in the USP9Y gene are haplogroups N1c and T (defining each time the whole haplogroup).

    Haplogroups J2b and R are each defined by a mutation is the UTY gene. So far no mutations in the other Y-chromosomal genes mentioned above are known to define any haplogroup or major subclade. The question is how exactly do these mutations defining haplogroups J2b, N1c, R, R1b-M222 and T affect cognitive functions and behaviour? Here is maybe a clue.


    "A further intriguing possibility when considering the genetic mechanisms underlying sexually dimorphic brain phenotypes, is that X and Y-linked homologues, in addition to being expressed at different levels, are expressed at different developmental stages and/or in different brain regions. Indeed, recent work by Xu et al. has shown that the paralogues Utx and Uty are differentially expressed in the paraventricular nucleus of the hypothalamus (high Uty expression) and in the amygdala (high Utx expression), possibly as a consequence of differential epigenetic marks. To our knowledge, no comprehensive survey comparing the relative spatiotemporal expression dynamics of X and Y homologues has yet been performed, although it has been shown that that there is some consistency in the expression patterns of Eif2s3y and Eif2s3x, with highest expression of both in the thalamus, hypothalamus, hippocampus and cerebellum."

    Haplogroup R is defined by a mutation in this UTY gene. This mutation, if it affects the paraventricular nucleus ofhypothalamus, would probably alter the secretion of hormones one way or another. This could include oxytocin (bonding hormone) or vasopressin (social behavior, sexual motivation and pair bonding) and ACTH (response to stress). If, on the other hand, it affects the UTX homologue, it could have implications for a variety of cognitive functions like memory, decision-making, and emotional reactions (including management of fear). When we know that haplogroup R is associated with the largest male expansion and conquest or land that has ever been known in human (pre)history, namely the Indo-European migrations, it wouldn't be surprising that haplogroup R men carrying this mutation would have had slightly different brains that allowed them to manage their fears and other emotions in a different way than other men.

    But this is just the beginning of research on how Y-chromosomal mutations may affect brain functions. Eif2s3y is a mouse gene with no human orthologue, but mutations in the Eif2s3y gene have been shown to alter functions in the hippocampus and the cerebellum in mice. In humans, the former would affect memory, while those in the cerebellum could be involved in a variety of cognitive aspects from motor control to attention, language as well as in regulating fear and pleasure responses.

    The study mentions that the ZFY gene appears to be expressed in the hypothalamus and cortex of adult humans.

    "One X-Y homologous gene pair which has received a lot of interest regarding its role in neurodevelopment is PCDH11X/Y. The homologous genes are located within a hominid-specific region of the sex chromosomes (Xq21.3 and Xp11.2), and encode members of the protocadherin superfamily responsible for cell-cell interactions during development of the central nervous system. Not only are PCDH11X and its Y counterpart structurally different (and therefore possibly functionally distinct) but they have been shown to exhibit differential expression patterns, most likely because the two genes possess different promoter regions. In the brain, transcripts from both PCDH11X and PCDH11Y are present most highly in the cortex, and also in several subregions including the amygdala, caudate nucleus, hippocampus and thalamus. Interestingly, PCDH11X seems to be the preferential transcript in the cerebellum; in the heart, transcripts are predominantly from PCDH11X, whereas in the kidney, liver, muscle and testis transcripts come mainly from PCDH11Y. Together these data indicate that PCDH11X/Y genes may play key modulatory roles in the sexual differentiation of a wide variety of organs (including the brain) in hominid mammals."

    This time a Y-chromosomal gene (PCDH11Y) is expressed in many parts of the brain. The amygdala has been mentioned above. The caudate nucleus is involved in motor functions, procedural learning, associative learning and inhibitory control of action. The hippocampus plays a major role in memory. The thalamus is the relay centre for sensory and motor signals to the cerebral cortex, but also plays a tole in the regulation of consciousness, sleep, and alertness. This kind of wide-ranging sexual differentiation of the brain would explain why boys and girls think and behave differently long before puberty and the production of sex hormones.

    I am certain that the function of more Y-DNA genes will be known, and that the all the major Y-DNA mutations will be discovered through full Y-DNA sequencing, we will see a correlation between the fast expansion of some Y-DNA lineages and mutations affecting male cognition and behaviour.
    Last edited by Maciamo; 29-03-17 at 12:59.
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    I encourage you to read the whole last section: Y chromosome effects on vulnerability to neuropsychiatric disorders. The authors explain that ADHD and schizophrenia are more common among men than women, and that female schizophrenic patients have a significantly better course of illness and better global functioning than male patients. They believe that the PCDH11Y gene could be involved in this sex bias.

