Table 1 Natural selection features associated with non-coding single-nucleotide variants mined in this work. Features are classified under different categories depending on the sequence context (i.e., position level, window level, and gene level) and evolutionary scale: interspecies (vertebrates, mammals, and primates, excluding humans), or recent and ongoing natural selection in humans. We note here that the query variant was excluded from the calculations involving mean allele frequencies and mean heterozygosity of a given region and that the variant allele frequency itself was not used as a feature in any training or pathogenicity prediction throughout the study
Category | Sequence context | Evolutionary scale | Model | Feature abbreviation used in this work | Definition | References |
|---|---|---|---|---|---|---|
Position-level and window-level features | Position-level | Interspecies (mammals) | A | GerpS | Base-wise Rejected Substitution (RS) score defined by Genomic Evolutionary Rate Profiling (GERP++ scores) from mammalian alignments, excluding humans | [63] |
Interspecies (mammals) | A | GerpN | Neutral evolution score defined by GERP++, excluding humans | [63] | ||
Recent and ongoing in humans | B | bStatistic | b Statistic: background selection score indicating the expected fraction of neutral diversity that is present at a site, with values close to 0 representing near complete removal of diversity as a result of selection and values near 1 indicating little effect. B-statistic was based on human single-nucleotide polymorphism data from Perlegen Sciences, HapMap phase II, the SeattleSNPs NHLBI Program for Genomic Applications, and the NIEHS Environmental Genome Project | [20] | ||
Interspecies (primates) | A | priPhCons | Primate PhastCons conservation score, excluding humans | |||
Interspecies (mammals) | A | mamPhCons | Mammalian PhastCons conservation scores, excluding humans | |||
Interspecies (vertebrates) | A | verPhCons | Vertebrate PhastCons conservation score, excluding humans | |||
Interspecies (primates) | A | priPhyloP | Primate PhyloP conservation score, excluding humans | [44] | ||
Interspecies (mammals) | A | mamPhyloP | Mammalian PhyloP conservation score, excluding humans | [44] | ||
Interspecies (vertebrates) | A | verPhyloP | Vertebrate PhyloP conservation score, excluding humans | [44] | ||
1000-bp window | Recent and ongoing in humans | B | meanDaf1000G | Mean derived allele frequency of variants in 1-kb window region calculated from the 1000 Genomes Project (excluding the query variant) | [11] | |
Recent and ongoing in humans | B | meanHet1000G | Mean heterozygosity of 1-kb window region calculated from the 1000 Genomes Project (excluding the query variant) | [11] | ||
Recent and ongoing in humans | B | meanMAF1000G | Mean minor allele frequency of variants in 1-kb flanking region calculated from 1000 Genomes Project (excluding the query variant) | [35] | ||
Recent and ongoing in humans | B | meanMAFGnomAD meanMAF_AFRGnomAD meanMAF_AMRGnomAD meanMAF_EASGnomAD meanMAF_FINGnomAD meanMAF_NFEGnomAD meanMAF_OTHGnomAD meanMAF_ASJGnomAD | Mean minor allele frequency of variants in 1-kb window region calculated from GnomAD genome data (excluding the query variant from the calculation). Mean MAF was assessed for the global population and for population-specific frequencies: Africans and African Americans (AFR), Admixed Americans (AMR), East Asians (EAS), Finnish (FIN), non-Finnish Europeans (NFE), Ashkenazi Jewish (ASJ), and other populations (OTH) | [35] | ||
30-kb window | Recent and ongoing in humans | B | TajimasD_CHB_pvalue TajimasD_CEU_pvalue TajimasD_YRI_pvalue | Tajima’s D p value: neutrality test that compares estimates of the number of segregating sites and the mean pair-wise difference between sequences. The test is performed within 3 subpopulations of the 1000 Genome Project, producing population-specific scores. | [65] | |
30-kb window | Recent and ongoing in humans | B | FuLisD_CEU_pvalue FuLisD_CHB_pvalue FuLisD_YRI_pvalue FuLisF_CEU_pvalue FuLisF_CHB_pvalue FuLisF_YRI_pvalue | Fu and Li’s F* p value: neutrality test that compares the number of singletons with the average number of nucleotide differences between pairs of sequences. Fu and Li’s D* p value: neutrality test that compares the number of singletons with the total number of mutations in a genomic region within a group. These tests are performed within 3 subpopulations of the 1000 Genome Project, producing population-specific scores. | [35] | |
10-bp window | Recent and ongoing in humans | B | CDTS | The Context-Dependent Tolerance Score (CDTS) represents the difference between observed and expected variations in Humans. The expected variation is computed for each nucleotide genome-wide as the probability of variation of each nucleotide depending on its heptanucleotide context. CDTS was computed on 11,257 unrelated individuals. | [36] | |
75-bp flanking region | N/A | D | GC | Percent GC in a window of ± 75 bp | [63] | |
N/A | D | CpG | Percent CpG in a window of ± 75 bp | [63] | ||
Gene-level features | Non-coding region of the closest gene (a) | Recent and ongoing in humans | C | ncRVIS | Non-coding RVIS is a measure of the departure from the genome-wide average number of common variants found in the non-coding sequence of genes with a similar amount of non-coding mutational burden in humans. ncRVIS was computed on an in-house collection of whole genome sequencing of 690 individuals. | [72] |
Interspecies (mammals) | C | ncGERP | Average GERP++ score across a gene’s non-coding sequence | [46] | ||
Coding region of the closest gene | Interspecies (primates) | C | dN/dS | Primate dN/dS ratio, providing a measure of the coding-sequence conservation across primates | [68] | |
Recent and ongoing in humans | C | pLI | Probability of being loss-of-function intolerant (intolerant of heterozygous and homozygous loss-of-function variants), assessed from the ExAC database. | [35] | ||
Recent and ongoing in humans | C | RVIS percentile | Residual Variation Intolerance Score (RVIS) percentile, a measure of the departure from the average number of common functional mutations in genes with a similar amount of mutational burden in humans. RVIS was assessed on sequence data from 6503 whole exome from the NHLBI Exome Sequencing Project (ESP) | [71] | ||
Recent and ongoing in humans | C | GDI | Gene Damage Index, a gene-level metric of the mutational damage that has accumulated in the general population, based on CADD scores and on the 1000 Genomes Project data | [70] | ||
Phylo-genetic gene features | N/A | C | familyMemberCount | Number of human paralogs of the gene: Family member count (FMC) in OGEE database | [74] | |
N/A | C | gene_age | The gene age is estimating the origination time of genes from the presence or absence of orthologs in the vertebrate phylogeny. | [73] |