Haploinsufficiency and the sex chromosomes from yeasts to humans

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Figure 1

Consequences of the accumulation of haploinsufficient genes on the mating-type chromosomes of fungi and the sex chromosomes of animals. (a) In the diploid yeast cell, loss of one copy of the mating chromosome allows expression of the mating pheromones (typically suppressed in the diploid), generating a mating-competent diploid. The accumulation of haploinsufficient (HI) genes on this chromosome is proposed to be a selective mechanism against its loss, compromising fitness in the chromosome III monosome to such a degree as to preclude diploid mating. (b) In animals, the presence of HI genes on the sex chromosomes should incur a selective penalty in the heterogametic sex. In mammals and Caenorhabditis elegans, X chromosome inactivation in the female halves the expression of the genes along the entire chromosome, resulting in selective pressure against X-linked HI genes in the homogametic sex as well. In contrast, in Drosphila melanogaster males, the expression of the lone X chromosome is doubled, thus any HI genes present on the chromosome should present no detriment to the fitness of either sex.