Gene expression variability in human and chimpanzee populations share common determinants

Abstract

1Inter-individual variation in gene expression has been shown to be heritable and it is often 2 associated with differences in disease susceptibility between individuals. Many studies 3 focused on mapping associations between genetic and gene regulatory variation, yet much 4 less attention has been paid to the evolutionary processes that shape the observed 5 differences in gene regulation between individuals in humans or any other primate. To 6 begin addressing this gap, we performed a comparative analysis of gene expression 7 variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, 8 using gene expression data from primary heart samples. We found that expression 9 variability in both species is often determined by non-genetic sources, such as cell-type 10 heterogeneity. However, we also provide evidence that inter-individual variation in gene 11 regulation can be genetically controlled, and that the degree of such variability is generally 12 conserved in humans and chimpanzees. In particular, we found a significant overlap of 13 orthologous genes associated with eQTLs in both species. We conclude that gene expression 14 variability in humans and chimpanzees often evolves under similar evolutionary pressures. 15 comparative functional genomic studies. Here, we were able to collect the largest population 95 sample of chimpanzee primary tissues to date, allowing not only for sensitive assessment of 96 differences in mean expression levels between species, but also differences in variability within 97 species. To better isolate the genetic component of variability, we complemented the analysis of 98 gene expression levels with a comparative eQTL mapping approach. 99

The novel compound heterozygous rare variants may impact positively selected regions of TUBGCP6, a microcephaly associated gene

“…The MK test can be used to detect the violation of the neutral expectation, in which the ratio of non-synonymous and synonymous polymorphism (pN/pS) should be similar to the ratio of non-synonymous and synonymous divergence (dN/dS) (McDonald and Kreitman, 1991). Based on genomic analyses covering 26 chimpanzees (Fair et al, 2020;García-Pérez et al, 2021), 1,000 human individuals (Clarke et al, 2012), and the annotation of variants from gnomAD database (Gudmundsson et al, 2021), the MK test revealed that the divergence ratio (dN/dS = 1/5) is not significantly higher than the polymorphism ratio (pN/pS = 2/3, maf > 0.05) (p = 0.39). This result suggests multiple testable possibilities, including very weak positive selection in human protein of TUBGCP6, selection in regulatory regions instead of protein regions, selection in evolutionary past instead of modern human branch.…”

“…The statistical significance was estimated by following a chi-square distribution, with two times the difference in log-likelihood values and freedom degree as the difference in number of parameters for the two models. The MK test was based on the variants datasets covering 26 chimpanzees (Fair et al, 2020;García-Pérez et al, 2021), 1,000 human individuals (Clarke et al, 2012), and the annotation of variants from gnomAD database (Gudmundsson et al, 2021). HKA test and nucleotide diversity (π) based on human and chimpanzee genomic data were also performed along the genic coordinates (Hudson et al, 1987;Booker and Keightley, 2018).…”