Hillis David A, Yadgary Liran, Weinstock George M, de Villena Fernando Pardo-Manuel, Pomp Daniel, Garland Theodore
Genetics, Genomics, and Bioinformatics Graduate Program, University of California, Riverside, California, United States of America.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS One. 2024 Aug 1;19(8):e0306397. doi: 10.1371/journal.pone.0306397. eCollection 2024.
In various organisms, sequencing of selectively bred lines at apparent selection limits has demonstrated that genetic variation can remain at many loci, implying that evolution at the genetic level may continue even if the population mean phenotype remains constant. We compared selection signatures at generations 22 and 61 of the "High Runner" mouse experiment, which includes 4 replicate lines bred for voluntary wheel-running behavior (HR) and 4 non-selected control (C) lines. Previously, we reported multiple regions of differentiation between the HR and C lines, based on whole-genome sequence data for 10 mice from each line at generation 61, which was >31 generations after selection limits had been reached in all HR lines. Here, we analyzed pooled sequencing data from ~20 mice for each of the 8 lines at generation 22, around when HR lines were reaching limits. Differentiation analyses of allele frequencies at ~4.4 million SNP loci used the regularized T-test and detected 258 differentiated regions with FDR = 0.01. Comparable analyses involving pooling generation 61 individual mouse genotypes into allele frequencies by line produced only 11 such regions, with almost no overlap among the largest and most statistically significant peaks between the two generations. These results implicate a sort of "genetic churn" that continues at loci relevant for running. Simulations indicate that loss of statistical power due to random genetic drift and sampling error are insufficient to explain the differences in selection signatures. The 13 differentiated regions at generation 22 with strict culling measures include 79 genes related to a wide variety of functions. Gene ontology identified pathways related to olfaction and vomeronasal pathways as being overrepresented, consistent with generation 61 analyses, despite those specific regions differing between generations. Genes Dspp and Rbm24 are also identified as potentially explaining known bone and skeletal muscle differences, respectively, between the linetypes.
在各种生物体中，对处于明显选择极限的选择性培育品系进行测序表明，许多基因座上仍存在遗传变异，这意味着即使群体平均表型保持不变，遗传水平的进化仍可能继续。我们比较了“高奔跑者”小鼠实验第22代和第61代的选择特征，该实验包括4个为自愿转轮行为培育的重复品系（HR）和4个未选择的对照（C）品系。此前，我们基于第61代每个品系10只小鼠的全基因组序列数据，报道了HR和C品系之间的多个分化区域，此时所有HR品系均已达到选择极限31代以上。在这里，我们分析了第22代8个品系中每个品系约20只小鼠的混合测序数据，此时HR品系正接近极限。对约440万个单核苷酸多态性（SNP）位点的等位基因频率进行分化分析时使用了正则化t检验，并检测到258个分化区域，错误发现率（FDR）=0.01。将第61代个体小鼠基因型按品系合并为等位基因频率的类似分析仅产生了11个这样的区域，两代之间最大且统计学意义最显著的峰值几乎没有重叠。这些结果表明在与奔跑相关的基因座上存在一种持续的“遗传搅动”。模拟表明，随机遗传漂变和抽样误差导致的统计效力丧失不足以解释选择特征的差异。第22代采用严格淘汰措施的13个分化区域包括79个与多种功能相关的基因。基因本体分析确定嗅觉和犁鼻器途径相关的通路过度富集，这与第61代的分析一致，尽管两代之间的具体区域有所不同。基因Dspp和Rbm24也分别被确定为可能解释品系类型之间已知的骨骼和骨骼肌差异的基因。