    "With regard to specific candidate genes for the male-bias in neuropsychiatric disorders, numerous factors make the PCDH11Y gene an attractive proposition. Firstly, it appears to be expressed in males in a highly regulated and spatiotemporally dynamic manner and is involved in synapse formation and neuronal path finding in the brain, processes which go awry in a number of common male-biased mental conditions. The fact that PCDH11Y is not expressed (or only weakly expressed) in the cerebellum, whereas it is expressed elsewhere in the brain, could potentially explain why males are especially vulnerable to disorders with known cerebellar pathology (e.g. ADHD and autism). Finally, as mentioned previously, PCDH11Y is specific to the hominid lineages and is absent in non-human primates such as chimpanzees and gorillas; moreover, the gene has shown accelerated sequence change in the hominid lineage. For this reason, it has been proposed, most vociferously by Timothy Crow and colleagues, that aberrant expression of the protein encoded by PCDH11Y could predispose males to disorders of human-specific functions such as language (thought to be a correlate of cerebral asymmetry), theory of mind and problem-solving flexibility. There is convincing evidence that these types of human-specific function are impaired in a number of male-biased disorders, notably schizophrenia and autism."


    "A second candidate gene that could potentially influence neuropsychiatric phenotypes is NLGN4Y, the Y homologue of NLGN4X. These genes encode cell adhesion molecules which interact with β-neurexins at the postsynaptic membrane during the process of synaptogenesis. Early findings that mutations in NLGN4X were present in families with mental retardation and autism spectrum disorders suggested a possible causal link between the disorders and the gene mutation. The results of subsequent studies have suggested that, if mutations in NLGN4X are pathogenic, they are likely to be rare, and are not likely to explain the majority of cases of autism."

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    2 members found this post helpful.
    I have found that yet important haplogroups or subclades are defined by a gene-altering polymorphisms.

    Haplogroup I1 is defined by over 300 mutations. The best known is M253 (rs9341296), which affects the DDX3Y gene, linked to male fertility. I1 is also defined by other gene-latering mutations, such as M307.1 (rs13447354) altering the EIF1AY gene, as well as P30 and P40 in the ARSDP1 pseudogene.

    I1-M227, a mostly Polish branch, corresponds to rs9341274 in the UTY gene.

    I1-P109, a large branch of the Nordic haplogroup I1-L22, corresponds to i4000146, which is also in the UTY gene.


    Haplogroup I2 is defined among others by M438/P215/S31 (rs17307294), a mutation in the NLGN4Y (Neuroligin 4, Y-Linked), which affects neuroligin, a membrane protein that mediates the formation and maintenance of synapses between neurons.

    Haplogroup I2a1a-M26 (rs2032629) has a mutation altering the KDM5D gene, encoding an enzyme related to the immune system.


    Haplogroup J1 is defined by 185 SNPs, including M267 (rs9341313) in the EIF1AY gene.


    Over 90% of people belonging to haplogroup J2 belong to J2a1a-L26, also defined by the L27 mutation (rs34126399), which alters the GAPDHP17 pseudogene.


    Haplogroup J2b is defined by189 mutations, including M221 (rs2032667), which is found in the UTY gene.


    Haplogroup N1c is defined by 57 mutations, the most famous being Tat/M46/Page70 (rs34442126), in the USP9Y gene.


    Haplogroup R is defined by 56 mutations. I already mentioned the M207 mutation in the UTY gene, but there is also M306 (rs1558843) in the EIF1AY gene.

    Haplogroup R1b1b2, the branch of R1b associated with the Proto-Indo-European expansion, is defined by 105 mutations, including M269 (rs9786153) in the EIF1AY gene. Its main branch commonly known as R1b-L23 is also defined by L49 (rs9786142) affecting the ZFY gene, which like SRY may be a sex-determining gene.


    Most Y-DNA mutations occur in the non-coding intergenic regions. There are, however, quite a few SNPs that correspond to gene-altering mutations, but they aren't clearly reported as such, like the SRY mutations. One has to browse through all the SNPs one by one on SNPedia to verify if they are located in a gene, which is very time consuming.
    Last edited by Maciamo; 29-03-17 at 12:09.

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    2 members found this post helpful.
    The study by Kopsida et al. mentioned that mutations in the PCDH11Y could be linked to ADHD and schizophrenia. I searched SNPedia for mutations in this gene and found five mutations associated with haplogroups.

