Molecular Phylogenetics and Evolution 67 (2013) 541–545

Contents lists available at SciVerse ScienceDirect

Molecular Phylogenetics and Evolution

journal homepage: www.elsevier.com/locate/ympev

Review

Evolution and function of de novo originated genes

Dong-Dong Wu ⇑, Ya-Ping Zhang ⇑
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

a r t i c l e i n f o a b s t r a c t

Article history: De novo origination has recently been appreciated to be an important mechanism contributing to the ori-
Received 6 December 2012 gin of genes. Evidence indicates that de novo originated genes can evolve important and even essential
Revised 10 February 2013 functions rapidly. We present an ‘‘adaptation following neutrality’’ process to explain the evolution of
Accepted 13 February 2013
essential function of new genes. How new de novo originated genes become involved in pathways and
Available online 27 February 2013
interact with other old genes, and the exact functions of these new genes, however, remains largely
undocumented. Examinations of the function of de novo origin and the function of noncoding RNA genes
Keywords:
should become more frequent and appreciated in the future studies.
De novo origin
New gene
Ó 2013 Elsevier Inc. All rights reserved.
Evolution

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
2. De novo origination of genes, and its contribution to the origin of new genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
3. Roles in lineage specific adaptation of de novo originated genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
4. From evolution to function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
5. ‘‘Adaptation following neutrality’’ process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
5.1. Neutral process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
5.2. Adaptive process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544

1. Introduction zero’’ in a paper he published in 1976 (Jacob, 1977). De novo orig-

Emergence of new genes provides the raw material for evolu-
tionary innovation. New genes can originate through multiple
mechanisms such as duplication, lateral gene transfer, gene fu-
sion/fission, and de novo origination (Long et al., 2003). De novo
origination is mechanism by which genes originate from non-func-
tional DNA regions – a sequence that was previously not a gene.
Previously, it was assumed that the de novo origin of a gene was
a very rare process. Susumu Ohno, in his book ‘‘Evolution by Gene
Duplication’’ (Ohno, 1970), proposed that all new genes arise from
existing genes, and that the de novo gene origination of a gene
from a random sequence would be highly unlikely. Francois Jacob
even claimed that ‘‘the probability that a functional protein would
appear de novo by random association of amino acid is practically
⇑ Corresponding authors. Fax: +86 871 65130513.
E-mail addresses: dongdongw86@yahoo.com.cn (D.-D. Wu), zhangyp@mail.k-
iz.ac.cn (Y.-P. Zhang).
inated genes however, have been identified with the advent of
large scale of genomes, and the development of comparative
genomics. The de novo origination of genes has received increasing
attention recently (Ding et al., 2012; Tautz and Domazet-Loso,
2011; Wu et al., 2011; Zhou et al., 2008).
2. De novo origination of genes, and its contribution to the
origin of new genes
Since 2006, the de novo origin of genes has been studied in
many species, including Drosophila (Begun et al., 2007; Chen
et al., 2007, 2010; Levine et al., 2006; Zhou et al., 2008), mammals
(Meunier et al., 2012), primates (Toll-Riera et al., 2009; Xie et al.,
2012), humans (Knowles and McLysaght, 2009; Li et al., 2010a;
Wu et al., 2011), mouse (Heinen et al., 2009), yeast (Cai et al.,
2008; Carvunis et al., 2012; Ekman and Elofsson, 2010; Li et al.,
2010b), rice (Xiao et al., 2009), Arabidopsis thaliana (de Felippes

