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Open questions in the study of de novo genes: what, how and why

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Abstract

The study of de novo protein-coding genes is maturing from the ad hoc reporting of individual cases to the systematic analysis of extensive genomic data from several species. We identify three key challenges for this emerging field: understanding how best to identify de novo genes, how they arise and why they spread. We highlight the intellectual challenges of understanding how a de novo gene becomes integrated into pre-existing functions and becomes essential. We suggest that, as with protein sequence evolution, antagonistic co-evolution may be key to de novo gene evolution, particularly for new essential genes and new cancer-associated genes.

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Figure 1: A systematic approach to the classification of novel genes.
Figure 2: Validation of novel genes.
Figure 3: Features of genome anatomy that alter the likelihood of novel gene origination.

Change history

  • 27 July 2016

    In Table 1 of the original version of this article the gene name NCYM was incorrectly written as NYCM. This has now been corrected. The editors apologize for this error.

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Acknowledgements

A.M. and L.D.H. are supported by funding from the European Research Council grant agreements 309834 and 669207, respectively.

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Correspondence to Aoife McLysaght.

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Glossary

Apert syndrome

A congenital disorder that is caused by the failure of appropriate apoptosis to occur during fetal development, resulting in malformed skull, face, hands and feet.

Biased gene conversion

Gene conversion (that is, the replacement of a DNA sequence by homologous sequence from the other allele at the same locus, or from elsewhere in the genome) involving a process that repairs mismatches in a non-random fashion. Gene conversion in mammals is thought to be weakly biased towards GC residues over AT residues.

dN/dS analysis

(Also known as Ka/Ks analysis). Analysis to determine the ratio of nonsynonymous substitutions per nonsynonymous site (dN) to synonymous substitutions per synonymous site (dS), which is indicative of the mode of evolution acting on a protein-coding gene. This is interpreted as purifying selection if less than 1; positive selection if greater than 1; and neutral evolution if effectively 1. The numbers of substitutions are estimated by counting the observed differences in orthologous genes identified in at least two different species.

Domesticated genes

Exogenous genetic material that has become incorporated into a genome and subsequently adapted for a host function.

Fixed

An allele is said to be fixed in a population once it rises to 100% frequency.

Independent lineage sorting

This phenomenon is observed when population polymorphism segregating in an ancestral species is maintained past two (or more) speciation events, such that the descendent species each contains alleles that date back to before the speciation events. The descendent species may each independently fix one or other of the ancestral alleles (independently sorting the alleles). When sister species fix different alleles to each other the phylogenetic relationship of the genes is different from the phylogenetic relationship of the species.

Maternal effect lethals

Loci in which the maternal genotype determines the viability of the zygote.

Meiotic drive

Any process that causes a given allele to be overrepresented in the gametes following meiosis. Most commonly, the term is restricted to cases in which the distorted segregation ratios affect whole chromosomes rather than just a particular chromosomal location.

Neofunctionalization

Evolution of a novel function, which may exist alongside an ancestral function or replace an ancestral function.

Open chromatin

Decondensed chromosomal structure associated with gene expression.

Orthologues

Homologous genes that diverged following a speciation event.

Paralogues

Homologous genes that diverged following a gene duplication event; duplicated genes.

Phylostratigraphic approach

An approach for estimating gene age based on its phylogenetic distribution. Commonly, genes are inferred to have been present in the common ancestor of any organisms in which they are detectable by sequence similarity search (such as BLAST), and their origin is assigned to the branch on the tree just prior to the node corresponding to that common ancestor. The term is a portmanteau of phylogenetics and stratigraphy, the latter being the study and dating of rock layers.

Purifying selection

(Also known as negative selection). Removal of deleterious mutations from a population by selection.

Red Queen co-evolution

Named after the Red Queen in Lewis Carroll's Alice Through the Looking Glass who is continually running to stay in the same place. This describes an evolutionary scenario in which two interacting loci (often one from a parasite and one from a host) are both rapidly evolving but the relationship (the interaction) has no qualitative change.

Selective sweeps

Positive selection on a DNA mutation that incidentally carries closely linked variation to high frequency, thus reducing the genetic diversity in the surrounding region of the genome.

Site frequency spectrum

Distribution of allele frequencies at a set of loci. The shape of the distribution can be used to infer demography and natural selection (for example, through hitchhiking).

Spurious gene expression

Gene expression with no selective advantage. A necessary concept but one that in practice is hard to demonstrate, not least because the strength of selective effects relevant to the evolutionary process is typically more subtle than the effects measured in the laboratory. Selective advantage may be defined with respect to the bearer genome or to a selfish element.

Subfunctionalization

Partitioning of functions of an ancestral, multifunctional gene between daughter paralogues.

Synteny

Meaning 'same chromosome', this describes the physical genetic linkage of two or more loci on a chromosome. A region of shared synteny between genomes (where the orthologous genes have an equivalent relative location) is indicative of genome arrangement conservation since their most recent common ancestor. In the context of de novo genes, the syntenic location in the ancestral genome is the expected location of origin of the gene.

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McLysaght, A., Hurst, L. Open questions in the study of de novo genes: what, how and why. Nat Rev Genet 17, 567–578 (2016). https://doi.org/10.1038/nrg.2016.78

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