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Sex differences in expression of X and Y genes during development of the human and chimpanzee central nervous system
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. (Jazin)
(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 [en]
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
URN: urn:nbn:se:uu:diva-261685OAI: oai:DiVA.org:uu-261685DiVA: diva2:851232
Swedish Research Council, K2012-61X-22089-01-3
Available from: 2015-09-04 Created: 2015-09-02 Last updated: 2015-10-05
In thesis
1. The Human Y chromosome and its role in the developing male nervous system
Open this publication in new window or tab >>The Human Y chromosome and its role in the developing male nervous system
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1285
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
Research subject
Biology with specialization in Animal Development
urn:nbn:se:uu:diva-261789 (URN)978-91-554-9331-8 (ISBN)
Public defence
2015-10-23, Zootissalen (EBC 01.01006), Evolutionsbiologiskt centrum, EBC, Villavägen 9, Uppsala, 13:15 (English)
Swedish Research Council, K2012-61X-22089-01-3

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

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