Whole-exome screen identifies additional potential recessive mutations in the four candidate autism genes.

<p>Summary of the results of sequence analysis of the 4 candidate autism genes in an independent cohort of 418 autism cases and 371 controls from the ARRA Autism Sequencing Consortium. All four genes (<i>UBE3B</i>, <i>CLTCL1</i>, <i>NCKAP5L</i>, and <i>ZNF18</i>) were analyzed for recessive mutations, either homozygous or compound heterozygous.</p

Candidate autism genes identified in 4 AGRE patients.

<p>The Table summarizes genes identified by combined homozygosity mapping and whole exome sequencing, as described in the text. All mutations were homozygous in affected individuals and present within runs of homozygosity (ROH) ranging from 0.9–11.7 cM. All mutations were heterozygous in the parents, while unaffected siblings were either heterozygous or homozygous for the alternate allele. All candidate genes are expressed in the brain. Conservation scores were derived from the UCSC Genome Browser Vertebrate Multiz Alignment and Conservation (17 Species) track.</p

Regulation of four candidate autism genes by neuronal activity.

<p>qRT-PCR analysis of total RNA from depolarized mouse cortical neurons stimulated with KCl for 6 hours (the dashed line represents no KCl treatment, values are mean ± SEM from three independent experiments, each experiment was performed in triplicate, ***<i>P</i><0.0001, **<i>P</i><0.004, *<i>P</i><0.04, <i>t</i>-test).</p

Homozygosity analysis in the AGRE collection.

<p>(A) A plot of the percent homozygosity in the genome of probands from the entire AGRE collection. All affected individuals with runs of homozygosity (ROHs) >5 cM are plotted. Offspring of first cousin marriages are expected to have 6.25% homozygosity in their genomes, while those of second cousin marriages are expected to have 1.6%. IBD: identity by descent. (B) The average sizes of the ROHs in cM are plotted for each of the 16 AGRE samples that were sequenced. The number of the ROHs is shown in each bar. Values are mean ± SEM. (C) ROHs containing candidate disease variants are shared by affected individuals and absent from unaffected individuals. Sample names are indicated on the left (Aff.Sib: affected sibling, Unaff.Sib: unaffected sibling). Homozygous SNPs are shown in red or blue and heterozygous SNPs are shown in green. ROHs are enclosed in the dotted box. The candidate autism gene in each family is shown in navy below the ROHs. All other genes in grey did not contain rare, potentially pathogenic variants. No whole genome SNP data is available for individual AU035203, but we genotyped the sample for all homozygous variants identified by the whole exome sequencing of AU035204.</p

EIF1AX-regulated growth and translation in uveal melanoma.

<p><b>(A)</b> Distribution of <i>EIF1AX</i> mutations observed in cohort of 52 uveal melanomas in comparison to other cancer types (as reported by <a href="http://www.tumorportal.org" target="_blank">http://www.tumorportal.org</a>). <b>(B)</b> <i>EIF1AX</i> wild type (WT) or mutant (MUT) uveal melanoma cells were infected with <i>EIF1AX</i> or control shRNAs and cell viability was determined after 6 days using MTS. Percent growth is relative to shLuc-expressing cells. Error bars represent SD of mean from 3 independent experiments. <b>(C)</b> Immunoblot analysis of EIF1AX protein levels in shRNA-expressing cells. <b>(D)</b> Polysome profiles of cell lines expressing shRNAs against <i>EIF1AX</i> and <i>Luciferase</i>.</p

Somatic mutations in primary and metastatic uveal melanoma.

<p><b>(A)</b> The number of synonymous and nonsynonymous mutations per megabase of DNA sequence for 52 samples, arranged in columns. <b>(B)</b> Mutations in recurrently mutated genes are color-coded and ordered by significance. <b>(C)</b> Boxplots represent the distributions of allelic fractions observed per sample where the thick line represents 25-75^th percentile, and thin line 5-95^th. <b>(D)</b> The percentage of tumor cells (CCF) harboring a given mutation in the primary tumor in comparison to a metastatic liver sample from the same patient (UM45). <b>(E)</b> As in (D), but comparing a pre-treatment metastatic tumor sample to a post-treatment metastasis (Trio 2).</p

Decreased EIF1AX expression impairs translation of protein synthesis machinery in wildtype, but not mutated setting.

<p><b>(A)</b> Principal component analysis depicts 4 color-coded clusters of 141 genes. <b>(B)</b> The trend in translational efficiency is depicted for each cluster in cells expressing control shRNAs (CN) or <i>EIF1AX</i> shRNAs (KD). Each line represents a different gene. Ribosomal protein genes are highlighted in red. Translational efficiency was calculated as polysome CPM / total CPM. <b>(C)</b> Boxplots demonstrate the distribution of the translational efficiencies of 78 ribosomal proteins in cells as in (B).</p

SNP variants associated with lipid traits in CARe European Americans and African Americans.

<p>AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies all derived from ARIC (largest cohort for both African Americans and European Americans). Bold indicates the most highly associated SNP (lowest <i>P</i> value) at IBC significance (<i>P</i><1×10⁻⁶) for locus + trait + ethnicity. Direction is modeled on the first allele listed in Alleles column.</p

Independent SNP variants associated with lipid traits within single gene regions.

<p>AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies and R² values all derived from ARIC (largest cohort for both African Americans and European Americans). Direction is modeled on the first allele listed in “Alleles” column. Independent SNPs (when they exist) are indicated as: * = lowest <i>P</i> value for locus + trait + ethnicity; ** = lowest <i>P</i> value at or near IBC significance (<i>P</i><1×10⁻⁶) after conditioning on first SNP; *** = lowest <i>P</i> value at or near IBC significance (<i>P</i><1×10⁻⁶) after conditioning on first two independent SNPs; etc. Locus R2 values calculated from all independently significant SNPs at the corresponding locus.</p