Uncovering Natural Longevity Alleles from Intercrossed Pools of Aging Fission Yeast Cells.
Uncovering Natural Longevity Alleles from Intercrossed Pools of Aging Fission Yeast Cells.
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DOI：
10.1534/genetics.118.301262
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发表时间：
2018-10
期刊：
影响因子：
3.3
通讯作者：
Bähler J
中科院分区：
文献类型：
--
作者：
Ellis DA;Mustonen V;Rodríguez-López M;Rallis C;Malecki M;Jeffares DC;Bähler J
非分裂酵母细胞的时间顺序寿命是反映细胞老化的数量性状。通过监测老化分离池中的等位基因频率，Ellis等人发现了两个基因的5'-非翻译区域的调控变异。数量性状往往表现出由多种遗传因素引起的较大变异。其中一个特征是不分裂的酵母细胞按时间顺序的寿命，作为细胞衰老的模型。筛选与衰老有关的遗传因素，通常是检测蛋白质编码基因的突变。为了确定导致细胞衰老的自然遗传变异，我们利用了分裂酵母的两种菌株，分裂糖酵母，它们在时间上的寿命不同。我们从这些菌株中产生分离池，并对它们进行多代高级杂交，以打破连锁群。我们按时间顺序对交叉的隔离池进行了老化，然后在不同的时间进行了基因组测序，以检测随着年龄的增长而可重复富集的遗传变异。2号染色体上的一个区域在衰老过程中表现出强烈的正选择。基于预期的功能，来自该区域的两个候选变体最有可能是长寿菌株的因果关系：ppk31和SPBC409.08的5 ' -非翻译区域的小插入和缺失。Ppk31是Rim15的同源物，Rim15是一种保守的激酶，控制细胞对营养物质的增殖，而SPBC409.08是一种预测的精胺跨膜转运蛋白。Rim15和精胺前体亚精胺都与衰老有关，因为它们参与了依赖自噬的寿命延长。单等位基因和双等位基因替换表明，这两种变异，单独或联合，对细胞寿命有微妙的影响。此外，ppk31和SPBC409.08的缺失突变体挽救了亚精胺引起的生长缺陷。我们提出Ppk31和SPBC409.08可能共同调节寿命，从而将Rim15/Ppk31与亚精胺代谢联系起来。
Chronological lifespan of non-dividing yeast cells is a quantitative trait that reflects cellular aging. By monitoring allele frequencies in aging segregant pools, Ellis et al. uncover regulatory variants in the 5'-untranslated regions of two genes... Quantitative traits often show large variation caused by multiple genetic factors . One such trait is the chronological lifespan of non-dividing yeast cells, serving as a model for cellular aging. Screens for genetic factors involved in aging typically assay mutants of protein-coding genes. To identify natural genetic variants contributing to cellular aging, we exploited two strains of the fission yeast, Schizosaccharomyces pombe, that differ in chronological lifespan. We generated segregant pools from these strains and subjected them to advanced intercrossing over multiple generations to break up linkage groups. We chronologically aged the intercrossed segregant pool, followed by genome sequencing at different times to detect genetic variants that became reproducibly enriched as a function of age. A region on Chromosome II showed strong positive selection during aging. Based on expected functions, two candidate variants from this region in the long-lived strain were most promising to be causal: small insertions and deletions in the 5′-untranslated regions of ppk31 and SPBC409.08. Ppk31 is an ortholog of Rim15, a conserved kinase controlling cell proliferation in response to nutrients, while SPBC409.08 is a predicted spermine transmembrane transporter. Both Rim15 and the spermine-precursor, spermidine, are implicated in aging as they are involved in autophagy-dependent lifespan extension. Single and double allele replacement suggests that both variants, alone or combined, have subtle effects on cellular longevity. Furthermore, deletion mutants of both ppk31 and SPBC409.08 rescued growth defects caused by spermidine. We propose that Ppk31 and SPBC409.08 may function together to modulate lifespan, thus linking Rim15/Ppk31 with spermidine metabolism.