Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, UK.
BMC Biol. 2011 Feb 28;9:15. doi: 10.1186/1741-7007-9-15.
Haploinsufficient (HI) genes are those for which a reduction in copy number in a diploid from two to one results in significantly reduced fitness. Haploinsufficiency is increasingly implicated in human disease, and so predicting this phenotype could provide insights into the genetic mechanisms behind many human diseases, including some cancers.
In the present work we show that orthologues of Saccharomyces cerevisiae HI genes are preferentially retained across the kingdom Fungi, and that the HI genes of S. cerevisiae can be used to predict haploinsufficiency in humans. Our HI gene predictions confirm known associations between haploinsufficiency and genetic disease, and predict several further disorders in which the phenotype may be relevant. Haploinsufficiency is also clearly relevant to the gene-dosage imbalances inherent in eukaryotic sex-determination systems. In S. cerevisiae, HI genes are over-represented on chromosome III, the chromosome that determines yeast's mating type. This may be a device to select against the loss of one copy of chromosome III from a diploid. We found that orthologues of S. cerevisiae HI genes are also over-represented on the mating-type chromosomes of other yeasts and filamentous fungi. In animals with heterogametic sex determination, accumulation of HI genes on the sex chromosomes would compromise fitness in both sexes, given X chromosome inactivation in females. We found that orthologues of S. cerevisiae HI genes are significantly under-represented on the X chromosomes of mammals and of Caenorhabditis elegans. There is no X inactivation in Drosophila melanogaster (increased expression of X in the male is used instead) and, in this species, we found no depletion of orthologues to yeast HI genes on the sex chromosomes.
A special relationship between HI genes and the sex/mating-type chromosome extends from S. cerevisiae to Homo sapiens, with the microbe being a useful model for species throughout the evolutionary range. Furthermore, haploinsufficiency in yeast can predict the phenotype in higher organisms.
杂合不足（HI）基因是指在二倍体中，一个基因的拷贝数从两个减少到一个，导致其功能显著降低的基因。杂合不足越来越多地与人类疾病有关，因此预测这种表型可以深入了解许多人类疾病（包括一些癌症）的遗传机制。
在本研究中，我们发现酿酒酵母 HI 基因的直系同源物在真菌界中优先保留，并且酿酒酵母的 HI 基因可用于预测人类的杂合不足。我们的 HI 基因预测证实了已知的杂合不足与遗传疾病之间的关联，并预测了在其他疾病中可能存在的进一步表现。杂合不足也与真核生物性别决定系统中固有的基因剂量失衡明显相关。在酿酒酵母中，HI 基因在决定酵母交配型的第 III 号染色体上过度表达。这可能是一种选择机制，以防止二倍体从第 III 号染色体丢失一个拷贝。我们发现，酿酒酵母 HI 基因的直系同源物在其他酵母和丝状真菌的交配型染色体上也过度表达。在具有异型性别的动物中，由于雌性的 X 染色体失活，X 染色体上 HI 基因的积累会影响两性的适应性。我们发现，酿酒酵母 HI 基因的直系同源物在哺乳动物和秀丽隐杆线虫的 X 染色体上显著减少。在黑腹果蝇（Drosophila melanogaster）中没有 X 染色体失活（雄性中 X 染色体的表达增加），在这个物种中，我们没有发现酿酒酵母 HI 基因的直系同源物在性染色体上的缺失。
从酿酒酵母到智人，HI 基因与性/交配型染色体之间的特殊关系延伸到整个进化范围的物种中，微生物是一个有用的模型。此外，酵母中的杂合不足可以预测高等生物的表型。
