About this Research Topic
The study of natural genome variation in humans when manifested by Mendelian diseases (MD) has been probably the most effective strategy to link genotype to phenotype. Following the success of whole exome sequencing (WES), which has made it possible to explain the molecular causes underlying about 35% of affected individuals, moving to whole genome sequencing (WGS) has been the logical outcome to approach the great complexity of genome structure. However, after excluding protein coding regions, canonical splice sites, or structural variants overlapping known MD-associated genes, to date WGS has yielded few discoveries of novel genes. In those cases, the key to success was reducing the search space via linkage analysis, homozygosity mapping, or identification of shared chromosomal microdeletions or duplications. Hence, new in silico methods are needed to identify different classes of variants and prioritize them at the whole-genome scale.
WES/WGS experiments are producing a wealth of information about human genome variation, including single/multiple (SNV/MNV) nucleotide variants, insertions/deletions (INDEL) and more complex structural variants (SV). However, the identification and interpretation of all these variants could be challenging, since “general-purpose” algorithms developed to date in most cases lack sensitivity for specific classes of variations that could underlie Mendelian traits. In fact, efficient variant prioritization requires integration with various levels of annotations. The goal of this Research Topic will be to extend prioritization strategies from WES/WGS data to interpret functional impact of VUS (variants of unknown significance) for variants which do not show any effect on protein coding regions, e.g., those with regulatory effects on splicing or in the UTRs (mutations in CpG islands, in the poly-A signal, miRNAs, miRNA/RNA-binding protein binding sites), multiallelic sites, imprinted regions and simple tandem repeats, or in the mitochondrial genome.
This Research Topic welcomes Original Research papers, Reviews, and new ideas/proof-of-concept studies related to the in silico identification and functional interpretation of VUS apart from nonsynonymous and canonical splice sites. Different strategies in the WGS data analysis could be based on the specific VUS genomic context or on the affected biological processes, including, but not limited, to the following list:
• Variants in multiallelic sites (e.g., segmental duplications);
• Variants in mitochondrial genome;
• Variants affecting expansions of short tandem repeats (STRs);
• Regulatory variants in UTRs/ncRNA interacting with proteins and miRNAs;
• Exonic/intronic variants affecting splicing regulation;
• Variants affecting imprinted genomic regions.
Topic Editor Daniel Koboldt holds a technology license for software related to the Research Topic subject. All other Topic Editors declare no competing interests.
Keywords: genomic variation, variant prioritization, functional genomics
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