1055-7903/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ympev.2013.02.013
542 D.-D. Wu, Y.-P. Zhang / Molecular Phylogenetics and Evolution 67 (2013) 541–545
et al., 2008), Plasmodium vivax (Yang and Huang, 2011), Escherichia
coli (Delaye et al., 2008) and viruses (Sabath et al., 2012). The de
novo origination of genes has occurred widely during evolution
in viruses, prokaryotes, and eukaryotes.
Species of Drosophila have commonly been used for the study of
the origin and evolution of new genes due to their extensively
characterized biology and the availability of complete genome se-
quences for a number of species that diverged relatively recently
(Clark et al., 2007). In 2006, Levine et al. identified five genes de-
rived from non-functional DNA in Drosophila melanogaster (Levine
et al., 2006), a first example of de novo originated genes. A subse-
quent study by Begun et al. found that the Acp genes originated
from noncoding DNA, and coded for small proteins in Drosophila
(Begun et al., 2006), while in a second study in 2007, Begun et al.
identified several genes with testis-biased expression that evolved
de novo in the Drosophila yakuba/Drosophila erecta clade (Begun
et al., 2007). In a genome-wide study in 2008 by Zhou et al. nine
genes were identified that originated de novo, and with this the
authors proposed that the de novo origin of genes plays an impor-
tant role in the origination of new genes. Zhou et al. (2008) con-
cluded that about 11.9% of the new genes that originated during
the evolution of the D. melanogaster complex had arisen through
the process of de novo origin. Similar to Zhou et al. (2008), Zhang
et al. (2010) used a genome wide synteny-based method to date
the origin of Drosophila melanogaster protein coding genes on the
Drosophila phylogeny. A total of 947 genes were found to have
originated on the lineage leading to the D. melanogaster within
Sophophora subgenus, of which 843 originated by gene duplication
and 104, or approximately 11%, originated de novo during the evo-
lution of D. melanogaster.
Another species that has been studied extensively for the de
novo origin of genes is our own, humans, with the genomes of
many closely related primates used to help identify young genes
(Fig. 1). In 2009, Knowles and McLysaght were the first to identify
human de novo genes, finding three putative de novo originated
protein coding genes: CLLU1, c22orf45, and DNAH10OS. These three
genes were found in the human genome by employing a protein
similarity procedure, and Knowles and McLysaght (2009) esti-
mated that about 0.075% of the human protein coding genes may
have originated de novo from noncoding regions. In 2010, another
de novo protein-coding gene C20orf203, which is associated with
brain function in humans, was found by Li et al. (2010a). Using a
genome wide synteny based strategy that used in Drosophila
(Fig. 1), Zhang et al. (2011) identified 1828 primate specific genes,
389 human specific genes, 3111 rodent specific genes, and 1452
mouse specific genes, including 82, 14, 251 and 61 genes, respec-
Ortholog
Fig. 1. Phylogenetic tree of primate species that have high quality genome sequences. Genome data from closely related species help identify new genes based on the synteny
of orthologous genes. New genes that have no homology with any other gene are likely to have originated de novo.
tively in each of those lineages, that had no homology with other
proteins found in humans and mice (provided by Dr. Yong E.
Zhang). The genes that show no homology are probably de novo-
originated protein coding genes. The constant updates in the anno-
tations of genomes are a challenge for searches for new genes.
Gene annotations are frequently updated in gene database (e.g.
FlyBase, NCBI, UCSC and Ensembl), and new genes are frequently
removed from the updated database as the new genes are com-
monly under-represented in functional studies (Zhang et al.,
2012). The number of new genes, including de novo originated
genes, likely has been underestimated (Zhang et al., 2012). For
example, in a study by Wu et al. (2011), 27 de novo originated
genes were identified in the human lineage based on the version
56 of the Ensembl human protein annotation database, and an-
other 33 de novo genes that had been annotated as genes in earlier
version of the Ensembl database but had been removed from ver-
sion 56 of this database. Therefore, precise size of the repertoire of
young human genes is still unclear. The proportion of new protein
coding genes that originated de novo among all new genes that
originated in human lineage is possible about 10%, a percentage
similar to that seen in Drosophila.
The remarkable functions of noncoding RNAs, such as microR-
