Introduction to Evolutionary Conservation

From Proteopedia

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Mutations occur spontaneously in each generation, randomly changing the amino acid sequences of proteins. Individuals with mutations that impair critical functions of proteins may have resulting problems that make them less able to reproduce. Harmful mutations are lost from the gene pool because the individuals carrying them reproduce less effectively. Over time, only harmless (or very rare beneficial) mutations are maintained in the gene pool. This is evolution.

Contents 1 Examples 1.1 Locations of Mutations in 3D Model 2 Finding Conservation 3 Notes and References

Examples

Consider the protein methyl CpG binding protein 2 (MeCP2; UniProt MECP2_HUMAN). Although its function is still unclear, it is expressed throughout the body, and disruption of its function causes problems with brain development and function^[1]. Some mutations in MeCP2 cause Rett Syndrome, a severely debilitating condition affecting mostly women.

Effect of mutation on protein function	Genetic consequence	Example
Function LOST**	CONSERVED: mutation LOST from gene pool	R133C*
None	NOT conserved: mutation remains in gene pool	E143?*
* in methyl CpG binding protein 2 (MeCP2), 3c2i. Amino acid sequence in 1 letter code:    ASASPKQRRS IIRDRGPMYD DPTLPEGWTR KLKQRKSGRS AGKYDVYLIN    PQGKAFRSKV ELIMYFEKVG DTSLDPNDFD FTVTGRGSPS RHHHHHH          ^          ^  ** Mutation R133C causes Rett syndrome, a severe neurological disorder. E143 is highly variable, so mutations here are harmless and remain in the gene pool. Gray: disordered in crystal, absent in model 3c2i.

Locations of Mutations in 3D Model

spinqualitylabelsall models MeCp2 protein bound to DNA (crystal structure 3cpi). Conservation calculated by ConSurf-DB. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The positions of conserved Arg133 and variable Glu143 are highlighted with  yellow  halos. You can see that conserved Arg133 is in intimate contact with the DNA, while variable Glu143 is on the surface, and remote from the contact with the DNA.

Finding Conservation

Evolutionary conservation in proteins is identified by aligning the amino acid sequences of proteins with the same function from different taxa (orthologs). As an example, we'll use the glycolytic enzyme enolase, present in a wide range of taxa. Take a quick look to get an impression of a multiple sequence alignment for ~400 amino acids in enolase for taxa ranging from eubacteria and archaebacteria through yeast, insects, and humans. In the full multiple sequence alignment is one  segment highlighted in pink . This segment is enlarged below.

Notes and References

1. ↑ MECP2 article in the National Library of Medicine's Genetic Home Reference