Distribution of events of positive selection and population differentiation in a metabolic pathway: the

case of asparagine N-glycosylation

Our hypothesis

Selective constraints are not uniform among positions of a pathway

Genes in upstream positions, or with an higher number of interactions, should be more selectively constrained than  others

Pathway-level analysis

Pathway databases are not yet ready for large scale analysis

Too many false positives in the annotations The same annotation can have multiple 

interpretations

So, the best approach is to focus on single pathways, one at a time

The pathway of N­Glycosylation is a good start for studying how selective constraints are related to pathway position and degree

What is Glycosylation?

Glycosylation is a common form of post­translational protein modification

Almost 50% of the proteins in SwissProt are glycosylated 

(mostly membrane, secreted, signal proteins)

Glycosylation increases the protein's stability and is frequently used as a signal

N-glycosylation(upstream part)

Linear pathway Produces a single sugar 

called “N­Glycan precursor”

This sugar is required for the proper folding of most membrane proteins

Adapted from Stanley, P., Schachter, H., & Taniguchi, N. (2009). N-Glycans. Essentials of Glycobiology.

N-Glycosylation(upstream part)

The product of the upstream part of the N­Glycosylation pathway is used as a “label” for the folding status of proteins.

Folded proteins are marked with

Unfolded proteins are marked with              or

N-Glycosylation(downstream part)

Complex pathway composed by thousands of reactions

Produces multiple sugars, important for cell­to­cell interactions

Hossler, P., Mulukutla, B. C., & Hu, W.-S. (2007). Systems analysis of N-glycan processing in mammalian cells. PloS one, 2(1), e713. doi:10.1371/journal.pone.0000713

N-Glycosylation(downstream part)

Protein A

Surface of linfocite

Protein A

Surface of erithrocite

The products of the downstream part of the N­Glycosylation pathway are used to “decorate” proteins on the membrane

Downstream part of Glycosylation is involved in

immunity

Protein A

Surface of host's cell

Protein A

Surface of pathogen

Resume: structure of N-glycosylation pathway

Upstream: linear and conserved among species Downstream: complex and related to immunity Hypothesis: genetic diversity should be higher in 

the downstream part.

Results

Signatures of high F

ST are more 

frequent in the downstream part of the pathway

iHS signals are more or less equally distributed

My group!

● Jaume Bertranpetit (PI)● Hafid Laayouni (my 

supervisor)● Ludovica Montanucci● Pierre Luisi● Brandon Invergo● Marc Pybus● Ferran Casals● Martino Colombo

Protein A