# PanSel: a tool finding conserved/divergent regions

Matthias Zytnicki

► To cite this version:

Matthias Zytnicki. PanSel: a tool finding conserved/divergent regions. Methods for Interfacing with Graphs of Genomic Sequences, Camille Marchet; Guillaume Gautreau; Thomas Derrien, Sep 2024, Rennes, France. hal-05064558

HAL Id: hal-05064558

https://hal.inrae.fr/hal-05064558v1

Submitted on 12 May 2025

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# PanSel: a tool finding conserved/divergent regions

Matthias Zytnicki

MIAT, INRAE

MIGGS 2024
Introduction

* Transition from a unique (reference) genome to a pangenome requires adaptation of many downstream tools (mapping, visualization, etc.).

* Among them: how to find conserved/divergent regions?

* General aim: is my gene of conserved/divergent in the species?

<figure><img src="image_2.png" /></figure>
Current tools GERP/GERP++, PhastCons, PhyloP, etc)

* Use a global inter-species alignment, and a phylogeny.

* Infer the branch length at each position.

* Quantify the conservation.

<figure><img src="image_3.png" /><figcaption>UCSC genome browser</figcaption></figure>
Back to pangenome graph

* Most of the information is in the graph.

* Phylogenetic tree is probably not defined.

* I did not find a way to get a base-level score (please feel free to suggest!).

* Rough idea:

* use a sliding window

* compute a simple “edit distance” between each pair of haplotypes

* compute the mean edit distance: this is your score!

* Used PanSel on the Draft Human Pangenome, with the MiniGraph-Cactus GFA files. Bin sizes of 1k, 10k, 100k.
Step 1: find anchor nodes

* Parse all the paths.

* Get all the nodes that are shared by all paths.

* Find pairs distant by w (the bin size)

<figure><img src="image_4.png" /><figcaption>Sequence Tube Map</figcaption></figure>
Step 1: find anchor nodes

* Parse all the paths.

* Get all the nodes that are shared by all paths.

* Find pairs distant by w (the bin size)

<figure><img src="image_5.png" /></figure>
Step 1: find anchor nodes

* Parse all the paths.

* Get all the nodes that are shared by all paths.

* Find pairs distant by w (the bin size)

<figure><img src="image_6.png" /><figcaption>Sequence Tube Map</figcaption></figure>
Step 2: compute a weighted Jaccard index

Considering a bin:

* Extract all the sub-paths.

* For each pair of paths $P_1, P_2$, compute

$$ \frac{\sum_{n \in P_1 \cap P_2} |n|}{\sum_{n \in P_1 \cup P_2} |n|} $$

* Compute the mean of it: this is the score for the bin.
Step 3: fit the distribution

* Transform [0, 1] values to $R_+$ using – log transform.

* Fit curve using a mixture of normal and log-normal (divergent distribution).

* Get a p-value for divergent and conserved distributions.

