Genetic influences on motor learning and superperformance mutants revealed by random mutational survey of mouse locomotion.
Genetic influences on motor learning and superperformance mutants revealed by random mutational survey of mouse locomotion.
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通过对小鼠运动的随机突变调查揭示了遗传对运动学习和超性能突变体的影响。
DOI：
10.1101/2023.06.28.546756
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Pascual,JuanM
中科院分区：
文献类型：
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作者：
Jakkamsetti,Vikram;Ma,Qian;Angulo,Gustavo;Scudder,William;Beutler,Bruce;Pascual,JuanM
进化取决于影响生理的遗传变异。如在遗传筛选中所定义的，表型性能可以通过这样的突变而增强或降低。我们着手检测影响运动功能的突变，包括运动学习。因此，我们测试了36，444个非同义编码/剪接突变的运动效应，在C57 BL/6 J小鼠的种系中用N-乙基-N-亚硝基脲诱导，通过测量重复旋转试验的性能变化，同时对基因型设盲。自动减数分裂作图被用来暗示个别突变的因果关系。筛选了32，726只携带所有变异等位基因的小鼠。同时对1，408只正常小鼠进行了测试，以供参考。因此，在至少3只小鼠中检测的纯合性和运动突变使16.3%的常染色体基因呈现可检测的亚型或无效。这种方法使我们能够识别Rif 1，Tk 1，Fan 1和Mn 1中的超性能突变。这些基因主要与核酸生物学相关，以及其他不太好表征的功能。我们还将不同的运动学习模式与功能相关的基因组联系起来。这些功能集包括优先组蛋白H3甲基转移酶活性的小鼠，学习在一个加速的速度相对于其余的突变小鼠。这些结果允许估计可以修改对进化有影响的行为（如运动）的突变的比例。一旦这些基因座得到进一步验证并阐明其机制，它们还可以利用新发现的基因的活性来增强运动能力或抵消残疾或疾病。
Evolution depends upon genetic variations that influence physiology. As defined in a genetic screen, phenotypic performance may be enhanced or degraded by such mutations. We set out to detect mutations that influence motor function, including motor learning. Thus, we tested the motor effects of 36,444 non-synonymous coding/splicing mutations induced in the germline of C57BL/6J mice with N-ethyl-N-nitrosourea by measuring changes in the performance of repetitive rotarod trials while blinded to genotype. Automated meiotic mapping was used to implicate individual mutations in causation. 32,726 mice bearing all the variant alleles were screened. This was complemented with the simultaneous testing of 1,408 normal mice for reference. 16.3% of autosomal genes were thus rendered detectably hypomorphic or nullified by mutations in homozygosity and motor tested in at least 3 mice. This approach allowed us to identify superperformance mutations in Rif1, Tk1, Fan1 and Mn1. These genes are primarily related, among other less well characterized functions, to nucleic acid biology. We also associated distinct motor learning patterns with groups of functionally related genes. These functional sets included preferentially histone H3 methyltransferase activity for mice that learnt at an accelerated rate relative to the rest of mutant mice. The results allow for an estimation of the fraction of mutations that can modify a behavior influential for evolution such as locomotion. They may also enable, once the loci are further validated and the mechanisms elucidated, the harnessing of the activity of the newly identified genes to enhance motor ability or to counterbalance disability or disease.