Significance of the resequencing of the chimpanzee genome

Question

Introductory remark: I am not a biologist, but a somewhat knowledgeable layperson.

I have been told that sequencing of chimpanzee DNA until recently has been done almost exclusively using human DNA as a “template” to help piece together short DNA sequences. The similarity that emerges to human DNA could then perhaps be somewhat misleading, as the structure of human DNA affects the end result obtained for chimpanzees.

However, recently (2018) a new study was performed in which the assembled DNA fragments from various apes were assembled completely separately from human DNA, giving a better estimate of the similarities and differences between the DNA of humans, chimpanzees and other apes (Kronenberg et al. Science vol 360 issue 6393, eaar6343).

What new information has emerged and to what extent does it alter previous results?

Answer 1

The effect of re-sequencing the great ape genomes (orangutan as well as chimpanzee) without the use of a human genome as a guide to assembly has in general been to correct mistakes and improve the ape genome sequences so that they can be compared better with the human genome.

As far as I am aware, it appears that in a broad sense the same genes are present in humans and great apes, i.e. each will have a similar (orthologous) gene for, e.g. insulin, trypsin, keratin, generally at the same position on the chromosome. As the species are different these differences are thought to come from differences in these orthologous genes or in the regions of the genome that control their expression as RNA and then protein. The differences could also affect their activity, where they are expressed in the body or whether different variants occur (by differential splicing of transcripts).

So with improved and independent genome sequences it was possible to identify a greater number of variants in these orthogonal genes.

The focus of this work was on genes that are expressed in brain cells, because a key feature that distinguishes man from the great apes is brain size. The interest was in genes that were found in separate experiments to have significantly different expression when glial or neuronal cells of human or non-human species were compared. The authors report mutational variation in 252 genes with such differences in glial cells and 123 in neuronal cells.

To quote the discussion:

These improved genomes yield a comprehensive view of intermediate-size structural variation among apes. As we focused on SVs (structural variants) that potentially disrupt genes or regulatory sequences, we began to address potential functional effect. Differential gene expression, especially in cortical radial glia, has been hypothesized to be a critical effector of brain size and a likely selective target of human brain evolution. Nearly 41% of the genes down-regulated in human radial glia, when compared to chimpanzee radial glial analogs from cerebral organoids, associate with an fhSV (fixed human-specific structural variants) and most often as a deletion or a retroposon insertion. These findings are consistent with the “less-is-more” hypothesis, which argues that the loss of functional elements underlies critical aspects of human evolution.

So, they haven’t found what makes us human yet, but have laid the foundations for studies that may at least find out why we have bigger brains.