Ohnologs are overrepresented in pathogenic copy number mutations

Abstract

A number of rare copy number variants (CNVs), including both deletions and duplications, have been associated with developmental disorders, including schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study.

Positive and balancing selection onSLC18A1gene associated with psychiatric disorders and human-unique personality traits

“…Our fine‐tuned evolutionary rate analysis revealed that few PD genes were positively selected in the human lineage, which differs from the results of a previous study (Crespi et al ), and that PD genes are generally conserved as previous studies show (McLysaght et al ; Ogawa and Vallender ). However, the three detected PD‐PSGs ( CLSTN2, FAT1 , and SLC18A1 ), exhibited the unique signature of diversifying selection, estimated from the MK test and the DoS statistic.…”

Fruit Flies in Biomedical Research

“…These findings are to some extent supported by studies focusing on vertebrate genomes in which differences have been noted between genes resulting from whole-genome duplication events vs. single gene duplication events (Makino and McLysaght 2010;Dickerson and Robertson 2012;Singh et al 2012Singh et al , 2014McLysaght et al 2014). Indeed, genes resulting from whole-genome duplications are overrepresented in pathogenic vs. nonpathogenic copy number variants in humans (McLysaght et al 2014).…”

“…Indeed, genes resulting from whole-genome duplications are overrepresented in pathogenic vs. nonpathogenic copy number variants in humans (McLysaght et al 2014). Therefore, whether an essential fly gene has multiple or single human homologs is important for its potential role in disease.…”

Familial aortic disease and a large duplication in chromosome 16p13.1

“…The pathogenicity of the MYH11 duplication in the presented family is not proven, in spite of suggestive evidence for an association of this duplication with arterial dissection (Kuang et al., ; Grond‐Ginsbach, Chen, et al., ). The observation that the duplication at 16p13.1 encompasses four ohnologs ( NDE1, MYH11, ABCC1, and ABCC6) further suggests its pathogenicity, because ohnologs were shown to be dose‐sensitive and overrepresented in pathogenic copy number variation (Makino & McLysaght, ; McLysaght et al., ; Tropeano et al., ).…”