J Mol Evol

DOI 10.1007/s00239-015-9668-x

RANDOM WALKING

The Life Histories of Genes

Esther Betran

Received: 23 January 2015 / Accepted: 27 January 2015

Springer Science+Business Media New York 2015

Genes do not only originate. Genes have their own life

histories. Life histories of genes might differ in the way the
genes originate, but also in how fast they become established, and how long they persist in the genome. To
understand the diversity of life histories of genes, it is
necessary to consider genes of various ages as each age
group can illustrate a different kind of life history. We can
find examples of the live fast, die young existence only
among young gene cohorts and of the live slow, die old
lifestyle within old genes. We gain this information using
the comparative genomics approach that is becoming
increasingly productive thanks to the abundance of wholegenome sequence data generated within the last 20 years.
Often, this genomic information is accompanied by age-,
tissue-, and sex-specific gene expression data as well as
functional studies that can give us a sense of the genes
function/s and complement the evolutionary analyses.
There are multiple mechanisms for the origin of genes
including gene duplication, horizontal gene transfer,
domestication of transposable elements or viruses, and de
novo formation from non-coding sequences. These mechanisms generate new protein-coding genes as well as new
non-coding RNA genes (e.g., microRNAs) and might
produce duplications at different rates in different regions
of the genome or in different lineages. Most of these new
genes are lost without ever reaching fixation in a population. Many of those that do fix are pseudogenized in the
absence of selection for their retention. But a small fraction
of new genes is functional and is integrated into previously

E. Betran (&)
Department of Biology, University of Texas at Arlington,
Box 19498, Arlington, TX 76019, USA
e-mail: [email protected]

established gene networks that participate in various biological processes. The differences in the life histories of
these new genes include the origination process, how fast
they become established in the genome, the strength and
nature of selection they experience, and their life span. I
will highlight some contrasting life histories here, although
there are many more possibilities that fall in between these.
I will argue that thinking about the genes from the perspective of their life histories helps us recognize gene
turnover patterns (i.e., patterns of recurrent gene gain and
gene loss) and, consequently, should help us understand the
selective pressures experienced by diverse tissues and
pathways in different lineages.
Many genes are born through gene/genome duplication
or gene recombination (i.e., from pre-existing genes).
These are the new genes we currently know the most about
and include the best instances of the differing life histories.
Some developmental regulatory genes constitute examples
of long-lived, conserved gene duplications. For example,
there have been expansions of Hox genes through tandem
duplication, which account for changes in body plans by
providing diverged transcription factors that specify the
identity of different segments. Despite some turnover or
additional duplications in some lineages, some Hox gene
homeodomains have remained conserved, and their biochemical functions have remained the same despite regulating different sets of genes (e.g., overexpression of
Hoxb1, the vertebrate ortholog of the fly labial gene, or of
labial itself in flies show similar phenotypes). Such conservation implies strong purifying selection which in turn
suggests that the process of development is not easily
modified. Hox genes are transcription factors that regulate
many downstream genes and changes in their DNA-binding domain are likely to have disastrous consequences for
development.

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J Mol Evol

For a younger gene cohort, it has been observed that

some relatively recently duplicated genes have become
essential. In particular, Chen et al. (2010) targeted young fly
genes (most of them gene duplicates) using RNAi and found
that *30 % have become essential for viability. Many of
these genes are expressed in late larva, and their knockdown
leads to pupae arrest. These developmental stages are known
to transcribe genes of intermediate age (i.e., these tissues
experience an intermediate level of turnover; Domazet-Loso
et al. 2010). While it is still unknown how many of these
genes are essential because they partition the function of an
essential gene, there are examples showing how such genes
can become essential by acquiring new functions. In one
instance, the gene Umbrea acquired essential centromeric
function owing to a loss of a heterochromatin-binding
domain and several changes in its amino acid sequence
while the loss of function of the parental gene encoding a
heterochromatin protein does not compromise viability
(Ross et al. 2013). This neofunctionalization to an essential
function must have contributed to increased life span of
Umbrea in Drosophila melanogaster as this gene is lost in
some lineages where such changes did not occur. Ross and
colleagues propose that genetic conflict involving centromeric function might require the recurrent recruitment of
new proteins. This example reveals an essential pathway that
actually experiences some gene turnover.
Among even younger genes, we now have ample evidence that some duplicated genes are under strong selection for high turnover and for frequent changes in the
protein sequence. Such genes are often involved in interactions with the environment or participate in arms races,
including malemale competition, malefemale antagonism, and host defense against infections or selfish genetic
elements. The life histories of these genes can be illustrated
by some testis-specific genes in Drosophila. In some
instances selection for male-specific functions has been
proposed to act even before the gene is duplicated, generating balanced polymorphism/allelic divergence at the
parental gene (Connallon and Clark 2011; Gallach and
Betran 2011). Subsequent gene duplication may involve
gene relocation that facilitates the acquisition of a male
germ line specific expression pattern and prevents gene
conversion (Gallach and Betran 2011; Sorourian et al.
2014) enabling the evolution of a new function. This
explains why under such circumstances it is often the new
copy that acquires a new function. Many such genes do not
remain in the genome for long, but are quickly lost, presumably because their function becomes obsolete in this
fast-evolving tissue. This might explain why many young
genes are expressed in testis but not as many older genes
are transcribed in this tissue providing an additional
explanation to previous observations by Vinckenbosch
et al. (2006). Drosophila testis is thus a dynamic tissue

