A

High-Resolution Map of

Evolutionary Constraint

In the human genome

by Lindblad-Toh & colleagues, Nature 2011

Presented by Nacho Caballero

Constrained Diversity

Is the Key to Comparative Genomics

Average # of Subs. per Site (Branch Length) 0.8 1.25 1.5 3 5

1+ subs 2+ subs 3+ subs 4+ subs

1 -

0.5 -

0 -

Percentage of Sites that Have Undergone Substitutions

0 1 2 3 4 6 5 Number of Neutral Substitutions per Site

0.5 -

0.3 -

0.1 -

0.8 subs/site 1.25 subs/site

3 subs/site 5 subs/site

1.5 subs/site

Percentage of Sites that Have Undergone Substitutions

4 Genomes - 50 bp

29 Genomes – 12 bp

4 genomes 29 genomes

NPAS4

Individual Binding Sites Higher Resolution Uncovers

bias

start stop

Evolutionary Signatures Help Discover Novel Genes

Synonymous Substitution Non-Synonymous Substitution

Frame-Preserving Indel Frame-shifting Indel

Stop Codons

Annotated as an Intron

Identify Stop-Codon Readthrough

1st stop codon 2nd stop codon

SACM1L

Synonymous Substitution Non-Synonymous Substitution

Frame-Preserving Indel Frame-shifting Indel

Stop Codons

Evolutionary Signatures Help

Identify Stop-Codon Readthrough

1st stop codon

2nd stop codon

Evolutionary Signatures Help

A Richer Picture of Conservation: Synonymous Constrained Elements

HOXA2

Basewise Conservation

Synonymous Constrained Rate

Enhancer   Enhancer  

A Richer Picture of Conservation: Codon-Specific Selection

dN/dS = 1 Neutral Selection dN/dS < 0.5 Purifying Selection

dN/dS > 1.5 Positive Selection

dN/dS = 1 Neutral Selection dN/dS < 0.5 Purifying Selection

dN/dS > 1.5 Positive Selection

A Richer Picture of Conservation: Codon-Specific Selection

dN/dS = 1 Neutral Selection dN/dS < 0.5 Purifying Selection

dN/dS > 1.5 Positive Selection

A Richer Picture of Conservation: Codon-Specific Selection

40% of the Constrained Genome

Is Uncharted territory

Constrained Diversity Is the Key to

Comparative Genomics

100-200 Mammalian Genomes

Will Allow Single-Nt Resolution