Mechanisms mediating rare copy number variation: implications for neurodevelopmental disorders

Abstract

Introduction

Deletions and duplications of genomic regions (CNVs) can arise through replication errors during the DNA replication (S) phase of normal cell division, or through recombination errors during meiotic cell division. Recent technological advances have allowed genome-wide screening of sub-microscopic CNVs in large samples, yielding numerous reports in the last three years of CNVs associated with disease – in particular neurodevelopmental disorders such as schizophrenia, autism, and mental retardation.

Methods

CNVs were detected in a large European multicenter sample (SGENE+), of schizophrenia patients and control individuals, by quantifying probe intensities from Illumina SNP microarrays.

Results

CNVs on chromosomes 1, 2, 15,16, and 22 were over-represented in patients compared with controls. At all but one loci the CNVs were flanked by low copy repeats (LCR) suggesting non-allelic homologous recombination as the mediating mechanism; in fact this was confirmed for one of the CNVs. The associated CNVs on chromosome 2 had characteristics that differ from the other associated CNVs, compatible with replication-based mechanisms mediating CNV formation.

Discussion

CNVs are undoubtedly an important factor in genetic susceptibility for schizophrenia and other neurodevelopmental disorders. Replication- and recombination-based mechanisms of CNV formation may present different modes of gene-environment interactions, and have different implications when considering genetic and aetiological models for these disorders.

 

 

Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, DK-4000 Roskilde, Denmark