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where proteins evolve fast, where recruitment of new genes

occurs frequently and where gene loss is also common.
Consistent with this, the adult males have been shown to
express younger genes than adult females or other life
cycle stages (Domazet-Loso et al. 2010).
The high turnover tissue or stage does not always need
to be an adult male tissue. In zebrafish, early embryogenesis appears to transcribe a lot of young genes (DomazetLoso et al. 2010), although adult male tissues still transcribe a lot of young genes in zebrafish. High turnover of
some non-coding RNA genes has also been observed.
Adult male tissues show expression of these young noncoding genes (Lyu et al. 2014) in D. melanogaster, but
turnover is observed during early embryogenesis for microRNAs in D. virilis (Ninova et al. 2014). Thus, the
prevalence of particular gene life histories differs between
tissues, protein-coding, and non-coding genes and between
lineages as well.
There are many other variations in such live fast, die
young gene life history. For example, in the absence of
relocation of the duplicate, gene conversion can speed up
adaptation for the whole gene family by facilitating the
exploration of adaptive combinations through ectopic
recombination. That is, some fast-evolving/fast turnover
genes are organized in tandemly duplicated gene families
(Kelleher and Markow 2009). It has also been proposed
that in some instances the fast turnover might occur even if
a beneficial dose effect is the important attribute of the new
gene, e.g., the duplication of some genes believed to be
suppressors of selfish male meiotic drive systems (Phadnis
et al. 2012).
Why do these differences in life histories exist? Our
current knowledge of gene functions, biological processes
they participate in, and their patterns of molecular evolution builds a multi-layered, telescoping image of an
organism. There are processes that form the basic cellular
and developmental pathways of a functioning organism
maintain homeostasis and create a stable environment that
allows for other more dynamic processes. Selection pressures dictate how dynamic the processes are, and the life
histories of genes reflect the process they are recruited into.
Conserved, long-lived genes are frequently involved in
fundamental biological processes that are rarely disturbed
and that recruit new genes less often, while fast-evolving
genes that are prone to loss and recurrent duplication participate in the processes that are under strong selection for
change.
In addition to gene birth through duplication, other
processes like horizontal gene transfer and transposable
element or virus domestication are known to give rise to
new genes. Somewhat unexpectedly, data are accumulating to support de novo gene birth as well. New genes
that arise through these mechanisms differ from genes

J Mol Evol

that are born from pre-existing genes in one important

aspect: they are foreign to the host genome. What life
histories will they have? What tissues are going to recruit
these foreign new genes? One clear prediction is that
tissues that are enriched for dynamic and fast-evolving
processes would be more likely to incorporate these foreign genes. In contrast, limited recruitment of these genes
is expected in tissues with highly constrained pathways. Is
this what has been observed? Some data have accumulated recently for de novo genes, and it seems that, yes,
again de novo genes are often transcribed and acquire new
functions in Drosophila and human testis (Xie et al. 2012;
Zhao et al. 2014; Palmieri et al. 2014) and in human brain
(another tissue that shows quite a bit of turnover in
humans; Xie et al. 2012).Tissues under strong pressures to
change will frequently incorporate foreign genes, but, in
these tissues, new genes should also suffer frequent losses. At the same time, some genes might evolve interactions that could make them survive longer and eventually
even express in other tissues. Among genes domesticated
from transposable elements or viruses, some are recruited
into tissues with conflicts that can lead to high gene
turnover. These include placenta where there is a motheroffspring conflict (Malik 2012) or immune cells (Malik
and Henikoff 2005). On the other hand, many domesticated genes from transposable elements are old transposases involved in chromatin remodeling or act as
transcription factors (Feschotte and Pritham 2007), indicating that they are currently recruited into stable gene
networks. As incorporation of a new foreign gene directly
into well-functioning pathway is unlikely, these transposases might illustrate an alternative way of establishing
stable interactions. Initially, these proteins could have
originated as chromatin remodeling proteins within a fastevolving network (Levine and Malik 2013) but later
evolved into transcription factors participating in a stable
and long-lasting biological process. This is likely a general route on the way to establish a permanent residence in
the genome. New genes are most often recruited to carry
out short-lived functions in highly dynamic tissues but
occasionally secure additional, more central roles.
The study of genes in the context of their life histories
reveals the extent of gene turnover, making it necessary to
consider the biological processes the genes are involved in
and forcing us to examine the precise selective pressures
that govern the evolution of these processes.
Acknowledgements I thank Anna Williford for numerous discussions and Anna Williford and Jeff Demuth for reading and providing

comments to the text. The Betran laboratory is supported by the

National Institute of General Medical Sciences of the National
Institutes of Health under award number R01GM071813 to E.B. The
content of this publication is solely the responsibility of the author
and does not necessarily represent the official views of the National
Institutes of Health.

References
Chen S, Zhang YE, Long M (2010) New genes in Drosophila quickly
become essential. Science 330(6011):16821685
Connallon T, Clark AG (2011) The resolution of sexual antagonism
by gene duplication. Genetics 187(3):919937
Domazet-Loso T, Tautz D (2010) A phylogenetically based transcriptome age index mirrors ontogenetic divergence patterns.
Nature 468(7325):815818
Feschotte C, Pritham EJ (2007) DNA transposons and the evolution
of eukaryotic genomes. Annu Rev Genet 41:331368
Gallach M, Betran E (2011) Intralocus sexual conflict resolved
through gene duplication. Trends Ecol Evol 26(5):222228
Kelleher ES, Markow TA (2009) Duplication, selection and gene
conversion in a Drosophila mojavensis female reproductive
protein family. Genetics 181(4):14511465
Levine MT, Malik HS (2013) A rapidly evolving genomic toolkit for
Drosophila heterochromatin. Fly (Austin) 7(3):137141
Lyu Y, Shen Y, Li H, Chen Y, Guo L, Zhao Y, Hungate E, Shi S, Wu
CI, Tang T (2014) New microRNAs in Drosophilabirth, death
and cycles of adaptive evolution. PLoS Genet 10(1):e1004096
Malik HS (2012) Retroviruses push the envelope for mammalian
placentation. Proc Natl Acad Sci USA 109(7):21842185
Malik HS, Henikoff S (2005) Positive selection of Iris, a retroviral
envelope-derived host gene in Drosophila melanogaster. PLoS
Genet 1(4):e44
Ninova M, Ronshaugen M, Griffiths-Jones S (2014) Fast-evolving
microRNAs are highly expressed in the early embryo of
Drosophila virilis. RNA 20(3):360372
Palmieri N, Kosiol C, Schlotterer C (2014) The life cycle of
Drosophila orphan genes. eLife 3:e01311
Phadnis N, Hsieh E, Malik HS (2012) Birth, death, and replacement
of karyopherins in Drosophila. Mol Biol Evol 29(5):14291440
Ross BD, Rosin L, Thomae AW, Hiatt MA, Vermaak D, de la Cruz
AF, Imhof A, Mellone BG, Malik HS (2013) Stepwise evolution
of essential centromere function in a Drosophila neogene.
Science 340(6137):12111214
zdil F, Ro JEB
Sorourian M, Kunte MM, Domingues S, Gallach M, O
(2014) Relocation facilitates the acquisition of short cis-regulatory regions that drive the expression of retrogenes during
spermatogenesis in Drosophila. Mol Biol Evol 31(8):21702180
Vinckenbosch N, Dupanloup I, Kaessmann H (2006) Evolutionary
fate of retroposed gene copies in the human genome. Proc Natl
Acad Sci USA 103(9):32203225
Xie C, Zhang YE, Chen JY, Liu CJ, Zhou WZ, Li Y, Zhang M, Zhang
R, Wei L, Li CY (2012) Hominoid-specific de novo proteincoding genes originating from long non-coding RNAs. PLoS
Genet 8(9):e1002942
Zhao L, Saelao P, Jones CD, Begun DJ (2014) Origin and spread of
de novo genes in Drosophila melanogaster populations. Science
343(6172):769772

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