The Institute of Zoology collaborative team revealed the domestication mechanism of mouse behavioral and neural genes

Experimental mice are one of the most commonly used mammalian models in biological and medical research, derived
from long-term domestication of wild house mice.
There are significant differences
in body size, physiology and behavior between experimental mice and wild house mice.
In particular, the aggressive behavior and docile behavior of mice were weakened and docile behavior increased
under laboratory domestication.
The genomes of experimental mice are known to come from three subspecies of house mice, Mus musculus (M.
m.
domesticus), M.
m.
musculus, and M.
m.
castaneus, of which M.
m.
domesticus and M.
m.
musculus There are hybridization bands
in the adjacent areas of its continental European distribution.
Due to the lack of genomic data in wild house mice, the genetic mechanism of mouse domestication has not been fully elucidated
.

Through years of efforts, the scientific research cooperation team led by researcher Zhang Zhibin of the Institute of Zoology of the Chinese Academy of Sciences collected and measured 11 M.
m.
domesticus, 9 M.
m.
musculus, and 16 M.
m.
castaneus wild house mouse DNA samples and genome sequences from China and Europe, and conducted joint analysis with 36 known classical inbred lines It was found that the genomes of classical inbred mice were clustered into an independent branch, completely separated from wild domestic mice, and most closely related to M.
m.
domesticus (Figure 1
).
The results show that the genome of the classic inbred mice is a chimeric genome dominated by M.
m.
domesticus.
Under the artificial selection of the laboratory, its genetic structure has been greatly differentiated
.

The study used three methods: nucleotide diversity analysis, Fst, and XP-CLR to screen out 339 domesticated genes (Figure 2
).
The results of GO analysis showed that domestication selection genes were closely related to
brain function and behavior.
By comparing the NCBI mouse gene expression database, it was found that nearly 40% of the domesticated selection genes were highly expressed
in the brain.
Comparing the MGI database records on knockout/gene mutation mice, it was found that 245 of the 339 domesticated genes screened (51 percent) had neurological and behavioral changes
in knockout mice.
RNA-Seq assays found that 339 domesticated genes had a higher
proportion of differentially expressed genes in the hippocampus and frontal lobe.
GO analysis of differentially expressed genes showed that the genes in relation to neurological function and behavioural aspects were
enriched.
The results suggest that behavioral and neurological changes are the most significant feature
of the domestication of laboratory mice.

Using gene editing and point-mutant mouse models, it was found that after the rs27900929 site mutation in the intron of the Astn2 gene, mice were more likely to avoid active contact from the experimenter's hand and more easily bite the experimenter's hand (Figure 3).

Further analysis found that the change in the polymorphic site rs27900929 led to a change in the proportion of two different shearsomes in the Astn2 gene, which was associated with the above changes in the domestication behavior of mice (Figure 3).

Notably, the Astn2 gene has been linked to autism in
humans.

This study lays a foundation
for future biological and medical research using mouse models and for the behavioral, neurological, physiological and ecological regulation mechanisms of wild house mouse populations.

This study was published in Genome Biology on September 26, 2022, titled "Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice
.
" 。 Dr.
Liu Ming, Institute of Zoology, Chinese Academy of Sciences, Dr.
Yu Caixia, Beijing Institute of Genomics, Chinese Academy of Sciences, Zhang Zhichao of Beijing Nuohe Zhiyuan Technology Co.
, Ltd.
, Dr.
Song Mingjing, Institute of Medical Laboratory Zoology, Chinese Academy of Medical Sciences, are co-first authors, and Zhang Zhibin, researcher of Institute of Zoology, Chinese Academy of Sciences, and Zhang Bing, researcher of Beijing Institute of Genomics, Chinese Academy of Sciences, are co-corresponding authors
。 From the State Key Laboratory of Integrated Management of Agricultural Pests and Rats in the Institute of Zoology, Chinese Academy of Sciences, the International Zoological Society, the State Key Laboratory of Stem Cell and Reproductive Biology of the Institute of Zoology of the Chinese Academy of Sciences, the Beijing Institute of Genomics of the Chinese Academy of Sciences (National Bioinformatics), Beijing Nuohe Zhiyuan Technology Co.
, Ltd.
, Beijing Gezhi Boya Biotechnology Co.
, Ltd.
, the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences, the Institute of Vertebrate Animals of the Czech Academy of Sciences, the German Institute of Horticulture and Forest Plant Protection/ Researchers from the Institute of Epidemiology and Pathogen Diagnostics, College of Life Sciences of Zhengzhou University, Institute of Plant Protection of Heilongjiang Academy of Agricultural Sciences, College of Life Sciences of Central China Normal University, Institute of Subtropical Agriculture of Chinese Academy of Sciences, Center for Excellence in Biological Intercropping Innovation of University of Chinese Academy of Sciences, Institute of Plant Protection of Guangdong Academy of Agricultural Sciences, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, and Department of Psychology of Florida State University participated in the study
.

The research has been funded by the Pilot Project of the Chinese Academy of Sciences (XDB11050300, XDPB16), the Key Project of the National Natural Science Foundation of China (31330013), the Foreign Cooperation Project of the Chinese Academy of Sciences (152111KYSB20150023, 152111KYSB20160089), the State Key Laboratory of Integrated Management of Agricultural Pests and Rats (Chinese IPM1615), and the Key Technical Talents Program of the Chinese Academy of Sciences.
Project support
.

Full-text link: https://genomebiology.
biomedcentral.
com/articles/10.
1186/s13059-022-02772-1

　　Liu M#, Yu C#, Zhang Z#, Song M#, Sun X, Piálek J, Jacob J, Lu J, Cong L, Zhang H, Wang Y, Li G, Feng Z, Du Z, Wang M, Wan X, Wang D, Wang YL, Li H, Wang Z, Zhang B*, Zhang Z*.
Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice.
2022.
Genome Biology, 23: 203.

Figure 1.
Genome-based Mice Phylogenetic Relationships and Population Structure (since Liu et al.
2022.
Genome Biology）

Figure 2.
Genome-based mouse domestication gene screening (since Liu et al.
2022.
Genome Biology）

Figure 3.
Effects of Astn2 intron point mutation (T > C) on aggressive behavior in mice (since Liu et al.
2022.
Genome Biology）