Joaquín Dopazo

Clinical Bioinformatics Research Area,

Fundación Progreso y Salud,

Functional Genomics Node, (INB-ELIXIR-es),

Bioinformatics in Rare Diseases (BiER-CIBERER),

Sevilla, Spain.

A look at the human mutational

load from the systems biology

perspective

http://www.clinbioinfosspa.es/ http://www.babelomics.org @xdopazo @ClinicalBioinfo

Molecular Evolution and Medicine Symposium Temple University, Philadelphia, USA 16-17 September, 2017

A high level of deleterious variability

exists in the human genome

Variants predicted to severely affect the function of human protein coding genes known as loss-of-function (LOF) variants were thought:

To have a potential deleterious effect

To be associated to severe Mendelian disease

However, an unexpectedly large number of LOF variants have been found in the genomes of apparently healthy individuals: 281-515 missense substitutions per individual, 40-85 of them in homozygous state and predicted to be highly damaging.

A similar proportion was observed in miRNAs and possibly occurs in any functional element in the genome

Problem: when a Loss-of-Function (LoF) variant is deleterious?

Highly relevant in diagnosis: more than 40% patients with Mendelian

diseases do not present a clear diagnostic variant, only VUS (variants

of unknown significance)

Deleterious variation in disease

Hypertension Diabetes

Dopazo et al., Mol Biol Evol, 2016

Deleterious variation of rare diseases is population-specific and is useful to detect new disease genes

However, interpreting disease in terms of single gene deleterious variation is naïve. Most human genetic diseases (actually, almost all traits) have a modular nature. Causative genes for the same or phenotypically similar diseases generally reside in the same biological module, either a protein complex, a sub-network of protein interactions , or a pathway

Goh 2007 PNAS

Usher Marfan

Co

mm

on

R

are

Potentially deleterious mutations

(LoF) are conditionally deleterious (learning from healthy individuals)

Abraham Wald’s original

WWII study. Where should

you put the armor?

Deleterious mutations in 1000g (up) and somatic CLL

deleterious mutations (down)

Garcia-Alonso 2014 Mol Syst Biol

• When LoF mutations

occur in the interactome

periphery you have

healthy people (1000g)

• When LoF mutations

occur in internal parts

you have disease (CLL)

LoF are conditionally deleterious

From left to right column: 1) Actual 1000g individuals, 2)

synthetic individuals with only LoFs observed in 1000g

randomly sampled, 3) same number of random LoF

Garcia-Alonso 2014 Mol Syst Biol

You may think that genes in the periphery

are less important but…

LoF observed in healthy

individuals are not

neutral with respect to

relevant network

properties.

Healthy individuals

seem to accommodate

LoF in a way that better

preserves network

properties

𝑆𝑛 = 𝜐𝑛 ∙ 1 − 1− 𝑠𝑎

𝑠𝑎∈𝐴

⋅ 1− 𝑠𝑖

𝑠𝑖∈𝐼

From individual gene

expression profiles

To profiles of circuit

activity (and cell

functional activity)

Two types of activities

Linking genotype to phenotype via cell

function: models of signaling pathways

LoF mutations can be introduced in the model as KOs in the proper transcriptional context

Signaling models uncover the molecular

mechanisms behind cancer hallmarks

Hanahan, Weinberg, 2011

Hallmarks of cancer: the next

generation. Cell 144, 646

Negative regulation of release of cytochrome c

from mitochondria (inhibition of apoptosis)

Impact of LoF mutations occurring in healthy people on human signaling

Signaling circuits that change across the human population tree

There are many circuits affected by

mutations linked to functions such as:

immune system, melanogenesis,

metabolism of lipids, glycolysis, hormones

(thyroid, progesterone, etc.), several

cancer pathways, etc. Asia (EAS)

Africa

Europe

Asia (SAS)

America

Tolerated LoF can combine without

increasing effect on signaling

Impact

on c

ircuit a

ctivity

Effect of mutations

on specific tissues

in KEGG pathways.

GTEx is used for

deriving an average

tissue value for

gene expression

and CADD>20 to

define a variant as

LoF. Recessive

model is assumed.

Like in PPI networks, pathways are robust structures that can undergo a

number of LoF mutations with lower impact than expected by chance

The use of new algorithms that enable the transformation of genomic

measurements into cell functionality measurements that account for

disease mechanisms and for drug mechanisms of action will ultimately

allow the real transition from today’s empirical medicine to precision

medicine and provide an increasingly personalized treatments

The real transition to precision medicine

Intuitive Based on trial

and error

Identification of probabilistic

patterns

Decisions and actions based on knowledge

Intuitive Medicine Empirical Medicine Precision Medicine

Today Tomorrow

Degree of personalization

Clinical Bioinformatics Research Area

Fundación Progreso y Salud, Sevilla, Spain, and…

...the INB-ELIXIR-ES, National Institute of Bioinformatics and the BiER (CIBERER Network of Centers for Research in Rare Diseases)

@xdopazo @ClinicalBioinfo Follow us on twitter

https://www.slideshare.net/xdopazo/