Lecture 3 'Human-specific duplicated genes and their role in human brain development and disease'

Question 1

how can we accumulate how long ago the duplication taks place?

Answer 1

Because we can see how many mutations and SNPs there are.
Aligning sequences between different haplotypes allows us to estimate the time to most recent common ancestor and reconstruct the evolutionary trajectory of the region.

Question 2

Segmental duplications

Answer 2

are genomic regions greater than 1 kilobase, with greater than 90% identical sequence. A segmental duplicated region is not showing a 100% similairity because there are mutations happend over time.
segmental duplications are the most seen in telomers and centromers, but also in other ‘hot-spots’
Segmental duplications can be evolutionary benefital and included genes or parts of genes

Question 3

core duplications

Answer 3

the oldest duplications are located in the core of the duplicated segment, new duplications are forming on the sides. Snowball effect –> the duplicated segment will increase over time.

Question 4

Why are neurological diseases linked to segmental duplications?

Answer 4

Because many genes located in highly duplicated regions serve critical neurodevelopmental functions

Question 5

fusion transcript

Answer 5

develops when there is only a part of the gene duplicated, which can lead to a new functional transcript. The potential consequences of these transcripts for protein expression depend on whether the fusion is in or out frame

Question 6

How to detect variation in segmental duplications between people?

Answer 6

With fluorescence in situ hybridization (FISH).
FISH uses fluorescent DNA probes to target specific chromosomal locations within the nucleus, resulting in colored signals that can be detected using a fluorescent microscope.

Analysis with sequencing can tell you more about the copy number but not about the orientation and arrangement of the segmental duplications.

Question 7

increasing genome complexity

Answer 7

segmental duplications –> new genes with new functions –> genetic deletions –> neurological disorders

Question 8

Genes arising from duplication events are not subject to strong selection, so can accumulate mutations at a greater pace

Answer 8

• Degenerative mutations may accumulate until eventually the duplicate becomes
  a pseudogene
• The duplicated copy may acquire a new function
• Both the ancestral and duplicated copies may acquire degenerative mutations,
  but the defects are complemented by the other copy (subfunctionalization)

Question 9

inserted segmental duplications

Answer 9

A segmental duplication can be inserted with a forward/direct orientation (H1) or a reversed/inverted orientation (H2).

Question 10

Koolen de Vries syndrome (microdeletion syndrome)

Answer 10

a syndrome where the reversed orientation of a duplicated gene has multiple duplications in it, 17q21.31. reconstructing the evolutionary history of 17q21.31 locus is possible with aligning