NAs and long noncoding RNAs, have been only recently been
appreciated (Bartel, 2004, 2009; Mercer et al., 2009). Studies on
the origin of these noncoding RNA genes, however, have been far
fewer than those for protein coding genes. Noncoding RNA genes
can emerge more easily than protein coding genes by de novo orig-
ination, due to the promiscuity of transcription and the lack of a
requirement of having coding potential. For example, (Meunier
et al., 2012) found that de novo origination and duplication mech-
anisms contributed to similar degrees to the origin of miRNA genes
during the evolution of mammals. This observation suggests that
rate of de novo origination of noncoding genes is higher than rate
of de novo origination for protein coding genes. The origin and evo-
lution of de novo noncoding genes deserve more attentions. Iden-
tifying new long noncoding RNA genes that originated de novo
however is difficult. While it is relatively easy to find an expressed
RNA in a lineage, finding its orthologous sequence in another line-
age, and proving that it is not expressed is difficult.
3. Roles in lineage specific adaptation of de novo originated
genes
Evidence for the role of the lineage specific adaptation of de
novo originated genes comes primarily from studies of orphan
New gene
 D.-D. Wu, Y.-P. Zhang / Molecular Phylogenetics and Evolution 67 (2013) 541–545
genes, genes that lack homologues in other genomes. Orphan genes
mainly originate by the de novo mechanism, although others
mechanisms such as divergence following gene duplication also
contribute to their number (Khalturin et al., 2009; Tautz and Dom-
azet-Loso, 2011). De novo originated protein coding genes in Dro-
sophila typically demonstrate a testis biased expression pattern
(Begun et al., 2007; Chen et al., 2007; Levine et al., 2006). Similarly
in the house mouse (Mus musculus), the de novo originated gene
Poldi, which appeared within the past 2.5–3.5 million years, is also
expressed highly in the testis. Knockout of Poldi in mice results in
reduced sperm motility and testis weight (Heinen et al., 2009). Hu-
man de novo originated genes demonstrate a relatively higher level
of gene expression in testis (Wu et al., 2011). It is not only de novo
originated genes, but also newly duplicated and chimeric genes
that show a testis-biased expression (review in Kaessmann
(2010)). The testis appears to be a catalyst for the birth and evolu-
tion of new genes in animals (Kaessmann, 2010). Kaessmann spec-
ulated that the chromatin state in spermatocytes and spermatids,
with widespread demethylation of CpG enriched promoter se-
quences and the presence of modified histones in spermatocytes
and spermatids (Kleene, 2001), would cause an elevation in the
levels of components of the transcriptional machinery and permit
promiscuous transcription of nonfunctional sequences, and should
facilitate the initial transcription of a newly arisen gene (Kaess-
mann, 2010). Expression of de novo genes in the testis also sug-
gests that they might be associated with male reproduction, and
therefore could significantly contribute to lineage specific adapta-
tion and/or species incompatibilities.
During human evolution cognitive ability have improved, which
is often assumed to be attributable to the rapid evolution of brain
(Gilbert et al., 2005; Vallender et al., 2008). Great efforts have been
made to explore the genetic basis of improved cognitive ability in
humans (Hill and Walsh, 2005), such as examining the contribu-
tions of positive natural selection on brain development genes
(Sabeti et al., 2006) and the changes in the expression (Cáceres
et al., 2003; Giger et al., 2010; Khaitovich et al., 2006) and alterna-
tive splicing of genes that are expressed in the brain (Lin et al.,
2010). The discovery of new genes has provided new information
and new strategies for this field. Zhang et al. (2011) found that hu-
man fetal or infant brain have recruited larger proportion of young
genes, including genes from both duplication and de novo origina-
tion, and that young human genes have an expression pattern
biased toward the early developing brain. Li et al. identified the hu-
man-specific de novo-originated protein coding gene FLJ33706
(C20orf203) that is abundantly expressed in the brain, with ele-
vated expression levels found in the brains of Alzheimer patients
(Li et al., 2010a). Among 60 identified human-specific de novo-
originated protein coding genes, several have high expression in
the cerebral cortex (Wu et al., 2011). It is possible that these genes
are involved in brain-associated traits, such as the development of
cognitive ability, and were co-opted with a high expression level to
brain tissues during the evolution of humans, for increased cogni-