    - L459 (rs141984805), another SNP defining haplogroup R1b-L21
    - V89/PF1359 (rs182668234) defining haplogroup A1b1b2b3~ (found among the Khoisan, Ethiopians and Nilotic people)
    - V93 (rs187262945) defining haplogroup B2a (found among the Mbuti pygmies)
    - V98 (rs185597746) defining haplogroup A1b1b2b3~
    - V174 (rs2563344) defining haplogroup A1

    Interestingly most of these mutations are found in Sub-Saharan Africans, and especially among old hunter-gatherer tribes (San, Pygmies) rather than farmers. It had been postulated that ADHD was actually beneficial for hunter-gatherers, so it is not impossible that those mutations do increase the propensity to have ADHD.

    It is extremely doubtful that the mutation in R1b-L21 also increases the risk of ADHD and even less schizophrenia. Mutations could work either way, so this one might possibly be protective, or have no effect at all on these traits.

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    So basically. If a man were to have Haplogroup R1b and mtdna I, does that mean they would have the most superior genetics? (not really)

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    2 members found this post helpful.
    Quote Originally Posted by Redmayne View Post
    So basically. If a man were to have Haplogroup R1b and mtdna I, does that mean they would have the most superior genetics? (not really)
    It takes screwed up brain to even consider this. And of course lack of basic genetic knowledge, because they both constitute only 2% of whole genome.
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    Regular Member Redmayne's Avatar
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    Quote Originally Posted by LeBrok View Post
    It takes screwed up brain to even consider this. And of course lack of basic genetic knowledge, because they both constitute only 2% of whole genome.
    Thank-you LeBrok, that was what I was implying.

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    Quote Originally Posted by Redmayne View Post
    So basically. If a man were to have Haplogroup R1b and mtdna I, does that mean they would have the most superior genetics? (not really)
    Of course not. Most genes are on other chromosomes than the Y. I am listing the mutations on the Y chromosome influencing brain functions, but there is no way at present to know if the effect of these mutations are positive, neutral or negative. In any case, there are plenty of other haplogroups here than R1b.

    MtDNA is not even on a chromosome and is almost only in the cell's energy production. Why do you even mention mtDNA in this thread? Where did you read that mtDNA I is superior, and in what regard?

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    This was in response to the other post, in which I posted about I2 men apparently being lesser intelligent; which I had doubted. But I made a response here. I wasn't claiming that mtdna I was the most superior. It's that you said in your other post, that countries might be doomed due to their genetics. To which I responded here with a jest.

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    Regular Member Redmayne's Avatar
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    Quote Originally Posted by Maciamo View Post
    Of course not. Most genes are on other chromosomes than the Y. I am listing the mutations on the Y chromosome influencing brain functions, but there is no way at present to know if the effect of these mutations are positive, neutral or negative. In any case, there are plenty of other haplogroups here than R1b.

    MtDNA is not even on a chromosome and is almost only in the cell's energy production. Why do you even mention mtDNA in this thread? Where did you read that mtDNA I is superior, and in what regard?
    If I am not mistaken. Did you not once claim on your website; that haplogroup C and haplogroups I1 or I2 (whichever) had more chances of infertility? Could have sworn I read somewhere about that. But most of your postings about infertility were in regard the mtdna T, I believe.

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    Quote Originally Posted by Redmayne View Post
    If I am not mistaken. Did you not once claim on your website; that haplogroup C and haplogroups I1 or I2 (whichever) had more chances of infertility? Could have sworn I read somewhere about that. But most of your postings about infertility were in regard the mtdna T, I believe.
    I wrote here that certain haplogroups are associated with increased or reduced sperm count and/or motility, and hypothesised that one of the reasons why R1b-L11 and subclades became dominant in Western Europe might be better male fertility than the haplogroups it replaced (mostly G2a and I2, with some C1a2). That doesn't mean that men belonging to G2a or I2 are infertile! As an analogy, I can't run as fast as Usain Bolt, but that doesn't make me a paraplegic.

    There was indeed a study that found that men belonging to mtDNA haplogroup T were more likely to suffer from asthenozoospermia (reduced sperm motility). MtDNA influences the energy in cells, and some haplogroups are indeed far more represented among high-level athletes. R0/HV and W are the most represented among power athletes, while H and X correlate with endurance athletes.

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    Have there ever been any studies done in terms of fertility in women?

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    Quote Originally Posted by Redmayne View Post
    This was in response to the other post, in which I posted about I2 men apparently being lesser intelligent; which I had doubted. But I made a response here. I wasn't claiming that mtdna I was the most superior. It's that you said in your other post, that countries might be doomed due to their genetics. To which I responded here with a jest.
    Bill Gates is I2, his IQ is well above Genius level.

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