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Gene duplications: evolutionary role
Liliya Kazantseva
A suggestion 35 years ago that gene duplication is a key
factor shaping the evolution still attract much attention
today.
Fate of the duplicated genes
Classical view

One member of the pair becomes nonfunctional  pseudogene.

Evidence of transcription of pseudogene.
MYLKP1 inhibit the expression of parent gene MYLK.

Neofuncionalization
Phospholipase A2s in mammals  signal transduction, lipid digestion
and production of eicosanoids.
In snakes (Laticuadata laticuadata) it is important component of the
venom: appeared from non toxic gene.
Post duplicative divergence  accumulation
of nonsynonimous mutations  positive
selection.

Subfuncionalization
Original gene had two functions.
Protein in different
tissues
Duplication
Subfuncionalization
by mutations in
regulatory region
There is a portioning of ancestral functions between duplicated genes.
PAX6 is a transcriptional factor.
 Role in the eye, brain and endocrine pancreas cell development.
 Mutations  absence of eyes and brain abnormalities.
 In zebrafish is duplicated:
Pax6a  expressed in brain and retain the regulatory region for brain
expression.
Pax6b  expressed in developing pancreas has a downstream loss of
brain elements, while upstream evolved to be pancreas specific.

No functional divergence

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Robustness  molecular and morphological diversification
(evolutionary innovations)
Heart development is controlled by a network of transcriptional
factors genes, that have more duplications than in the ancestral.
MEF2  myocyte enhancer factor 2 is responsible of the contractile
proteins. Vertebrates have 4 copies of the gene.
Loss of function  no contractile proteins and right ventricle.
Multigene family: concerted evolution
Duplication


Recombination
Mutation
Gene family must evolve as a block.
This model is not able to explain the high diversity.
Homogenization
of the copies
Multigene family: birth and death evolution.


The original gene retains its function.
The duplicated gene suffers mutations  evolve via silent
synonymous nucleotide substitutions.
Phenotypic spectrum of duplicated
genes


The copy number increase of AMY1 (human salivary amylase gene)
 adaptation to high starch diet.
The copy number increase of CCL3L1 gene is associated with low
susceptibility to HIV infection.

Duplication in Charcot – Marie – Tooth disease  duplication of
PMP22 gene, that encodes major myelin protein.

This normally involves enzymes that show little variation in function
over gene duplication.

MECP2 (methyl – CpG – binding protein 2) is linked in the
transcriptional repression. Is involved in Rett syndrome.


Parkinson disease: duplication of SNCA (alpha synuclein).
Alzheimer disease: duplication of APP (amyloid beta precursor
protein). There are many mechanisms that lead to increase in the
aggregation, like Down syndrome or mutations in this gene.
Conclusions


Gene duplications are responsible for the phenotypic
variations in the disease.
Pathogenic duplications involve dosage sensitive genes
with both similar and dissimilar over and underexpression
phenotypes, and genes encoding proteins with a
propensity to aggregate.
References
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Condrad B, Antonarakis E. Gene duplication: a drive for phenotypic
diversity and cause of human disease. Annu Rev Genomics Hum Genet
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Pei B, Sisu C, Frankish A, Howald C, Habegger L, Mu XJ, Harte R,
Balasubramanian S, Tanzer A, Diekhans M, Reymond A, Hubbard TJ,
Harrow J, Gerstein MB. The GENCODE pseudogene resource.
Genome Biol 2012; 13:51.
Lynch VJ. Inventing and arsenal: adaptive evolution and
neofuncionalization of snake venom phospholipase A2 genes. BMC
Dev Biol 2007; 7:2.
Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB,
Damante G, Seawright A, Hever AM, Yeyati PL, van Heyningen V,
Coutinho P. Subfunctionalization of duplicated zebrafish pax6 genes
by cis – regulatory divergence. PloS Genet 2008; 4(2): e29.
Wagner A. Gene duplications, robustness and evolutionary
innovations. BioEssays 2008; 30: 367 – 373.