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Robust inference of positive selection on regulatory sequences in the human brain.

ABSTRACT: A longstanding hypothesis is that divergence between humans and chimpanzees might have been driven more by regulatory level adaptations than by protein sequence adaptations. This has especially been suggested for regulatory adaptations in the evolution of the human brain. We present a new method to detect positive selection on transcription factor binding sites on the basis of measuring predicted affinity change with a machine learning model of binding. Unlike other methods, this approach requires neither defining a priori neutral sites nor detecting accelerated evolution, thus removing major sources of bias. We scanned the signals of positive selection for CTCF binding sites in 29 human and 11 mouse tissues or cell types. We found that human brain-related cell types have the highest proportion of positive selection. This result is consistent with the view that adaptive evolution to gene regulation has played an important role in evolution of the human brain.

SUBMITTER: Liu J

PROVIDER: S-EPMC7695467 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Robust inference of positive selection on regulatory sequences in the human brain.

Liu Jialin J Robinson-Rechavi Marc M

Science advances 20201127 48

A longstanding hypothesis is that divergence between humans and chimpanzees might have been driven more by regulatory level adaptations than by protein sequence adaptations. This has especially been suggested for regulatory adaptations in the evolution of the human brain. We present a new method to detect positive selection on transcription factor binding sites on the basis of measuring predicted affinity change with a machine learning model of binding. Unlike other methods, this approach requir ...[more]

PMID: 33246961

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Project description:Gene regulatory factors (GRFs), such as transcription factors, co-factors and histone-modifying enzymes, play many important roles in modifying gene expression in biological processes. They have also been proposed to underlie speciation and adaptation. To investigate potential contributions of GRFs to primate evolution, we analyzed GRF genes in 27 publicly available primate genomes. Genes coding for zinc finger (ZNF) proteins, especially ZNFs with a Krüppel-associated box (KRAB) domain were the most abundant TFs in all genomes. Gene numbers per TF family differed between all species. To detect signs of positive selection in GRF genes we investigated more than 3,000 human GRFs with their more than 70,000 orthologs in 26 non-human primates. We implemented two independent tests for positive selection, the branch-site-model of the PAML suite and aBSREL of the HyPhy suite, focusing on the human and great ape branch. Our workflow included rigorous procedures to reduce the number of false positives: excluding distantly similar orthologs, manual corrections of alignments, and considering only genes and sites detected by both tests for positive selection. Furthermore, we verified the candidate sites for selection by investigating their variation within human and non-human great ape population data. In order to approximately assign a date to positively selected sites in the human lineage, we analyzed archaic human genomes. Our work revealed with high confidence five GRFs that have been positively selected on the human lineage and one GRF that has been positively selected on the great ape lineage. These GRFs are scattered on different chromosomes and have been previously linked to diverse functions. For some of them a role in speciation and/or adaptation can be proposed based on the expression pattern or association with human diseases, but it seems that they all contributed independently to human evolution. Four of the positively selected GRFs are KRAB-ZNF proteins, that induce changes in target genes co-expression and/or through arms race with transposable elements. Since each positively selected GRF contains several sites with evidence for positive selection, we suggest that these GRFs participated pleiotropically to phenotypic adaptations in humans.

Project description:Conditional logistic regression (CLR) is widely used to analyze habitat selection and movement of animals when resource availability changes over space and time. Observations used for these analyses are typically autocorrelated, which biases model-based variance estimation of CLR parameters. This bias can be corrected using generalized estimating equations (GEE), an approach that requires partitioning the data into independent clusters. Here we establish the link between clustering rules in GEE and their effectiveness to remove statistical biases in variance estimation of CLR parameters. The current lack of guidelines is such that broad variation in clustering rules can be found among studies (e.g., 14-450 clusters) with unknown consequences on the robustness of statistical inference. We simulated datasets reflecting conditions typical of field studies. Longitudinal data were generated based on several parameters of habitat selection with varying strength of autocorrelation and some individuals having more observations than others. We then evaluated how changing the number of clusters impacted the effectiveness of variance estimators. Simulations revealed that 30 clusters were sufficient to get unbiased and relatively precise estimates of variance of parameter estimates. The use of destructive sampling to increase the number of independent clusters was successful at removing statistical bias, but only when observations were temporally autocorrelated and the strength of inter-individual heterogeneity was weak. GEE also provided robust estimates of variance for different magnitudes of unbalanced datasets. Our simulations demonstrate that GEE should be estimated by assigning each individual to a cluster when at least 30 animals are followed, or by using destructive sampling for studies with fewer individuals having intermediate level of behavioural plasticity in selection and temporally autocorrelated observations. The simulations provide valuable information to build reliable habitat selection and movement models that allow for robustness of statistical inference without removing excessive amounts of ecological information.

Dataset Information

Robust inference of positive selection on regulatory sequences in the human brain.

Publications

Robust inference of positive selection on regulatory sequences in the human brain.

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