[Show abstract][Hide abstract] ABSTRACT: Copy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated.
We analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring.
Analysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping "dispensable" DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages.
The autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals.
Full-text · Article · Jan 2012 · Genetics in medicine: official journal of the American College of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: Our view of SNPs has evolved significantly from harmless mutational events that accumulated through the history of human race to important players in human health and disease. As a result, determining the pathologic vs. benign nature of SNPs on pure statistical basis is now viewed as too simplistic. Here, we show that two previously reported SNPs in COL6A2 and AGL represent disease-causing mutation for Ullrich Muscular Dystrophy and Glycogenosis type III, respectively, in homoallelic state. This report urges caution in interpreting SNPs in databases in the clinical genetics setting and calls for sequencing runs of homozygosity in healthy individuals as a promising approach to better annotate SNP databases.
No preview · Article · Oct 2010 · European journal of medical genetics