Analysis of candidate genes for behavioral differences in mice

Keshavarz, Maryam

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Analysis of candidate genes for behavioral differences in mice

Keshavarz, M. (2018). Analysis of candidate genes for behavioral differences in mice. PhD Thesis, Christian-Albrechts-Universität, Kiel.

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アイテムのパーマリンク: https://hdl.handle.net/21.11116/0000-0002-9C25-5 版のパーマリンク: https://hdl.handle.net/21.11116/0000-000D-548B-8

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Keshavarz, Maryam¹, 著者
Tautz, Diethard¹, 学位論文主査

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1Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445635

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要旨: Organisms have evolved different behavioral strategies for better survival and reproduction. However, the genetic basis for such traits remains still as a longstanding fascinating question in evolutionary biology. Mate choice strategy is one of the behavioral traits which can play an important role in the life history of organisms. A previous study had shown that mate choice preference between two populations of the Western house mouse (M. m. domesticus) is influenced by the genetic background of the fathers. Transcriptome analysis in a follow up study revealed an imprinted cluster on Chromosome 7, known as Prader-Willi Syndrome (PWS) region, and also Peg13 on Chromosome 15 as loci that are highly differentiated between mouse populations and therefore have been suggested as potential regions which may regulate this paternal preference in the house mouse. The present thesis was aimed to investigate the functional role of these two imprinted regions in Western house mice behavior.
In the first chapter, I investigated the role of the PWS region on Chromosome 7 through a variety of techniques, including copy number variation analysis, behavioral correlations and transcriptomics. I found that two paternally imprinted tandemly repeated regulatory RNA coding genes (SNORD115 and SNORD116) are of special interest. Their copy number evolves very fast and correlates highly with personality traits between individuals. Further I found that the copy number variation influences the expression of more than 130 genes including genes involved in serotonin regulation, vocalization and bone development. The findings suggest a molecular mechanism for the generation and variability of personality traits in mammals.
The second chapter focuses on the analysis of paternally imprinted Peg13 gene, which has so far not been functionally studied. This gene has been known as non-coding gene, but data from ribosomal profiling analysis revealed that this gene could indeed produce a small peptide and it is not a simple non-coding gene. By using knock out mice, I showed even a partial deletion at 3’ part of Peg13 could significantly change expression of hundreds genes in the brain and could thus influence various mouse behaviors. The phenotypic analysis showed a significant effect on mouse sexual and parental behavior. Since RNAseq analysis from mouse brain development timeline showed that this gene has highest expression in day 12.5, I propose that Peg13 may play important role in preoptic area development with possible direct role in sexual and mate choice behavior.
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Overall the work presented in this thesis describes the first major molecular mechanism underlying mouse personality traits. It presents also the first functional study on the Peg13 gene in mice, which highlights its possible role in mouse brain development and sexual behavior.

