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The Human Y chromosome and its role in the developing male nervous system
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. (Elena Jazin)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Recent research demonstrated that besides a role in sex determination and male fertility, the Y chromosome is involved in additional functions including prostate cancer, sex-specific effects on the brain and behaviour, graft-versus-host disease, nociception, aggression and autoimmune diseases. The results presented in this thesis include an analysis of sex-biased genes encoded on the X and Y chromosomes of rodents. Expression data from six different somatic tissues was analyzed and we found that the X chromosome is enriched in female biased genes and depleted of male biased ones. The second study described copy number variation (CNV) patterns in a world-wide collection of human Y chromosome samples. Contrary to expectations, duplications and not deletions were the most frequent variations. We also discovered novel CNV patterns of which some were significantly overrepresented in specific haplogroups. A substantial part of the thesis focuses on analysis of spatial expression of two Y-encoded brain-specific genes, namely PCDH11Y and NLGN4Y. The perhaps most surprising discovery was the observation that X and Y transcripts of both gene pairs are mostly expressed in different cells in human spinal cord and medulla oblongata. Also, we detected spatial expression differences for the PCDH11X gene in spinal cord. The main focus of the spatial investigations was to uncover genetically coded sexual differences in expression during early development of human central nervous system (CNS). Also, investigations of the expression profiles for 13 X and Y homolog gene pairs in human CNS, adult brain, testes and still-born chimpanzee brain samples were included. Contrary to previous studies, we found only three X-encoded genes from the 13 X/Y homologous gene pairs studied that exhibit female-bias. We also describe six novel non-coding RNAs encoded in the human MSY, some of which are polyadenylated and with conserved expression in chimpanzee brain. The description of dimorphic cellular expression patterns of X- and Y-linked genes should boost the interest in the human specific gene PCDH11Y, and draw attention to other Y-encoded genes expressed in the brain during development. This may help to elucidate the role of the Y chromosome in sex differences during early CNS development in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1285
Keyword [en]
MSY, sex differences, CNV, SNP, palindrome, palindromes, gr/gr duplication, gr/gr deletion, b2/b3 deletion, b2/b3 duplication, blue-grey duplication, blue-grey like duplication, IR2, U3, STS, AZFa, AZFb, AZFc, Olivary nucleus, Medulla oblongata, spinal cord, white matter, Affymetrix 6.0, embryo, embryonal, haplogroup, haplogroups, R1a, R1b, R-M207, E-M96, I-M170, J-M304, G-M201, Ashkenazi, Bolivian, Chinese, SNP array, padlock probing, AMY-tree
National Category
Genetics
Research subject
Biology with specialization in Animal Development
Identifiers
URN: urn:nbn:se:uu:diva-261789ISBN: 978-91-554-9331-8 (print)OAI: oai:DiVA.org:uu-261789DiVA: diva2:851233
Public defence
2015-10-23, Zootissalen (EBC 01.01006), Evolutionsbiologiskt centrum, EBC, Villavägen 9, Uppsala, 13:15 (English)
Opponent
Funder
Swedish Research Council, K2012-61X-22089-01-3
Note

chinese, finnish, norwegian, schizophrenia, bipolar, bipolar disorder, msy, male specific region Y, PAR1, PAR2, pseudoautosomal, male-biased, female-biased, male biased, female biased, ashkenazi population, structure, variants, YHRD, Elena Jazin, Björn Reinius, Per Ahlberg, brain, hjärna, CNS, central nervous system, IR2, inverted repeat 2, isodicentric, genetics, genetik, padlock, rolling circle, amplification, PCR, sY1191, sY1291, STS, DDX3Y, DAZ, AZFa, AZFb, AZFc, AZF, Repping, haplogroup J, rearrangements, DE-M145, I-M170, E-M96, Q-M242, R-M207, O-M175, G-M201, D-M174, C-M130, NO-M214, N-M231, poland

Available from: 2015-10-02 Created: 2015-09-04 Last updated: 2015-10-23Bibliographically approved
List of papers
1. Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome
Open this publication in new window or tab >>Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome
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2012 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, 607- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse.

RESULTS:

Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes.

CONCLUSION:

Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.

Keyword
X-chromosome, Sex chromosome; Somatic; Gene expression; Sexual antagonism; Sexual selection; Gender; Sex-bias; Female-bias; Male-bias; Sexual dimorphism; Dosage compensation; X-inactivation; Escape; Feminisation; Masculinisation; De-masculinisation; Microarray; Non-coding RNA; lncRNA; Tmem29; Kdm5c; Xist
National Category
Genetics
Research subject
Genetics; Biology with specialization in Animal Development; Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-191574 (URN)10.1186/1471-2164-13-607 (DOI)000312959100001 ()
Available from: 2013-01-11 Created: 2013-01-10 Last updated: 2017-12-06Bibliographically approved
2. Microarray Analysis of Copy Number Variants on the Human Y Chromosome Reveals Novel and Frequent Duplications Overrepresented in Specific Haplogroups
Open this publication in new window or tab >>Microarray Analysis of Copy Number Variants on the Human Y Chromosome Reveals Novel and Frequent Duplications Overrepresented in Specific Haplogroups
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, e0137223Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The human Y chromosome is almost always excluded from genome-wide investigations of copy number variants (CNVs) due to its highly repetitive structure. This chromosome should not be forgotten, not only for its well-known relevance in male fertility, but also for its involvement in clinical phenotypes such as cancers, heart failure and sex specific effects on brain and behaviour.

