PMC

Minimotifs show functional constraint. (A) Histogram of minimotif conservation. (B) Histogram of substitution rates for different genomic regions including minimotifs [n = 5 (50 000, 12 bp segments)]. **** indicates P < 0.0001 for differences in pairwise comparison to minimotifs SNPs. (C) Stacked Histogram for occurrences of variant SNPs located in minimotifs. Synonymous and nonsynonymous SNPs are shown. (D) Histogram for SNPs that alter the amino acid of a residue that is post-translationally modified (LOFMs). (C and D). The rare variant fraction has a MAF < 1%.

Some minimotif activities are more prone to selection than others. (A) Histogram of fraction of rare SNPs for different types of minimotifs. (B) Density plot showing the distribution of GERP scores (for different minimotif subactivities (see legends). A vertical line indicates the GERP score threshold of 2 (B). (C) Pie graphs showing the percentages of SNPs in different genomic regions and activity subgroups under neutral, negative, and positive selection as measured by the SLR statistic in Figure . Lipidation, O-glcnac, dephosphoryation and crotnylation had small numbers of minimotifs (n < 20).

Approximately half of nonsynonymous SNPs for minimotifs have undergone purifying selection. (A) Minimotif conservation plot showing PhyloP scores. (B) Histogram of fraction of rare SNPs for different genomic regions including minimotifs [n = 5 (50 000, 12 bp segments)]. **** indicates P < 0.0001 for differences in pairwise comparison to minimotifs SNPs. (C) Density plots showing the distribution of GERP scores for different genomic regions (see legend). A vertical line indicates the GERP score threshold of 2. (D) Pie graphs showing fraction of genomic elements with types of selection based on the SLR statistic for different genomic regions; see key, SLR < 4 = negative selection, 4 ≤ SLR ≥ 6 = neutral drift, and SLR > 6 = positive selection.

Minimotif alleles have a variable geographic distribution. Bin plot showing the intracontinental (A) and intercontinental (B) variability of DM and LOFM minimotif alleles. Continents are colored with primary colors and intercontinental relationships with related secondary colors. (A and B) Standard deviations were calculate from populations groups for the continents indicated (African – ASW, YRI, LWK; European – CEU, FIN, GBR, TSI; Asian – CHB, CHS, JPT). Abbreviations for populations are from the 1000 Genomes Project (). (C) A portion of the world atlas showing different minimotifs with intercontinental ΔDAFs > 50%. The embedded tables show the minimotifs, genes that contain the minimotif, minimotif functions and amino acid changes encoded by missense mutation alleles that have the highest differences between continental populations. Table rows that start with a ‘+’ indicate a DM and those with a ‘–’ indicate a LOFM. Continent and table colors are as in (A) and (B).

Most loss of function minimotifs have undergone purifying selection and most newly derived minimotifs have not. (A) Grid showing naming convention for SNPs that alter the modified residue of a minimotif and the frequency of alleles in humans and chimpanzees. (B) Quartile boxplots for GERP scores for LOFMs and DMs. The number of SNPs for each category is shown on top. A horizontal line indicates the GERP score threshold of 2. (C) Pie graphs showing the percentages of SNPs minimotif groups under neutral, negative, and positive selection as measured by the SLR statistic in Figure . (D) Ribbon diagram of the structure of the Alcohol Dehydrogenase 1B protein (1HSZ) showing the NADH cofactor (green), a β–strand for the last 5 amino acids in the protein (magneta) and the polymorphic amino acid involved in alcoholism (R370, magenta)().

SNPs present in histone minimotifs. (A) Surface plot of nucleosome showing locations of polymorphic minimotif residues. Histone H3 is colored light blue and DNA is colored gold. The structure is from 1AOI and accession number for the sequence is P02302. A portion of the N terminal tail of histone H3 that resolved in the crystal structure is shown as a stick figure with side chains colored red. The sequence of the portion of the N-terminal tail that did not resolve (residues 1–20) is shown as a sequence using single letter amino acid code. Labels in black or red bold font indicate sites of covalent modification in minimotifs. Fonts colored black are conserved and those colored red are polymorphic. Fonts colored cyan are neither polymorphic nor post-translationally modified. No polymorphic residues were located inside the core of histone H3. (B) Density plots for GERP scores for minimotifs present in the 53 human histones. A vertical line indicates the GERP score threshold of 2. (C) Pie graphs showing the percentages of histone minimotif SNPs groups under neutral, negative and positive selection as measured by the SLR statistic in Figure .