Whole-Exome Sequencing in the Isolated Populations of Cilento from South Italy

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.

Whole-exome analysis in Tunisian Imazighen and Arabs shows the impact of demography in functional variation

“…In order to assess the effective population size (N e ) of the present sample set, we explored N e history based on patterns of linkage disequilibrium (LD) with the whole-exome data 47 . The analysis of long-term N e (the harmonic mean of N e along the past generations explored) confirms that both Tunisian Amazigh and Mozabite populations have significantly lower long-term N e than the rest of populations (Fig.…”

“…The genetic functional consequences of demographic processes have been described and debated in several human population groups 24 , 36 , 37 , 45 – 47 , 56 . Within this framework, we have conducted the first study on the impact of demography in the distribution of functional variation in North African populations, being also one of the few works focused on biomedical function in North Africa to take into account the cultural differences of the studied populations (in our case, Amazigh and non-Amazigh), and the first to use our approach in the region.…”

“…Inference of effective population sizes (N e ) for all populations in the dataset was performed using the R-package NeON 95 , which bases the N e calculation in LD patterns and was previously used in whole-exome data in 47 . We calculated the long-term effective population size, which is the harmonic mean of the N e of the population sizes along the generations in the past, using each chromosome as replicate to calculate the mean (percentile 50th) and the confidence intervals (percentiles 5th and 95th), as provided by the Ne_CI function of the NeON package.…”

“…Runs of homozygosity (ROH) were detected at individual level using PLINK 2.0 89 and following the same approach as in 47 , which is optimized for whole-exome sequence analysis. Data was first pruned for linkage disequilibrium, which was detected using sliding windows of 50 kb with a step size of 5 SNPs, and a square correlation coefficient (r 2 threshold of 0.8, keeping 271,652 variants.…”

Functional and clinical implications of genetic structure in 1686 Italian exomes

“…In addition to the well‐known studies exploring human genetic variation worldwide from whole‐exome data, many groups (Dopazo et al, 2016; Kwak et al, 2017; Van Hout et al, 2020) have worked on national sequencing data sets with three main goals in mind: (i) studying the genetic structure of a population by also exploiting lower frequency variants, (ii) understanding the distribution of putative pathogenic variation in healthy cohorts, and, ultimately, (iii) generating a catalog of local variability. Previous large sequencing‐based studies, which contained Italian participants include the 1000 Genomes Project (with 107 Tuscans) and more recent studies that focused on specific isolates (Cocca et al, 2019; Nutile et al, 2019; Sidore et al, 2015; Xue et al, 2017).…”