title: Whole-exome sequencing in an isolated population from the Dalmatian island of Vis.
abstract: We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP. The majority of these variants (76%) are singletons. Comparable to data obtained from UK10K-Generation Scotland that were sequenced and analysed using the same protocols, we detected an enrichment of potentially damaging variants (non-synonymous and loss-of-function) in the low frequency and common variant categories. On average 115 (range 93-140) genotypes with loss-of-function variants, 23 (15-34) of which were homozygous, were identified per person. The landscape of loss-of-function variants across an exome revealed that variants mainly accumulated in genes on the xenobiotic-related pathways, of which majority coded for enzymes. The frequency of loss-of-function variants was additionally increased in Vis runs of homozygosity regions where variants mainly affected signalling pathways. This work confirms the isolate status of Vis population by means of whole-exome sequence and reveals the pattern of loss-of-function mutations, which resembles the trails of adaptive evolution that were found in other species. By cataloguing the exomic variants and describing the allelic structure of the Vis population, this study will serve as a valuable resource for future genetic studies of human diseases, population genetics and evolution in this population.
authors.affiliation: Department of Research in Biomedicine and Health, University of Split School of Medicine, Split, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Jeroncic
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Graham Rs
authors.initials: GR
authors.lastname: Ritchie
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Department of Mathematical and Statistical Sciences, University of Colorado, Denver, CO, USA.
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Hendricks
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Kolb-Kokocinski
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Matchan
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Public Health, University of Split School of Medicine, Split, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolcic
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Glodzik
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Centre for Global Health Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.affiliation: Centre for Global Health Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Department of Public Health, University of Split School of Medicine, Split, Croatia.|Centre for Global Health Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Department of Medical Biology, University of Split School of Medicine, Split, Croatia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Boraska Perica
mesh_terms: D017523:Croatia; D019143:Evolution, Molecular; D059472:Exome; D005787:Gene Frequency; D006801:Humans; D062312:Islands; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011153:Population / Q000235:genetics*; D060047:Reproductive Isolation