Hotspots of Large Rare Deletions in the Human Genome

Abstract

BackgroundWe have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parent-parent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder.Methodology/Principal FindingsDNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV combined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98% of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency (‘hotspots’), usually of 0.4–0.6 Mb in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on members of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort.Conclusions/SignificanceNine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others, including MACROD2 and CTNNA3. Our results also offer an alternative interpretation for the observations of deletions in tumors which have been proposed as reflecting tumor-suppressive activity of genes in these hotspots.

Single nucleotide polymorphism array analysis of microsatellite-stable, diploid/near-diploid colorectal carcinomas without the CpG island methylator phenotype

“…Similiarly, correlative microsatellite/expression studies of FHIT did not reveal an effect of LOH on gene expression (15). Aberrations of the MACROD2 gene have not previously been identified for colorectal carcinoma; studies have only considered MACROD2 deletions in population-based genotyping (16). Therefore, though counterintuitive, there is no evidence to suggest that the 'punched out' gene losses so indicative of a functional role are implicated in the suppressor pathway of colorectal carcinoma.…”

No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder

“…However, rare CNVs are known at the MACROD2 locus, which is a deletion hotspot [Bradley et al, 2010], although these seem too rare to cause genotyping problems. One strand of supportive evidence for a role for the MACROD2 gene in autism is a rare deletion of the locus, seen in a case of Kabuki syndrome [Maas et al, 2007], which can feature autistic-like symptoms [Ho and Eaves, 1997;Akin Sari et al, 2008] and one individual with schizophrenia [Xu et al, 2009], although the deletion was not seen in 43 other patients with Kabuki syndrome [Kuniba et al, 2008].…”

“…One strand of supportive evidence for a role for the MACROD2 gene in autism is a rare deletion of the locus, seen in a case of Kabuki syndrome [Maas et al, 2007], which can feature autistic-like symptoms [Ho and Eaves, 1997;Akin Sari et al, 2008] and one individual with schizophrenia [Xu et al, 2009], although the deletion was not seen in 43 other patients with Kabuki syndrome [Kuniba et al, 2008]. Without clear evidence of disease association to date, MACROD2 deletions are thought to be probably non-pathogenic [Bradley et al, 2010].…”

Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress

“…MACRO domain containing 2 NO NO The function of MACROD2 is unclear, but the presence of the MACRO domain suggests that its protein product binds poly-ADP-ribose (Bradley et al, 2010).…”