tive abilities.
4. From evolution to function
De novo-originated protein coding genes can now easily be re-
trieved from genomes, particularly with the advent of large-scale
genome sequencing of closely related species and the development
of comparative genomics (Fig. 1). Despite the identification of a
large number of de novo originated genes, few have much informa-
tion about their exact functions. Functional studies have mainly fo-
cused on expression data, with little true functional studies. Most
of the identified de novo originated genes likely have minor func-
tions, however, some may have significant and even essential func-
tions. De novo originate genes may have evolved interactions with
543
other genes that have important impact in complex pathways.
Studies on the precise function of these new genes should help
us to understand the processes of adaptive evolution, speciation,
and development of lineage specific traits.
5. ‘‘Adaptation following neutrality’’ process
How a de novo gene evolves from non-functional DNA and then
evolves a function remains largely undocumented. It is speculated
that de novo originated genes could initially play a minor function
but could gradually become more complex over evolutionary time
(Siepel, 2009). Indeed, young genes tend to be shower, less ex-
pressed but evolve rapidly (Cai and Petrov, 2010; Carvunis et al.,
2012; Wolf et al., 2009). Based on the study on the de novo gene
birth in yeast, Carvunis et al. (2012) developed an integrative evo-
lutionary model whereby de novo origin of new genes could pro-
ceed through intermediate and reversible proto-gene stage:
common translation of non-genic ORFs after transcription would
bring about proto-genes, which would provide adaptive potential
by exposing variations hidden usually in non-genic sequences,
and some proto-genes could be retained over evolutionary time,
retained proto-genes could gradually evolve the characteristics of
protein coding genes due to some advantages under special envi-
ronment, but other proto-genes might lose.
However, new gene could evolve rapidly essential function. A
recent study has found that about 30% of the new genes found in
Drosophila are essential, suggesting that new genes often quickly
evolve essential function (Chen et al., 2010). This study included
16 de novo-originated genes, and it was concluded that 3
(18.75%) of them had became essential (Chen et al., 2010). Our
study identified two Drosophila melanogaster specific de novo-orig-
inated protein coding genes which play important and essential
roles (Wu et al., submitted for publication). These findings raise
that de novo originated gene can quickly evolve an essential func-
tion. How does a de novo-originated protein-coding gene that
likely plays only a minor function quickly evolve to have an impor-
tant, and even an essential, function? Here, based on knowledge
that we have gained from our studies, we propose an ‘‘adaptation
following neutrality’’ process, a process that is illustrated in
Fig. 2, which is similar with the model described in the Carvunis
et al. (2012), to address the issue that new de novo originated
genes could evolve rapidly important functions. We reasoned that
positive selection could drive new genes to evolve quickly impor-
tant or essential functions if genes obtain special adaptive func-
tions. The steps in the process are:
5.1. Neutral process
(1) The ancestral non-functional genomic region must first be
transcribed. Large portions of genomes are transcribed,
including regions outside known gene regions (sequences
accounted by the current set of annotated genes, including
both coding and noncoding genes). This pervasive tran-
scribed ‘‘dark matter’’ is presumed to comprise potential
novel protein coding transcripts, noncoding RNAs, and anti-
sense transcripts (Clark et al., 2011; Johnson et al., 2005;
Ponting and Belgard, 2010; Willingham and Gingeras,
2006), thus, the existing transcription promiscuity indicates
that this step is not difficult.
(2) The transcript must evolve a complete translatable ORF
(open reading frame), which can be translated into a novel
protein. A completed ORF can be produced by random evo-
lution. For example, a randomly simulated 1 Mb DNA
sequence there should include approximately 212 (range
169–257) ORFs that are longer than 100 amino acids in
length (simulation not shown). Indeed, with the advent of
544 D.-D. Wu, Y.-P. Zhang / Molecular Phylogenetics and Evolution 67 (2013) 541–545
(1) (2)
(3)
(4)
(5)
Fig. 2. Adaptation following neutrality explains how young de novo-originated
protein genes can quickly evolve essential functions. (1) Ancestral non-functional
region was transcribed; (2) transcript evolved a complete translatable ORF (open
