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.
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.
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