<figure><img src="image_7.png" /></figure>
Comparison with other data

<table><caption>Left column: most divergent bins; right column: most conserved bins.</caption><thead><tr><th></th><th>#variants</th><th>conservation</th><th>cons. HS</th><th>PST</th><th>HET</th><th>Tx</th></tr></thead><tbody><tr><td>1.5e+07-</td><td>•</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1.0e+07-</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>5.0e+06-</td><td>•</td><td>•</td><td>•</td><td>•</td><td>•</td><td>•</td></tr><tr><td>0.08-</td><td></td><td></td><td></td><td></td><td>•</td><td></td></tr><tr><td>0.06-</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.04-</td><td></td><td></td><td>•</td><td></td><td></td><td></td></tr><tr><td>0.02-</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.00-</td><td>•</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.95-</td><td></td><td>•</td><td></td><td></td><td></td><td>•</td></tr><tr><td>0.90-</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.85-</td><td></td><td></td><td>•</td><td></td><td></td><td></td></tr><tr><td>2.4e+08-</td><td>•</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2.2e+08-</td><td></td><td></td><td></td><td></td><td>•</td><td></td></tr><tr><td>2.0e+08-</td><td></td><td>•</td><td></td><td>•</td><td></td><td></td></tr><tr><td>1.8e+08-</td><td></td><td>•</td><td></td><td></td><td></td><td></td></tr><tr><td>1.6e+08-</td><td>•</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2.4e+07-</td><td>•</td><td>•</td><td></td><td></td><td></td><td></td></tr><tr><td>2.2e+07-</td><td></td><td></td><td>•</td><td></td><td></td><td></td></tr><tr><td>2.0e+07-</td><td></td><td></td><td></td><td>•</td><td></td><td></td></tr><tr><td>1.8e+07-</td><td></td><td></td><td></td><td></td><td>•</td><td></td></tr><tr><td>3.5e+07-</td><td></td><td></td><td></td><td></td><td></td><td>•</td></tr><tr><td>3.0e+07-</td><td></td><td></td><td></td><td></td><td>•</td><td></td></tr><tr><td>2.5e+07-</td><td></td><td></td><td>•</td><td></td><td></td><td></td></tr><tr><td>2.0e+07-</td><td>•</td><td>•</td><td></td><td></td><td></td><td></td></tr></tbody></table>

$w = 1k$
Example of divergent gene: *NBPF20*

<figure><img src="image_8.png" /></figure>

A: exons; B: GRCh38; C: CHM13; D-F: haplotypes.

Bandage-NG
GO ontology of divergent genes

<figure><img src="image_9.png" /></figure>

<table><thead><tr><th>ID</th><th>Source</th><th>Term ID</th><th>Term Name</th><th>P-value (query_1)</th></tr></thead><tbody><tr><td>1</td><td>GO:MF</td><td>GO:0001823</td><td>antigen binding</td><td>1.69×10<sup>-15</sup></td></tr><tr><td>2</td><td>GO:BP</td><td>GO:0050896</td><td>response to stimulus</td><td>3.170×10<sup>-15</sup></td></tr><tr><td>3</td><td>GO:BP</td><td>GO:0022510</td><td>adaptive immune response</td><td>5.840×10<sup>-15</sup></td></tr><tr><td>4</td><td>GO:CC</td><td>GO:0017944</td><td>cell periphery</td><td>1.275×10<sup>-15</sup></td></tr><tr><td>5</td><td>GO:CC</td><td>GO:0101620</td><td>membrane</td><td>2.962×10<sup>-15</sup></td></tr><tr><td>6</td><td>GO:CC</td><td>GO:0050886</td><td>plasma membrane</td><td>1.564×10<sup>-15</sup></td></tr><tr><td>7</td><td>GO:CC</td><td>GO:0019814</td><td>immunoglobulin complex</td><td>7.383×10<sup>-15</sup></td></tr><tr><td>8</td><td>GO:CC</td><td>GO:0042995</td><td>cell projection</td><td>2.851×10<sup>-15</sup></td></tr><tr><td>9</td><td>GO:CC</td><td>GO:0101645</td><td>cellular anatomical entity</td><td>3.488×10<sup>-15</sup></td></tr><tr><td>10</td><td>GO:CC</td><td>GO:0120025</td><td>plasma membrane bounded cell projection</td><td>2.566×10<sup>-15</sup></td></tr><tr><td>11</td><td>GO:CC</td><td>GO:0098590</td><td>plasma membrane region</td><td>5.360×10<sup>-15</sup></td></tr><tr><td>12</td><td>GO:CC</td><td>GO:0043005</td><td>neuron projection</td><td>4.709×10<sup>-15</sup></td></tr><tr><td>13</td><td>GO:CC</td><td>GO:0005737</td><td>cytoplasm</td><td>4.547×10<sup>-15</sup></td></tr></tbody></table>

version e111 eg58_p18 l463989d

date 8/21/2024, 2:55:15 PM

organism hsapiens

g:Profiler
Conclusions

* PanSel, a tool for the quantification of conservation using sliding windows.

* What is next?

* Do not use sliding windows anymore.

* What to do when there is no anchor node?

* Score is not very discriminative when bin size is low (many 1's).

Thank you for your attention!