Potential damaging mutation in LRP5 from genome sequencing of the first reported chimpanzee with the Chiari malformation

Abstract

The genus Pan is the closest related to humans (Homo sapiens) and it includes two species: Pan troglodytes (chimpanzees) and Pan paniscus (bonobos). Different characteristics, some of biomedical aspect, separate them from us. For instance, some common human medical conditions are rare in chimpanzees (menopause, Alzheimer disease) although it is unclear to which extent longevity plays an active role in these differences. However, both humans and chimpanzees present similar pathologies, thus, understanding traits in chimpanzees can help unravel the molecular basis of human conditions. Here, we sequenced the genome of Nico, a central chimpanzee diagnosed with a particular biomedical condition, the Chiari malformation. We performed a variant calling analysis comparing his genome to 25 whole genomes from healthy individuals (bonobos and chimpanzees), and after predicting the effects of the genetic variants, we looked for genes within the OMIM database. We found a novel, private, predicted as damaging mutation in Nico in LRP5, a gene related to bone density alteration pathologies, and we suggest a link between this mutation and his Chiari malformation as previously shown in humans. Our results reinforce the idea that a comparison between humans and chimpanzees can be established in this genetic frame of common diseases.

Figure 1

Nico.

Figure 2

PCA. (A) PC1 (22.88% of variance) in x-axis and PC2 (14.63%) in y-axis. (B) PC2 in x-axis and PC3 (8.85%) in y-axis.

Figure 3

Number of heterozygous positions across the genome per kbp and per chromosome in Nico. The y-axis shows the heterozygosity and goes from 0 to 3 for each chromosome, while the x-axis shows the ordered positions for each chromosome.

Figure 4

Schematic and zoomed representation of exons 2–17 of the LRP5 gene along with all the mutations having a score for the used predictors. Each box is a predictor, from top to bottom: SIFT, PolyPhen2-HDIV, PolyPhen2-HVAR, PROVEAN and MutationTaster. The five mutations are missense variants in heterozygosity. The rest of the mutations that do not appear here are all of them considered as low by SnpEff, being most of them synonymous variants. For a full view of the mutations in LRP5 in all the individuals, see Supplementary Fig. S17. Note: the mutation of the Central 4 have been moved to the right to make the visualization more comprehensive.