Abstract
The present study describes the genetic architecture of the isolated populations of Cilento, through the analysis of exome sequence data of 245 representative individuals of these populations. By annotating the exome variants and cataloguing them according to their frequency and functional effects, we identified 347,684 variants, 67.4% of which are rare and low frequency variants, and 1% of them (corresponding to 319 variants per person) are classified as high functional impact variants; also, 39,946 (11.5% of the total) are novel variants, for which we determined a significant enrichment for deleterious effects. By comparing the allele frequencies in Cilento with those from the Tuscan population from the 1000 Genomes Project Phase 3, we highlighted an increase in allele frequency in Cilento especially for variants which map to genes involved in extracellular matrix formation and organization. Furthermore, among the variants showing increased frequency we identified several known rare disease-causing variants. By different population genetics analyses, we corroborated the status of the Cilento populations as genetic isolates. Finally, we showed that exome data of Cilento represents a useful local reference panel capable of improving the accuracy of genetic imputation, thus adding power to genetic studies of human traits in these populations.
Highlights
In this work we used the data coming from the WES study performed on the Cilento isolates to describe their genetic architecture, annotating the identified variants, cataloguing them according to their frequency and functional effects, and comparing their frequencies with those from a general Italian population
Fold increase Campora Gioi Cardile ncbi.nlm.nih.gov/clinvar)[23], we found 20 variants increased in allele frequencies (AF) described as pathogenic for rare genetic diseases in at least one village: 9 variants were identified in Campora, 6 in Gioi, and 12 in Cardile
Next-generation sequencing approaches have produced a more comprehensive survey of the genetic diversity in human population improving knowledge of population history and disease mapping studies. These studies are interesting in founder populations which constitute a special resource due to the effects of bottlenecks and drift on their genetic variation
Summary
In this work we used the data coming from the WES study performed on the Cilento isolates to describe their genetic architecture, annotating the identified variants, cataloguing them according to their frequency and functional effects, and comparing their frequencies with those from a general Italian population. Because of the initial population bottleneck followed by genetic drift during the first generations, it is expected that in these isolates the frequencies of some genetic variants may have changed compared to those of the founding pool. Allele frequencies in isolated populations and large populations are expected to differ the most at rare variants. Rare variants with increased allele frequencies in isolated populations could be more identified in genetic studies of traits with a Mendelian or complex inheritance. We focused our attention on variants which have an increased allele frequency in the Cilento isolates compared to a general Italian population. We tested the utility of using exome data as a local reference panel to improve the accuracy of imputation and potentially increase the power of further genetic studies on human traits in these populations
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