L1: Genomic basis of human traits

Question 1

How do primate brains compare to other species?

Answer 1

Primate brains are ~2 fold bigger than other species, based on the brain-body index.

Question 2

How do human brains compare to chimps?

Answer 2

Human brains are ~3 fold bigger than Chimpanzee brains. The brain size increased dramatically in the last 2 million years; deduced from cranial capacity. Earlier sizes were similar to chimpanzees. Even malnutritioned children, all energy goes into their brain development; big genetic drivers here although hampered by the availability of genomes to study this in early hominins.

Question 3

What shows expansion in our brain?

Answer 3

Most brain-structures have NOT extraordinarily expanded. The Neocortex, the part of our brain which we use to talk, think and create, shows the most dramatic evolutionary expansion; older structures relatively similar. Very small in rodents, hugely expanded almost like a tumour in humans.

Question 4

On what two levels does the expansion of the mouse progenitor pool occur in humans?

Answer 4

1) Radial Glial Cells: more self renewal
2) Intermediate Progenitors: In the primate brain, intermediate progenitors can divide up to 8 times before becoming neurons. In mouse, they divide only 2 times

Question 5

What layering differences are seen in the mouse and human neocortex?

Answer 5

The Primate neocortex exhibits an expanded proliferative compartment in the outer subventricular zone (OSVZ) (both form inside out)

Question 6

Why is it important to know about these anatomical evolutionary differences? (3)

Answer 6

• Subtle changes in progenitor proliferation kinetics can have huge size-consequences
• Lots of genes involved in progenitor cell division are associated with brain disorders that lead to a small brain (microcephaly)
• Small changes in gene expression in neuronal progenitor cells can have dramatic effects on brain size

Question 7

What is microcephaly?

Answer 7

Microcephaly is a disease associated with decreased brain size
* < 2SD below average head circumference
* Often associated with severe neurological/ neurodevelopmental defects
* Several genes are involved in brain size control
* Can we gain insights about the evolution of human brain size from these human genetic mutations?

Question 8

To what extent can we know the cause of a given case of microcephaly

Answer 8

50% of the time we know the cause of microcephaly; often to do with core processes in division- how the spindles are formed, how the processes are aligned. These also determine symmetric or asymmetric division.

Question 9

Name how 5 microcephaly (MCPH) loci may exert their effects

Answer 9

MCPH1 may affect premature mitotic entry leading to immature centrosomes. CDK5RAP2 and CENPJ can directly induce these immature centrosomes. Immature centrosomes can cause impaired spindle alignment. ASPM and SIL can also directly impair spindle alignment. Impaired spindle alignment can lead to higher levels of asymmetric cell divisions and thus a depletion of the cell pool.

Question 10

When we compare gene expression between humans and chimps, where do we see the most differences?

Answer 10

Differential gene expression highest in germ cells (testes). Virtually any tissue shows species-specific gene expression patterns. There are quite a lot of differences in every organ, the brain doesn’t even stand out, this was not expected. There are 10% differences in gene expression which is quite a lot. Testes stood out the most, this might be to do with inability to interbreed between species.

Question 11

What is likely the cause of the increase in the human brain?

Answer 11

The increase of the human brain is likely caused by multiple evolutionary changes, involving multiple different genes in our genome

Question 12

On what three levels does genomic evolution take place?

Answer 12

1) Changes in the coding part of genes
2) Changes in how genes are regulated - what tissues genes are expressed etc.
3) Creation of new genes / deletion of existing genes - Some times new genes will be created, other times you get these rearrangements creating these fusion genes/ transcripts.

Question 13

Give an example of changes on the coding part of our genes which could correspond to evolution in a particular human domain

Answer 13

The Molecular Evolution of FOXP2
* Just 2 amino acids different in human
* Mutation in FOXP2 results in speech disorders: people with mutations could understand language but could not speak it despite relatively normal cognitive abilities.
* Evolution of speech in humans?

Question 14

How was the FOXP2 gene function studied? What results were noted?

Answer 14

The ‘FOXP2’ Humanised mouse
* Carrying human FOXP2 gene
* Changes in learning ability and vocalisations

Question 15

Name three examples of recurrent genomic evolution of the FOXP2 gene locus

Answer 15

• Human: FOXP2 changes are ‘positively selected’, meaning the human species had benefits from these mutations
• Birds: FOXP2 involved in song learning in birds: parallel evolution?
  *Song birds in different locations with different
  vocalisations have differences in the FOXP2 gene.
• Bats: the FOXP2 gene is highly variable in bats, associates with differences in echolocation

Question 16

What did King & Wilson state regarding genes and evolution in 1975?

Answer 16

Changes in gene regulation, rather then the genes
themselves account for the differences between species: their macromolecules are so alike that regulatory mutations may account for their biological differences

Question 17

Give an example of a study which explored these regulatory mechanisms in a species

Answer 17

The genomic basis of adaptive evolution in threespine sticklebacks: These fish can live in salt or fresh water- have different anatomy despite having quite similar genomic profile. Put saltwater fish in freshwater and tracked in time what happened to them. Found that the marine sticklebacks slowly transformed to freshwater and vica versa.

Found severable gene points that were highly mutable. They found that these were in certain hotspots that are conserved across species. Shows that these changes can happen very rapidly, not just over hundreds of thousands of years. What are these hotspots? Could be due to instability. A lot died but those which survived made it work and repopulated the lake. Bought a big RV, turned it into a laboratory and went round fishing and shooting the shit.

Question 18

Give an example of increased complexity of gene regulatory networks in humans

Answer 18

GPR56:
The ancient adhesion GPCR gene likely consisted of a gene with a number of exons and a start site

Zebrafish GBR56 contains longer coding sequences and two transcription start sites. In mice you see an increase in these start sites and in humans you see a lot more.

You can see multiple different start sites in these genes and complexity rising over evolution in species with more complex brains.

Researchers found a deletion of 15BP in perisylvian polymicrogyria

Question 19

What could be the function of these increased start sites?

Answer 19

Not all sequences are driving expression, different cell types might use different promoters which affect how the gene is used. This depends on the promoters and regulators available in the cell. Increased gene-regulatory diversification (tissue-specificity; timing; strength etc) throughout genomic evolution could be a general trend

Question 20

Why might simpler species have smaller genomes?

Answer 20

Simpler species often have shorter genomes to speed up division, in more complex species there is a lot more investment in one member of the species- the bottleneck is very different.

Question 21

Where is conservation in our genome largely limited to?

Answer 21

The coding parts of our genome; New exons have emerged, new transcriptional start sites etc

Question 22

Why may non-coding regions be conserved?

Answer 22

Some regions not coding for anything are highly reserved and could be very important for the regulation of the gene, likely enhancement sequences.

Question 23

What are these new exons often due to?

Answer 23

You can see that new exons form in time, often this is due to retrotransposons. They hop backwards in the gene and are incorporated as new exons.