Sex Biased Gene Expression Profiling of Human Brains at Major Developmental Stages

There are many differences in brain structure and function between males and females. However, how these differences were manifested during development and maintained through adulthood are still unclear. Here we present a time series analyses of genome-wide transcription profiles of the human brain, and we identified genes showing sex biased expression at major developmental stages (prenatal time, early childhood, puberty time and adulthood). We observed a great number of genes (>2,000 genes) showing between-sex expression divergence at all developmental stages with the greatest number (4,164 genes) at puberty time. However, there are little overlap of sex-biased genes among the major developmental stages, an indication of dynamic expression regulation of the sex-biased genes in the brain during development. Notably, the male biased genes are highly enriched for genes involved in neurological and psychiatric disorders like schizophrenia, bipolar disorder, Alzheimer’s disease and autism, while no such pattern was seen for the female-biased genes, suggesting that the differences in brain disorder susceptibility between males and females are likely rooted from the sex-biased gene expression regulation during brain development. Collectively, these analyses reveal an important role of sex biased genes in brain development and neurodevelopmental disorders.

[1]  G. Tocchini-Valentini,et al.  Mice lacking the Parkinson's related GPR37/PAEL receptor show non‐motor behavioral phenotypes: age and gender effect , 2013, Genes, brain, and behavior.

[2]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[3]  S. Pääbo,et al.  Transcriptome analysis of male–female differences in prefrontal cortical development , 2009, Molecular Psychiatry.

[4]  E. Banks,et al.  De novo mutations in schizophrenia implicate synaptic networks , 2014, Nature.

[5]  Neda Jahanshad,et al.  Whole-genome analyses of whole-brain data: working within an expanded search space , 2014, Nature Neuroscience.

[6]  J. Parsch,et al.  Molecular evolution of sex-biased genes in Drosophila. , 2004, Molecular biology and evolution.

[7]  M. Dubois‐Dauphin,et al.  Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. , 2005, Developmental biology.

[8]  C. Sisk,et al.  The neural basis of puberty and adolescence , 2004, Nature Neuroscience.

[9]  Y. Gilad,et al.  An Evolutionarily Conserved Sexual Signature in the Primate Brain , 2008, PLoS genetics.

[10]  G. Tocchini-Valentini,et al.  Altered dopamine signaling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/parkin-associated endothelin-like receptor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Abbott,et al.  Sex differences in disease genetics: evidence, evolution, and detection. , 2014, Trends in genetics : TIG.

[12]  R. Pomerantz,et al.  Cell-cell fusion and internalization of the CNS-based, HIV-1 co-receptor, APJ. , 2003, Virology.

[13]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[14]  M. Mehler,et al.  Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. , 2010, Progress in brain research.

[15]  Ivo D Dinov,et al.  Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity. , 2011, Cerebral cortex.

[16]  Alex R. Smith,et al.  Sex differences in the structural connectome of the human brain , 2013, Proceedings of the National Academy of Sciences.

[17]  N. Benvenisty,et al.  Sex-dependent gene expression in human pluripotent stem cells. , 2014, Cell reports.

[18]  H. Kennedy,et al.  Making bigger brains–the evolution of neural-progenitor-cell division , 2008, Journal of Cell Science.

[19]  Jay N. Giedd,et al.  The influence of puberty on subcortical brain development , 2014, NeuroImage.

[20]  S. Blakemore,et al.  The role of puberty in the developing adolescent brain , 2010, Human brain mapping.

[21]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[22]  A. Ramasamy,et al.  Widespread sex differences in gene expression and splicing in the adult human brain , 2013, Nature Communications.

[23]  Yaqin Yu,et al.  Sex-biased methylome and transcriptome in human prefrontal cortex. , 2014, Human molecular genetics.

[24]  Daniele Merico,et al.  Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder , 2014, Nature Genetics.

[25]  P. Kappeler.  Sexual selection in primates: New and comparative perspectives , 2004 .

[26]  J. Mank,et al.  Ontogenetic complexity of sexual dimorphism and sex-specific selection. , 2010, Molecular biology and evolution.

[27]  Min Liu,et al.  Repeated electroacupuncture attenuating of apelin expression and function in the rostral ventrolateral medulla in stress-induced hypertensive rats , 2013, Brain Research Bulletin.

[28]  M. Nachman,et al.  Rates of protein evolution are positively correlated with developmental timing of expression during mouse spermatogenesis. , 2005, Molecular biology and evolution.

[29]  C. Woods,et al.  What primary microcephaly can tell us about brain growth. , 2006, Trends in molecular medicine.

[30]  B. Reinius,et al.  Prenatal sex differences in the human brain , 2009, Molecular Psychiatry.

[31]  Todd F. DeLuca,et al.  Genotator: A disease-agnostic tool for genetic annotation of disease , 2010, BMC Medical Genomics.

[32]  P. Grant,et al.  Sex differences in histone modifications in the neonatal mouse brain , 2009, Epigenetics.

[33]  Hans Ellegren,et al.  The evolution of sex-biased genes and sex-biased gene expression , 2007, Nature Reviews Genetics.

[34]  Sven Bergmann,et al.  A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. , 2014, American journal of human genetics.

[35]  S. Pääbo,et al.  Parallel Patterns of Evolution in the Genomes and Transcriptomes of Humans and Chimpanzees , 2005, Science.

[36]  L. Cahill,et al.  Sex differences in molecular neuroscience: from fruit flies to humans , 2010, Nature Reviews Neuroscience.

[37]  F. Schuit,et al.  Transcription of Genes Encoding Synaptic Vesicle Proteins in Human Neural Stem Cells , 2008, Journal of Biological Chemistry.

[38]  Zachary S. Lorsch,et al.  Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress , 2015, The Journal of Neuroscience.

[39]  A. Cutter,et al.  Sexual and temporal dynamics of molecular evolution in C. elegans development. , 2005, Molecular biology and evolution.

[40]  Peter W. Harrison,et al.  The Ontogeny and Evolution of Sex-Biased Gene Expression in Drosophila melanogaster , 2014, Molecular biology and evolution.

[41]  S. DeKosky,et al.  Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease , 2009, Molecular Psychiatry.

[42]  S. Lolait,et al.  The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. , 2013, The Journal of endocrinology.

[43]  C. Lebel,et al.  Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood , 2011, The Journal of Neuroscience.

[44]  L. Cahill.  Why sex matters for neuroscience , 2006, Nature Reviews Neuroscience.