Functional diversification accompanies gene family expansion of MED2 homologs in Candida albicans.
Functional diversification accompanies gene family expansion of MED2 homologs in Candida albicans.
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DOI：
10.1371/journal.pgen.1007326
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发表时间：
2018-04
期刊：
影响因子：
4.5
通讯作者：
Anderson MZ
中科院分区：
文献类型：
--
作者：
Dunn MJ;Kinney GM;Washington PM;Berman J;Anderson MZ
基因复制促进了功能多样化，并为生物体提供了更大的表型灵活性。扩大的基因家族是通过重复的基因复制而产生的，但由于难以分离单个家族成员的影响，因此通常未探索伴随每个旁系基因的功能分化程度。端粒相关（TLO）基因家族是基因家族扩展的一个显著例子，相对于密切相关的物种C. dubliniensis的两个TLO基因，在致病性较强的白色念珠菌中有14个成员。TLO基因编码主要转录调控复合体Mediator的可互换Med2亚基。为了确定与每个白色念珠菌TLO相关的生物学功能，使用Tet-ON系统调节单个家族成员的表达，并通过涉及生长和毒力性状的一系列表型对菌株进行评估。所有的TLOs影响多种表型，单一表型经常受到多种TLOs的影响，包括简单表型，如细胞聚集和复杂表型，如在mellonella感染模型中的毒力。没有表型受到所有TLOs的调节，这表明不同家族成员之间的祖先属性存在新功能化或亚功能化。重要的是，三种表型的调控可以映射到TLO基因中的单个多态性位点，包括与两种表型、蔗糖生长和巨噬细胞杀伤相关的指数。不同的选择压力作用于TLO序列，5 ‘保守的Med2结构域经历了纯化选择，而基因/进化枝特异性的3 ’端经历了广泛的正选择，这可能有助于个体TLO对表型变异性的影响。因此，TLO基因家族的扩展赋予了每个平行基因独特的调控特性，从而影响了一系列表型。我们认为，与这种扩张相关的遗传多样性有助于白色念珠菌作为共生和机会性病原体的成功。基因复制是一种快速产生额外序列的机制，以供自然选择发挥作用，并赋予更大的有机体适应性。如果额外的基因拷贝是有益的，这个过程可以重复产生一个扩展的基因家族，其中包含许多相关序列的拷贝。重复后，单个基因家族成员可能保留祖先基因的功能或通过突变获得新的功能。功能多样化是如何伴随扩展到大基因家族的，这在很大程度上仍未被探索，因为在剩余家族成员存在的情况下难以评估单个基因。在这里，我们使用一个诱导启动子来调节TLO基因家族的单个基因在共生酵母和条件致病菌白色念珠菌中的表达，这些基因编码一个主要转录调节因子的组成部分。单个TLO的诱导表达影响广泛的表型，使得TLO基因之间存在显著的功能重叠，并且大多数表型受到多个TLO的影响。在大多数情况下，单个TLO的诱导表达并没有产生大量的表型效应，这表明TLO基因之间的功能重叠可能会缓冲出现的新突变。TLO基因中的特定序列变异与某些表型相关，这些序列变异并不一定与整个基因的序列相似性相关。因此，个体TLO家族成员在重复之后进化出了特定的功能角色，这可能反映了遗传功能和新突变的结合。
Gene duplication facilitates functional diversification and provides greater phenotypic flexibility to an organism. Expanded gene families arise through repeated gene duplication but the extent of functional divergence that accompanies each paralogous gene is generally unexplored because of the difficulty in isolating the effects of single family members. The telomere-associated (TLO) gene family is a remarkable example of gene family expansion, with 14 members in the more pathogenic Candida albicans relative to two TLO genes in the closely-related species C. dubliniensis. TLO genes encode interchangeable Med2 subunits of the major transcriptional regulatory complex Mediator. To identify biological functions associated with each C. albicans TLO, expression of individual family members was regulated using a Tet-ON system and the strains were assessed across a range of phenotypes involved in growth and virulence traits. All TLOs affected multiple phenotypes and a single phenotype was often affected by multiple TLOs, including simple phenotypes such as cell aggregation and complex phenotypes such as virulence in a Galleria mellonella model of infection. No phenotype was regulated by all TLOs, suggesting neofunctionalization or subfunctionalization of ancestral properties among different family members. Importantly, regulation of three phenotypes could be mapped to individual polymorphic sites among the TLO genes, including an indel correlated with two phenotypes, growth in sucrose and macrophage killing. Different selective pressures have operated on the TLO sequence, with the 5’ conserved Med2 domain experiencing purifying selection and the gene/clade-specific 3’ end undergoing extensive positive selection that may contribute to the impact of individual TLOs on phenotypic variability. Therefore, expansion of the TLO gene family has conferred unique regulatory properties to each paralog such that it influences a range of phenotypes. We posit that the genetic diversity associated with this expansion contributed to C. albicans success as a commensal and opportunistic pathogen. Gene duplication is a rapid mechanism to generate additional sequences for natural selection to act upon and confer greater organismal fitness. If additional copies of the gene are beneficial, this process may be repeated to produce an expanded gene family containing many copies of related sequences. Following duplication, individual gene family members may retain functions of the ancestral gene or acquire new functions through mutation. How functional diversification accompanies expansion into large gene families remains largely unexplored due to the difficulty in assessing individual genes in the presence of the remaining family members. Here, we addressed this question using an inducible promoter to regulate expression of individual genes of the TLO gene family in the commensal yeast and opportunistic pathogen Candida albicans, which encode components of a major transcriptional regulator. Induced expression of individual TLOs affected a wide range of phenotypes such that significant functional overlap occurred among TLO genes and most phenotypes were affected by more than one TLO. Induced expression of individual TLOs did not produce massive phenotypic effects in most cases, suggesting that functional overlap among TLO genes may buffer new mutations that arise. Specific sequence variants among the TLO genes correlated with certain phenotypes and these sequence variants did not necessarily correlate with sequence similarity across the entire gene. Therefore, individual TLO family members evolved specific functional roles following duplication that likely reflect a combination of inherited function and new mutation.
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影响因子：
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通讯作者：
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