RESULTS:

We analysed Y chromosome data from Affymetrix 6.0 SNP arrays and found that the signal intensities for most of 8179 SNP/CN probes in the male specific region (MSY) discriminated between a male, background signals in a female and an isodicentric male containing a large deletion of the q-arm and a duplication of the p-arm of the Y chromosome. Therefore, this SNP/CN platform is suitable for identification of gain and loss of Y chromosome sequences. In a set of 1718 males, we found 25 different CNV patterns, many of which are novel. We confirmed some of these variants by PCR or qPCR. The total frequency of individuals with CNVs was 14.7%, including 9.5% with duplications, 4.5% with deletions and 0.7% exhibiting both. Hence, a novel observation is that the frequency of duplications was more than twice the frequency of deletions. Another striking result was that 10 of the 25 detected variants were significantly overrepresented in one or more haplogroups, demonstrating the importance to control for haplogroups in genome-wide investigations to avoid stratification. NO-M214(xM175) individuals presented the highest percentage (95%) of CNVs. If they were not counted, 12.4% of the rest included CNVs, and the difference between duplications (8.9%) and deletions (2.8%) was even larger.

CONCLUSIONS:

Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome. Future association studies of the full spectrum of Y chromosome variants will demonstrate the potential involvement of gain or loss of Y chromosome sequence in different human phenotypes.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-261976 (URN)10.1371/journal.pone.0137223 (DOI)000360435500068 ()26322892 (PubMedID)
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved
3. Cellular sexual dimorphism of X and Y homolog gene expression in human central nervous system during early male development
Open this publication in new window or tab >>Cellular sexual dimorphism of X and Y homolog gene expression in human central nervous system during early male development
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Renewed attention has been directed to the functions of the Y chromosome in the central nervous system during early human male development, due to the recent proposed involvement in neurodevelopmental diseases. PCDH11Y and NLGN4Y are of special interest, because they belong to gene families involved in cell fate determination and formation of dendrites and axons. We used RNA sequencing, immunocytochemistry and a padlock probing and rolling circle amplification strategy, to distinguish the expression of X and Y homologs in situ in human brain for the first time. To minimize influence of androgens on the sex differences in the brain, we focused our investigation to human embryos at 8-11 weeks post gestation. The most striking result was that the Y encoded genes are expressed in specific and heterogeneous cellular neural subpopulations that rarely express the X homologs. Our findings suggest that a male-specific cellular network may exist in the embryonic central nervous system.

Keyword
y chromosome, PCDH11Y, PCDH11X, NLGN4Y, NLGN4Y, spinal cord, medulla oblongata, fetal, embryo, early development, 8 week pcw, male, female, sex differences, expression, cellular, cellular networks, male specific, male specific cellular networks, neun, actb, sox10, olig2, white matter, eppendymal layer, olivary nucleus, padlock, padlock probing, in situ hybridization, rolling circle amplification
National Category
Neurosciences Developmental Biology
Research subject
Biology with specialization in Molecular Biology; Neurology; Biology with specialization in Evolutionary Organismal Biology
Identifiers
urn:nbn:se:uu:diva-261683 (URN)
Funder
Swedish Research Council, K2012-61X-22089-01-3
Available from: 2015-09-02 Created: 2015-09-02 Last updated: 2015-10-05
4. Sex differences in expression of X and Y genes during development of the human and chimpanzee central nervous system
Open this publication in new window or tab >>Sex differences in expression of X and Y genes during development of the human and chimpanzee central nervous system
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Global microarray gene expression analyses have demonstrated that female and male embryos differ in terms of gene expression during neurodevelopment. In particular, before sexual maturation of the gonads, the differences concentrate on the expression of genes encoded on the X and Y chromosomes. Precision measurements of expression levels of X and Y gametolog genes have been hampered by the high sequence identity between each pair of X and Y homologs. To address this issue, as well as to interrogate genome-wide for differences in expression during early human development, we combined high resolution RNA sequencing technology with a nested qPCR strategy to analyse CNS samples from 8-11 weeks old human embryos. We found that, besides genes known to bind oestrogen and androgen receptors, the largest biased group consisted of genes encoded on the Y chromosome. This list of Y chromosome genes included fifteen previously known MSY genes, thirteen of which have known gametologs encoded on the X chromosome. In addition, we found 6 novel non-annotated long non-coding RNAs, four of which are poly-adenylated and show conserved expression patterns in the brain of a chimpanzee male new born. Among X-encoded genes, we found that besides XIST, only seven genes had significantly higher expression in female embryos. Of these, only three, including ZFX, KDM5C, and NLGN4X have known gametologs encoded on the Y chromosome.

In summary, the contribution of Y chromosome gene expression during early CNS development is larger than previously anticipated, while the amount of X-encoded gametolog genes that presented female-bias was limited. These results clearly indicate that the time is ripe to conduct functional studies directed to understand the male specific function of Y genes during early CNS development.

Keyword
y chromosome, male, female, fetal, embryo, human, spinal cord, medulla oblongata, expression, sex biased, sex differences, conserved, chimpanzee, chimp, brain, XY, X chromosome, KDM5C, KDM5D, UTX, UTY, PCDH11Y, PCDH11X; NLGN4Y, NLGN4X, non-coding RNA, ncRNA, lincRNA, RNAseq, RNA sequencing, polyA, qPCR, Jazin, Johansson, könsskillnader
National Category
Neurosciences Developmental Biology
Research subject
Biology with specialization in Molecular Biology; Neurology
Identifiers
urn:nbn:se:uu:diva-261685 (URN)
Funder
Swedish Research Council, K2012-61X-22089-01-3
Available from: 2015-09-04 Created: 2015-09-02 Last updated: 2015-10-05

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