基因敲除效应与基因功能关系的进化学研究

遗传学中一个关键的假设认为：一个基因功能丧失后所引起的表型变化就是这个基因的功能。通过对基因敲除后性状的理解来获得基因功能的信息是经典的遗传学研究方法。然而，基因的敲除效应表现出很强的多效性，其中有许多统计学上十分明确的效应与被敲除基因没有直接的生物学联系。我们前期研究了转录因子HAP4的敲除效应，发现不同效应的保守性、可遗传性是不同的，而且这种差异与其能否对应其已知的功能有非常直接的关系，证明了从进化的角度来研究基因敲除效应与基因功能关系的可行性。本项目，我们将在不同种间种内亲缘酵母中敲除同一个基因（共28个基因），研究其所影响的表达性状以及酵母细胞形态学性状的进化规律；我们还将利用酵母杂交实验，研究这些效应的可遗传性。这一系统性的研究能够提供基因敲除效应与其“真功能”对应的依据。本项目将首次以进化的观点对基因的敲除效应进行解析，以期更好理解在现有统计框架下定义的遗传效应的生物学意义。

A key hypothesis of genetics is that the function of a gene is the phenotypic results of loss of function. One of classic methods of studying gene function is studying the effects of null mutations. The information of genetic effects can be derived by standard differential expression (or trait) analysis of expression (or trait) profiles. However, some of the effected genes could hardly be connected to the deleted gene in biological sense, showing the strong pleiotropy. Genetic effects defined by statistics may not necessarily represent biological interactions shaped by natural selection. We have studied the deletion effects of a transcriptional factor HAP4 and found some effects were conserved and heritable while some were not. The former echoed the annotated functions of HAP4, and the latter did not. It suggests a way of evolutionarily decoupling gene deletion effects from gene functions. In this study, the genetic effects with null mutations of 28 genes will be investigated in at least seven related yeast strains/species. The conservation and heritability will be systematically examined. Genetic effects will be decomposed evolutionarily, which can offer a better understanding of their biological meanings.