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言語: eng - English

日付: 受理: 2018-07出版: 2018-07

出版の状態: 出版

ページ: 155

出版情報: Kiel : Christian-Albrechts-Universität

目次: Contents
Summary ................................................................................................................................................. 9
Zusammenfassung ................................................................................................................................. 11
General introduction ............................................................................................................................. 14
Behavior and evolution ..................................................................................................................... 14
Mate choice ....................................................................................................................................... 14
Assortative mating ............................................................................................................................ 15
House mouse and paternal mate choice preference .......................................................................... 16
1-Competitive Ability .................................................................................................................... 17
2-Personality ................................................................................................................................. 18
3-Ultrasonic Vocalization ................................................................................................................. 18
Genomic imprinting .......................................................................................................................... 19
Genomic imprinting and brain development .................................................................................... 19
Imprinted gene and mate choice preference in house mouse ............................................................ 20
Aim of the project ............................................................................................................................. 22
Chapter1 ................................................................................................................................................ 24
Involvement of the Prader-Willi Syndrome (PWS) region genes in mouse behavior .......................... 24
Introduction ....................................................................................................................................... 25
Analysis of SNORD Copy Number Variation .................................................................................. 28
SNORD115 and 116 target genes ..................................................................................................... 30
Link between SNORD copy number and personality ....................................................................... 34
Correlation between SNORD115 and 116 copy numbers ................................................................ 42
Inheritance of SNORD copy numbers .............................................................................................. 45
SNORD copy number differences across tissues .............................................................................. 50
Variation of personality in inbred mice ............................................................................................ 51
SNORD copy number influence on the brain transcriptome ............................................................ 54
SNORD116 copy number and craniofacial features ......................................................................... 60
Differential gene expression through SNORD CNV ........................................................................ 64
Discussion ......................................................................................................................................... 66
SNROD115/ 116 CNV and personality ............................................................................................ 66
Correlation of personality and cognitive ability ............................................................................... 67
Correlation of personality and metabolism ....................................................................................... 68
Correlation of personality traits and vocalization ............................................................................. 68
Personality and craniofacial features ................................................................................................ 69
SNOD115/ 116 and the Prader-Willi syndrome ............................................................................... 69
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Inheritance of SNROD115 and 116 .................................................................................................. 70
Mice sample ...................................................................................................................................... 71
Mouse keeping .................................................................................................................................. 71
Mouse dissection ............................................................................................................................... 71
DNA extraction ................................................................................................................................. 71
mRNA extraction and cDNA synthesis ............................................................................................ 72
RNAseq analysis ............................................................................................................................... 73
Small RNA extraction, cDNA synthesis, library preparation and sequencing ................................. 73
Read mapping ................................................................................................................................... 74
snoRNA analysis ............................................................................................................................... 75
Droplet digital PCR ........................................................................................................................... 75
1- Finding a suitable reference gene ............................................................................................ 76
2-Primer designing ....................................................................................................................... 76
3-DNA digestion and ddPCR ........................................................................................................ 77
4-Copy Number Calculation ......................................................................................................... 78
Mouse Personality ............................................................................................................................. 81
Behavioral Tests................................................................................................................................ 81
Elevated Plus Maze ........................................................................................................................... 81
Open Field ......................................................................................................................................... 81
Dark/Light Box ................................................................................................................................. 81
Statistical Analysis ............................................................................................................................ 83
Shape phenotyping ............................................................................................................................ 85
Chapter 2 ............................................................................................................................................... 90
Functional analysis of the paternally expressed gene Peg13 ................................................................ 90
Introduction ....................................................................................................................................... 91
Results ............................................................................................................................................... 93
Peg13 and Trappc9 Expression ........................................................................................................ 93
Peg13 expression in the brain ........................................................................................................... 96
Peg13 expression during developmental stages ................................................................................ 97
A possible PEG13 protein ................................................................................................................. 98
Generation of Knock-out mice .......................................................................................................... 99
Peg13 3’-knockout mouse .............................................................................................................. 101
Behavioral tests on Peg13 3’-region knockout mice ...................................................................... 102
RNAseq analysis on Peg13 3’- region knockout mice ................................................................... 108
GO analysis ..................................................................................................................................... 109
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Discussion ....................................................................................................................................... 109
Expression of Peg13, Kcnk9 and Trappc9 are co-regulated ........................................................... 109
Peg13 is not a simple non-coding RNA .......................................................................................... 110
Behavior of Peg13 3’-region knockout mice .................................................................................. 110
Anxiety behavior of Peg13 3’-KO mice ......................................................................................... 111
Conclusion ...................................................................................................................................... 112
Material and Methods ..................................................................................................................... 113
RNAseq analysis across different tissues ........................................................................................ 113
Ribosomal profiling data analysis ................................................................................................... 113
Generation of knock-out mice by genOway ................................................................................... 113
Novel Object Test ........................................................................................................................... 114
Other procedures ............................................................................................................................. 114
General Discussion ............................................................................................................................. 116
The general background underlying this PhD thesis....................................................................... 116
The PWS region may be associated to the paternal mate choice preference in Western house mouse by regulating mouse personality ..................................................................................................... 117
Evolution of personality .................................................................................................................. 117
1-Selective Neutrality .................................................................................................................. 117
2-Mutation-selection balance ..................................................................................................... 118
3-Balancing Selection ................................................................................................................. 122
Personality and imprinting .............................................................................................................. 123
1-Different recombination rate between male and female .......................................................... 123
2-Co-adapted gene expression .................................................................................................... 123
Peg13 could be involved in sexual behavior in mouse ................................................................... 124
Conclusion .......................................................................................................................................... 126
Reference ............................................................................................................................................ 128
Acknowledgements ............................................................................................................................. 151
Contributions to the thesis .................................................................................................................. 153
Declaration .......................................................................................................................................... 154
Curriculum Vitae ................................................................................................................................ 155

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識別子（DOI, ISBNなど）: その他: Diss/13099

学位: 博士号 (PhD)

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