reading frame); (3) properties of conformational variability of protein, or the
changed properties after mutation, due to the low selective constraints, help these
proteins to interact, even slightly, with other proteins, raising the possibility of
gaining very minor roles (e.g., regulation); (4) if the minor function of the new gene
increases the fitness of an organism, then the gene could be co-opted for this
adaptive function; (5) during the process of adaptive evolution, the significance of
the gene function could increases rapidly due to positive selection, and the gene
may come to play an increasingly important role. The de novo gene would therefore
quickly become essential.
large scale genome sequencing, genome wide comparison
have found many novel ‘‘orphan’’ genes (Khalturin et al.,
2009), which have complete ORFs but have no homology
to known genes in any other species indicating that they
are lineage specific (e.g. in primates (Toll-Riera et al.,
2009), yeast (Dujon, 1996), Drosophila (Domazet-Loso and
Tautz, 2003)) (see review Khalturin et al., 2009; Tautz and
Domazet-Loso, 2011).
(3) Conformational variability is a common property of proteins,
and mediates protein promiscuity (Tokuriki and Tawfik,
2009). For example, many enzymes can promiscuously cata-
lyze reactions other than those which they are primarily
characterized for (Khersonsky et al., 2006; Tawfik, 2010).
Such dynamism and promiscuity is fundamental for protein
evolvability (Tokuriki and Tawfik, 2009). New evolved pro-
tein sequences could interact slightly with many other old
proteins. Even slight interactions with other proteins will
be exposed to natural selection, raising the possibility of
gaining a very minor role (e.g., regulation) in pathways or
phenotypes.
5.2. Adaptive process
(4) If the minor functions of one of these new genes increase the
fitness of an organism, due to the changeable and fluctuating
environment, then the gene could then be co-opted for this
adaptive function by increasing the level of expression or
by selecting adaptive mutations that increase its ability to
interact or regulate the other key genes. Young genes indeed
show faster evolution and higher rate of adaptation than old
genes (Cai and Petrov, 2010). The phenotypic effects of
mutations in younger genes would be less likely to be dele-
terious and more likely to be adaptive (Cai and Petrov, 2010).
(5) During the process of adaptive evolution, the significance of
the gene function could rapidly increases due to positive
selection, and thus the gene may play an increasingly impor-
tant role in the pathway or the phenotype. The de novo gene
would therefore quickly become essential in the special
environmental condition.
The classical gene co-option process defines the acquisition of
new roles by ancestral characters or new characters from old ones,
regardless of whether a gene duplication has occurred or not (True
and Carroll, 2002). Here, we extend the scope of gene co-option,
and propose that the process of co-option can occur during the ori-
gin and evolution of de novo-originated genes by co-opting the pri-
mary minor function of a de novo originated gene. For example, in
the yeast Saccharomyces cerevisiae, Cai et al. (2008) identified a de
novo-originated protein coding gene, BSC4, which is transcribed
and translated with many minor functions, including a function
in the DNA repair pathway. During the evolution of S. cerevisiae this
species frequently transitioned between nutrient-rich and nutri-
ent-poor environments. When encountering starvation, S. cerevisi-
ae stops growing, entering a stationary phase, and experiences an
aging-like process. During this process, yeast should accumulate
additional mutations (Madia et al., 2007), therefore, DNA base exci-
sion repair is essential for yeast to survive this stationary stage
(Maclean et al., 2003). Since BSC4 functions in DNA repair, any ben-
eficial mutation would be rapidly selected, given that the expres-
sion of BCS4 is unregulated during the stationary stage (Cai et al.,
2008). In humans, de novo originated genes demonstrate a brain-
biased expression pattern (Li et al., 2010a; Wu et al., 2011; Xie
et al., 2012). Genes likely to be involved in brain-associated traits,
such as the development of cognitive ability, may have been co-
opted with a high expression level in brain tissues during the evo-
lution of humans to increase cognitive abilities.
Acknowledgments
We thank Prof. David Irwin for revising the manuscript and
Prof. Yong E. Zhang and two anonymous reviewers for their com-
ments and suggestions. This work was supported by grants from
the National Natural Science Foundation of China (31271339 to
DDW).
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