title: Understanding the impact of 1q21.1 copy number variant.
abstract: BACKGROUND
  1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects.
  
  
  RESULTS
  Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated.
  
  
  CONCLUSIONS
  Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype.
authors.affiliation: Child and Family Research Institute, Molecular Cytogenetics and Array Laboratory, 950 West 28th Avenue, Vancouver, BC, Canada.
authors.forename: Chansonette
authors.initials: C
authors.lastname: Harvard
authors.forename: Emma
authors.initials: E
authors.lastname: Strong
authors.forename: Eloi
authors.initials: E
authors.lastname: Mercier
authors.forename: Rita
authors.initials: R
authors.lastname: Colnaghi
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.forename: Eva
authors.initials: E
authors.lastname: Chow
authors.forename: Sally
authors.initials: S
authors.lastname: Martell
authors.forename: Christine
authors.initials: C
authors.lastname: Tyson
authors.forename: Monica
authors.initials: M
authors.lastname: Hrynchak
authors.forename: Barbara
authors.initials: B
authors.lastname: McGillivray
authors.forename: Sara
authors.initials: S
authors.lastname: Hamilton
authors.forename: Sandra
authors.initials: S
authors.lastname: Marles
authors.forename: Aziz
authors.initials: A
authors.lastname: Mhanni
authors.forename: Angelika J
authors.initials: AJ
authors.lastname: Dawson
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiao
authors.forename: Jeanette J
authors.initials: JJ
authors.lastname: Holden
authors.forename: Suzanne M E
authors.initials: SM
authors.lastname: Lewis
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Evica
authors.initials: E
authors.lastname: Rajcan-Separovic
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D055028:Comparative Genomic Hybridization; D000013:Congenital Abnormalities / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005796:Genes; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D004268:DNA-Binding Proteins; C526183:PRKAB2 protein, human; D055372:AMP-Activated Protein Kinases; D004265:DNA Helicases; C543585:CHD1L protein, human