Expression profile and gene age jointly shaped the genome-wide distribution of premature termination codons in a Drosophila melanogaster population.

Haiwang Yang,Ying Wu,Yong E Zhang,Bin Z He,Chenyu Ma,Shun-Chern Tsaur,Chau-Ti Ting,Huijing Ma

doi:10.1093/molbev/msu299

Abstract

Widespread premature termination codon mutations (PTCs) were recently observed in human and fly populations. We took advantage of the population resequencing data in the Drosophila Genetic Reference Panel to investigate how the expression profile and the evolutionary age of genes shaped the allele frequency distribution of PTCs. After generating a high-quality data set of PTCs, we clustered genes harboring PTCs into three categories: genes encoding low-frequency PTCs (≤1.5%), moderate-frequency PTCs (1.5–10%), and high-frequency PTCs (>10%). All three groups show narrow transcription compared with PTC-free genes, with the moderate- and high-PTC frequency groups showing a pronounced pattern. Moreover, nearly half (42%) of the PTC-encoding genes are not expressed in any tissue. Interestingly, the moderate-frequency PTC group is strongly enriched for genes expressed in midgut, whereas genes harboring high-frequency PTCs tend to have sex-specific expression. We further find that although young genes born in the last 60 My compose a mere 9% of the genome, they represent 16%, 30%, and 50% of the genes containing low-, moderate-, and high-frequency PTCs, respectively. Among DNA-based and RNA-based duplicated genes, the child copy is approximately twice as likely to contain PTCs as the parent copy, whereas young de novo genes are as likely to encode PTCs as DNA-based duplicated new genes. Based on these results, we conclude that expression profile and gene age jointly shaped the landscape of PTC-mediated gene loss. Therefore, we propose that new genes may need a long time to become stably maintained after the origination.

Highlights

Loss-of-function (LoF) mutations are generally believed to be deleterious and have been discussed in the context of human medicine for decades (Chang and Kan 1979; Rosenfeld et al 1992; Frischmeyer and Dietz 1999)
To investigate the extent of this issue, we conducted polymerase chain reaction (PCR) and Sanger sequencing for 94 premature termination codon mutations (PTCs) sites randomly chosen to cover the allele frequency spectrum
We further focused on the proportion of young genes encoding moderate- and high-frequency PTCs because these two classes are more likely to lead to PTC-mediated gene loss

Summary

Introduction

Loss-of-function (LoF) mutations are generally believed to be deleterious and have been discussed in the context of human medicine for decades (Chang and Kan 1979; Rosenfeld et al 1992; Frischmeyer and Dietz 1999). Recent genomewide surveys in human and fly populations revealed an unexpected prevalence of LoF mutations with hundreds or thousands of genes harboring deletions and/or premature termination codon mutations (PTCs) (Hoehn et al 2012; Lee and Reinhardt 2012; MacArthur et al 2012). The first feature suggests that these LoF-encoding genes may have relatively low pleiotropy, whereas the second feature indicates a certain extent of compensation. These two features might explain why the loss of these genes is tolerable (MacArthur et al 2007, 2012).

Methods

Results

Conclusion