Human evolution: DNA regions in our brain contribute to make us human

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With only 1% difference, the human and chimpanzee protein-coding genomes are remarkably similar.

Understanding the biological features that make us human is part of a fascinating and intensely debated line of research. Researchers at the SIB Swiss Institute of Bioinformatics and the University of Lausanne have developed a new approach to pinpoint, for the first time, adaptive human-specific changes in the way genes are regulated in the brain.

These results open new perspectives in the study of human evolution, developmental biology and neurosciences.

The paper is published in Science Advances.

Gene expression, not gene sequence

To explain what sets human apart from their ape relatives, researchers have long hypothesized that it is not so much the DNA sequence, but rather the regulation of the genes (i.e. when, where and how strongly the gene is expressed), that plays the key role.

However, precisely pinpointing the regulatory elements which act as ‘gene dimmers’ and are positively selected is a challenging task that has thus far defeated researchers.

Marc Robinson-Rechavi, Group Leader at SIB and study co-author says: “To be able to answer such tantalizing questions, one has to be able identify the parts in the genome that have been under so called ‘positive’ selection. The answer is of great interest in addressing evolutionary questions, but also, ultimately, could help biomedical research as it offers a mechanistic view of how genes function.”

A high proportion of the regulatory elements in the human brain have been positively selected

Researchers at SIB and the University of Lausanne have developed a new method which has enabled them to identify a large set of gene regulatory regions in the brain, selected throughout human evolution.

Jialin Liu, Postdoctoral researcher and lead author of the study explains: “We show for the first time that the human brain has experienced a particularly high level of positive selection, as compared to the stomach or heart for instance.

This is exciting, because we now have a way to identify genomic regions that might have contributed to the evolution of our cognitive abilities!”

To reach their conclusions, the two researchers combined machine learning models with experimental data on how strongly proteins involved in gene regulation bind to their regulatory sequences in different tissues, and then performed evolutionary comparisons between human, chimpanzee and gorilla.

“We now know which are the positively selected regions controlling gene expression in the human brain.

And the more we learn about the genes they are controlling, the more complete our understanding of cognition and evolution, and the more scope there will be to act on that understanding,” concludes Marc Robinson-Rechavi.

Most random genetic mutations neither benefit nor harm an organism: they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common ancestor. In contrast, an acceleration in that rate in a particular part of the genome can reflect a positive selection for a mutation that helps an organism to survive and reproduce, which makes the mutation more likely to be passed on to future generations.

Gene regulatory elements are often only a few nucleotides long, which makes estimating their acceleration rate particularly difficult from a statistical point of view.


Humans have brains with significantly increased size and complexity compared to their ape counterparts (Rakic, 2009; Chenn & Walsh, 2002; Lui, Hansen & Kriegstein, 2011). Corresponding alterations in intelligence have helped humans survive and create tools (Deary, 2012).

Inspection of human genomic differences from our closest evolutionary relatives could help us to understand the intelligence-related genetic events during hominid evolution. The intelligence difference is thought to be derived from changes in genetics, owing to a small fraction of the 1% of sequence differences between the human genome and the chimpanzee genome, in which the human-specific gene insertions, deletions, and duplications played a critical role (Cheng et al., 2005).

Various approaches in molecular biology have been used to search for the human-specific genes and mutations therein that were related to the human intelligence. Several candidate genes involved in human intelligence evolution were identified based on human-ape comparative genomic analysis, gene expression profiling and other functional evidences.

For example, in a very recent study, the information from gene expression profiling was integrated with the information from gene duplications in the ape and human lineages, which was then used to search for the human-specific genes that were highly expressed during human corticogenesis. In > 35 candidates obtained through bioinformatics analysis, NOTCH2NL was functionally investigated—it was found that the gene was able to promote the expansion of cortical progenitors, serving as an important gene contributing to the evolution of the human brain (Fiddes et al., 2018; Suzuki et al., 2018).

More recently, several human-specific genes have been identified and the critical genetic changes often occurred in gene regulation regions or resulted from the human-specific gene duplications; these include the NOTCH2NL gene, as well as FZD8, SRGAP2, ARHGAP11B, and TBC1D3, (Boyd et al., 2015; Dennis et al., 2012; Charrier et al., 2012; Florio et al., 2015; Ju et al., 2016).

As a highly heritable trait, intelligence has been intensively investigated using forward genetic approaches (Davies et al., 2015; Davies et al., 2016; Sniekers et al., 2017; Trampush et al., 2017; Zabaneh et al., 2018; Savage et al., 2018; Davies et al., 2018; Hill et al., 2016; Hill et al., 2019).

Several genome-wide association studies (GWAS) and meta-analyses using very large human populations have been performed to identify causative genomic loci and genes underlying intelligence. Despite a significant enrichment in the nervous system, the functional links of the identified genes are diverse in which a wide variety of genes are involved (Davies et al., 2015; Davies et al., 2016; Sniekers et al., 2017; Trampush et al., 2017; Zabaneh et al., 2018; Savage et al., 2018).

This suggests that the evolution of human intelligence is a complicated process. While most causative genes may directly affect the central nervous system, genes from many related biological processes may be involved in the intelligence evolution as well.

Investigating the human-specific variations (genetic differences between humans and great apes) could provide key clues for understanding the process of the evolution of human intelligence. As the assembling gaps and errors in the previous reference genomes of the great apes (e.g., the human sequence guided assembling from short reads), the previous genomes were not qualified enough for the detection of complex structural variations (Prufer et al., 2012; Scally et al., 2012; Prado-Martinez et al., 2013) such as tandem repeats, large-scale inversions, and duplications.

These structural variations usually play important roles in human evolution (McLean et al., 2011). Hence, comparative genomic analysis from the complete genome sequences of both humans and great apes is needed to comprehensively identify the genetic variation.

Recently, the high-quality genome sequences of three of human’s closest relatives, chimpanzee, orangutan, and gorilla, were generated from long-read sequencing (PacBio technology) and de novo assembling (Kronenberg et al., 2018; Gordon et al., 2016). The chromosome-level contiguous genome assemblies facilitate a deeper understanding of the genomic differences between these species.

Among a number of genomic differences between humans and apes, it is very important but technically difficult to know which variants are specific to intelligence. In order to further search out the candidate genes related to the evolution of human intelligence, we suppose that some intelligence genes may have both inter-species (between humans and the great apes) and intra-species (within humans) variations.

For intra-species variations, we collected genomic loci identified by several sets of GWAS on human intelligence, and genes in these loci (termed as intelligence-associated-genes) could be regarded to contain intra-species intelligence differences. For inter-species variation, genomic differences between humans and the great apes, revealed by recent high-quality sequencing (Kronenberg et al., 2018; Gordon et al., 2016), were used and filtered.

Hence, intelligence evolution was integrated by the overlap of intelligence-associated genes and human-specific variations. We found that many of the intelligence-associated genes, including tens of strong candidate genes related to the evolution of human intelligence, contained human-specific structural variations. Coupled with the expression profiling of the genes, this genome-wide analysis provided a useful resource for the evolutionary genetic studies on intelligence.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167246/


Source:Swiss Institute of Bioinformatics

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