title: Autozygome sequencing expands the horizon of human knockout research and provides novel insights into human phenotypic variation.
abstract: The use of autozygosity as a mapping tool in the search for autosomal recessive disease genes is well established. We hypothesized that autozygosity not only unmasks the recessiveness of disease causing variants, but can also reveal natural knockouts of genes with less obvious phenotypic consequences. To test this hypothesis, we exome sequenced 77 well phenotyped individuals born to first cousin parents in search of genes that are biallelically inactivated. Using a very conservative estimate, we show that each of these individuals carries biallelic inactivation of 22.8 genes on average. For many of the 169 genes that appear to be biallelically inactivated, available data support involvement in modulating metabolism, immunity, perception, external appearance and other phenotypic aspects, and appear therefore to contribute to human phenotypic variation. Other genes with biallelic inactivation may contribute in yet unknown mechanisms or may be on their way to conversion into pseudogenes due to true recent dispensability. We conclude that sequencing the autozygome is an efficient way to map the contribution of genes to human phenotypic variation that goes beyond the classical definition of disease.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Internal Medicine, College of Medicine, King Saud bin-Abdul-Aziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Ahmed B
authors.initials: AB
authors.lastname: Alsalem
authors.affiliation: Molecular Biomedicine Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anason S
authors.initials: AS
authors.lastname: Halees
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Shamsa
authors.initials: S
authors.lastname: Anazi
authors.affiliation: Department of Ophthalmology, King Abdul-Aziz University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Shomoukh
authors.initials: S
authors.lastname: Alshamekh
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D003241:Consanguinity; D059472:Exome / Q000235:genetics*; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D005808:Genes, Recessive / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide