Genomics in Molecular Medicine

Genomics in Molecular Medicine
Comparative Genome Analysis
Workshop: What can the genome tell us about what makes us human?
To get the most out of the workshop, please read the following papers and reviews,
the PDFs are available on Moodle .
1. Nitzan Mekel-Bobrov, et al.
Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens
Science 309, 1720 (2005);
Patrick D. Evans, et al.
Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in
Humans Science 309, 1717 (2005);
Links Between Brain Genes, Evolution And Cognition Challenged
Science (2006) 314 1872
2. P.D Currie
Muscling in on hominid evolution
Nature (2004) 428 373
3. Geschwind and Konopka
Genes and Human Brain evolution
Nature (2012) 486 481
4. Ponting and Lunter
Human brain gene wins genome race
Nature (2006) 443 149
5. Faraneh Vargha-Khadem, David G. Gadian, Andrew Copp & Mortimer Mishkin
FoxP2 and language extracts from: FOXP2 and the neuroanatomy of speech and
language – on Moodle
Extracted from Nature Reviews Neuroscience (2005) 6,
And there is a good overview in
Mining the molecules that made our mind
Science 2006 313 1908 read this first.
Then, go through the guidance notes and questions below:
1. Do the genes microcephalin and ASPM determine the size of the brain?
i. What is the outcome when either the microcephalin or the ASPM gene are
mutated in humans?
ii. Does this give us a clue to the normal function of the gene?
iii. What test was done to identify these genes as candidates for the evolution of a
larger brain?
iv. Looking at the different sequences (haplotypes) of the ASPM gene, what
conclusions did they draw from their geographical distribution?v. Is there any evidence that the haplotypes contribute either to brain size or
cognitive ability?
vi. for a more philosophical debate about brain size and why the number 150 is
important to humans see:
http://www.theguardian.com/technology/2010/mar/14/my-bright-idea-robin-dunbar
2. Has a muscle mutation allowed the cranium to expand in humans?
i. How many different myosin genes are there in humans?
ii. Which one is a non-functional pseudogene in humans and where is it normally
found?
iii. What advantages have been proposed for the consequences of the possession of
a non-functional myosin pseudogene in humans?
iv. What changes in behaviour must have happened around the same time?
3. What determines the increased complexity of the human brain?
i. How many copies of the SRGAP2 gene are there in humans and when did they
arise?
ii. What is a dendritic spine and what is the role of SRGAP2C in the formation of
dendritic spines?
iii. Why might slower maturation and greater migration of neurons result in a more
complex brain?
iv. How could the function of SRGAP2C be tested experimentally?
4. Is it just protein coding genes that affect brain evolution?
i. How was the Har1F gene identified as a gene that has evolved rapidly in the
human lineage?
ii. Where is the Har1F gene expressed in humans and why is this significant?
iii. What do many of the HAR regions encode and what function might these
molecules perform?
5. Is there a genetic component to speech?
i. What approach was taken to find a gene that is associated with speech. Why was
the KE family important?
Ii What type of protein does FoxP2 express and where is it expressed?
iii. How conserved is the FoxP2 gene and is there any evidence for evolution of this
gene in the human lineage? Is this evolution in promoter or amino acid coding
regions?
iv. What other experiments could you do to look at the function of the FoxP2 gene in
speech.