From mouse to human: evolutionary genomics analysis of human orthologs of essential genes

Abstract

Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ~12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease.

Figure 1. Functional and evolutionary characteristics of essential genes.

A) Distribution of the 2472 essential genes (EG) across the genome (obtained from www.ensembl.org). B) Essential genes are significantly enriched in HGMD disease genes (P = 1.73×10⁻¹⁴), haploinsufficient genes (P = 1.75×10⁻³³) and ubiquitously expressed genes (P = 9.23×10⁻²¹) when compared to NLG. C) Comparison of non-synonymous to synonymous substitution rates between human and rhesus, chimp, mouse and rat in EG, NLG and ALL. Plotted substitution rates are normalized to Z-scores relative to the genome average.

Figure 2. Population genetics properties of essential genes.

A) Average numbers of exonic missense variants in EG, NLG and ALL. The plotted Z-score is normalized relative to the genome average. The plotted range is truncated to visualize differences between gene sets, with a full log-transformed plot available in Figure S7. B) Differences in the allele frequency distributions in four continental populations of the 1000G data for EG, NLG and ALL. A data point above the zero line corresponds to a relative excess of variants of a given allele frequency. It can be seen that the essential genes contain significantly more rare variants than either NLG or ALL. The reported p-values are with respect to all 1000 Genome samples combined.

Figure 3. Analysis of individual mutational load in essential genes.

The boxes span the lower and upper quartile with the median indicated by a red bar; whiskers extend to data points less than 1.5 times the interquartile range. Values are transformed to Z-scores relative to the genome average of all protein coding genes. The P-values given are for the comparison of EG versus NLG (top) and EG versus ALL (bottom). A) Ratio of non-synonymous to synonymous exonic variants. B) Gene-length corrected average number of exonic missense variants. C) Fraction of loss-of-function variants among all exonic missense variants. D) Estimates of mutational load in essential genes in each human genome at different allele frequencies. The plots show all exonic missense variants (blue), putative damaging exonic variants (orange) and loss-of-function variants (red). Error bars depict the standard deviation.

Figure 4. Analysis of enrichment of essential genes among genes with de novo mutations in ASD families from four recent studies.

Gene-length and GC content adjusted odds ratios (OR) and P-values for enrichment in EG in either (A) ASD affected probands or (B) family-based controls (i.e. unaffected siblings) are shown.