A map of copy number variations in the Tunisian population: a valuable tool for medical genomics in North Africa

Abstract

Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African populations remain underrepresented in public genetic databases in terms of single-nucleotide variants as well as for larger genomic mutations. In this study, we present the first CNV map for a North African population using the Affymetrix Genome-Wide SNP (single-nucleotide polymorphism) array 6.0 array genotyping intensity data to call CNVs in 102 Tunisian healthy individuals. Two softwares, PennCNV and Birdsuite, were used to call CNVs in order to provide reliable data. Subsequent bioinformatic analyses were performed to explore their features and patterns. The CNV map of the Tunisian population includes 1083 CNVs spanning 61.443 Mb of the genome. The CNV length ranged from 1.017 kb to 2.074 Mb with an average of 56.734 kb. Deletions represent 57.43% of the identified CNVs, while duplications and the mixed loci are less represented. One hundred and three genes disrupted by CNVs are reported to cause 155 Mendelian diseases/phenotypes. Drug response genes were also reported to be affected by CNVs. Data on genes overlapped by deletions and duplications segments and the sequence properties in and around them also provided insights into the functional and health impacts of CNVs. These findings represent valuable clues to genetic diversity and personalized medicine in the Tunisian population as well as in the ethnically similar populations from North Africa.

Fig. 1. Global map CNV size distribution.

Overall length distribution of the global CNV map.

Fig. 2. Scatter plot of frequencies of CNVs in Tunisia identified in the 1000 Genome project.

A positive and high correlation is shown (Pearson correlation r = 0.70, 95% CI = [0.67;0.73], p value < 2.2e – 16).

Fig. 3. Circular plot showing a chromosomal view of the global CNV map of the Tunisian population.

The innermost circle with vertical lines represents all the CNV from chromosomes 1 to 22: blue, red, and green color lines represent deletions, duplications, and mixed loci, respectively. The frequency of each CNV is depicted by the second track. The third concentric circle represents the genomic distribution of CNV genes overlapped according to the type of the CNV.

Fig. 4. CNV length, gene content and frequency distributions.

CNVs were plotted according to event type (color), size (y-axis), frequency in the Tunisian population (x-axis, number of individuals), and number of RefSeq genes affected (circle size).

Fig. 5. WHO ICD-10 classification of diseases caused by CNV genes.

Three major disease groups are caused by CNV genes. Disease classes are colored according to the inheritance mode.

Fig. 6. The correlation between the r² and the distance between CNV deletion and single-nucleotide polymorphism (SNP).

The decrease of the r² strength as the distance of the CNVs and the SNP increases is shown.