Evolution of Gene Families
T Ohta, National Institute of Genetics, Mishima, Japan
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by L Silver, volume 2, pp 666–669, © 2001, Elsevier Inc.
Glossary
Hox genes A family of genes that contain homeobox
sequence of 180 nucleotides. Homeobox encodes 60­
amino acid homeodomain, which is known to bind DNA
and is essential for transcriptional regulation.
Human leukocyte antigen (HLA) HLA genes locate in
major histocompatibility complex (MHC) region of
human genome. They contain immunoglobulin domain
and belong to the immunoglobulin superfamily. Class I
and class II families of HLA are best studied and known to
be responsible to antigen presentation.
Genomic Complexity Increases by Gene Duplication
As compared with primitive prokaryotes, eukaryotes generally
have complex genomes, and the complexity evolved through a
repeated process of duplication and divergence. Duplication
events can occur essentially at random throughout the genome
and the size of the duplication unit can vary from as little as a
few nucleotides to large subchromosomal sections that are
tens, or even hundreds, of megabases in length. When the
duplicated segment contains one or more genes, either the
original or duplicated copy of each is set free to accumulate
mutations without harm to the organism since the other good
copy with an original function will still be present.
Duplicated regions, like all other genetic novelties, must
originate in the genome of a single individual and their initial
survival in each subsequent generation of a population is, most
often, a simple matter of chance. This is because the addition of
one extra copy of most genes – to the two already present in a
diploid genome – is usually tolerated without significant harm
to the individual animal.
Three Main Ways of Gene Duplication
1. Whole-genome duplication (polyploidization). Whole-
genome duplication has been important for formation
of new species. Autopolyploid that originates by duplica­
tion of the same genome in an individual is thought to be
important for species with undifferentiated sex. This is
because, when sex is differentiated, gametes with unba­
lanced chromosome sets are formed from a hybrid
between polyploid and diploid individuals, and elimi­
nated by natural selection. Allopolyploid that originates
by duplication of closely related genomes of a hybrid
individual is commonly found in cultivated plant species
such as wheat and cotton.
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 2 doi:10.1016/B978-0-12-374984-0.00497-6
MADS-box genes A family of genes that contain
MADS-box sequence encoding 60 amino acids. This
domain binds to DNA and is highly conserved.
Major histocompatibility complex (MHC) The region of
mammalian genome that contains various genes relating
to immune response. This region is widely known because
of extraordinary polymorphisms, which have significant
effects on disease susceptibility and tissue transplantation.
Regulatory element A DNA region that regulates
expression of genes. The region contains binding sites of
transcription factors and other regulatory proteins.
2. Duplication by unequal crossing-over. The second broad
class of duplication events results from unequal
crossing-over. Normal crossing-over, or recombination,
can occur between equivalent sequences on homologous
chromatids present in a synaptonemal complex that
forms during the pachytene stage of meiosis in both
male and female mammals. Unequal crossing-over –
also referred to as illegitimate recombination – refers to
crossover events that occur between nonequivalent
sequences. Unequal crossing-over can be initiated by the
presence of related sequences – such as highly repeated
retroposon-dispersed selfish elements – located nearby in
the genome. Although the event is unequal, in this case, it
is still mediated by the homology that exists at the two
nonequivalent sites. Nonhomologous unequal crossovers
can also occur, although they are much rarer than homo­
logous events. The initial duplication event that produces
a two-gene cluster may be either homologous or nonho­
mologous, but once two units of related sequence are
present in tandem, further rounds of homologous
unequal crossing-over can be easily initiated between
nonequivalent members of the pair as illustrated in
Figure 1. Thus, it is easy to see how clusters can expand
to contain three, four, and many more copies of an origi­
nal DNA sequence. In all cases, unequal crossing-over
between homologs results in two reciprocal chromosomal
products: one will have a duplication of the region located
between the two sites and the other will have a deletion
that covers the same exact region (Figure 1). Their survival
in evolution is dependent upon natural selection and
genetic drift. Duplicates having hundreds of kilobases
are called segmental duplications.
3. Duplication by transposition. Transposition is responsible
for the dispersion and duplication of DNA sequences.
Transposition refers to a process in which one region of
the genome relocates to a new chromosomal location.
Transposition can occur either through the direct
563
564 Evolution of Gene Families
Initial duplication of single-copy region
A B C
Genetic
exchange
sites
A� B�
Reciprocal products
Deleted chromosome
A C�
A� B� B C
Duplicated segments
Figure 1 Unequal crossing-over generates gene families. The left side illustrates an unequal crossing-over event and the two products that are
generated. One product is deleted and the other is duplicated for the same region. In this example, the duplicated region contains a second complete copy
of a single gene (B). The right side illustrates a second round of unequal crossing-over that can occur in a genome that is homozygous for the original or
duplicated chromosome. In this case, the crossover event has occurred between the two copies of the original gene. Only the duplicated product generated
by this event is shown. Over time, the three copies of the B gene can diverge into three distinct functional units of a gene family cluster.
movement of original sequences from one site to another
or through an RNA intermediate. The latter is most com­
mon, and occurs by means of an intermediate RNA
transcript that is reverse-transcribed into DNA and then
inserted randomly into the genome. This process is referred
to as retrotransposition. The size of the retrotransposition
unit – called a retroposon – cannot be larger than the size
of the intermediate RNA transcript. Retrotransposition has
been exploited by various families of selfish genetic ele­
ments, some of which have been copied into 100 000 or
more locations dispersed throughout the genome with a
self-encoded reverse transcriptase. But, examples of func­
tional, intronless retroposons – such as Pgk2 and Pdha2 –
have also been identified. In such cases, functionality is
absolutely dependent upon novel regulatory elements
either present at the site of insertion or created by subse­
quent mutations in these sequences.
How Duplicated Genes Diverge?
Many extra genes attained by duplication degenerate and
become pseudogenes, but some may diverge to have new func­
tions. Degeneration can occur at one of the duplicate gene
copies because the other gene retains the original function
that is needed for the organisms. Duplicated genes may
differentiate with respect to expression pattern (subfunctiona­
lization). Modification of expression pattern is mainly due to
changes of regulatory elements. There are many examples of
genes that arose by duplication followed by differentiation of
expression patterns. The examples include very important gene
families for evolution of complexity, such as Hox genes,
MADS-box family genes, and immunoglobulin family genes.
Note that Hox genes are members of a transcription factor
Further expansion from a two-repeat cluster
A B� B C
B C
B�
Region of
pairing Crossover
site
A B� B/B� B C
Divergence
A B1 B2 B3 C
Three-member gene family cluster
family that is most important in animal development.
MADS-box genes are also members of another transcription
factor family, which participates in flower development.
Duplicated genes may also acquire new functions by differ­
entiation of coding region sequences (neofunctionalization).
An interesting example is the globin gene family where differ­
entiation of both coding and regulatory regions is important.
However, some gene families like those of cytochrome
P450 and olfactory receptor acquire neofunctions without
subfunctionalization.
Concerted Evolution via Genetic Exchange between
Duplicated Gene Copies
There are many examples in the genome where genetic
information appears to flow from one DNA element to other
related – but nonallelic – elements (duplicate genes) located
nearby or even on different chromosomes. In some special
cases, the flow of information is so extreme as to allow all
members of a gene family to coevolve with near-identity as in
the case of ribosomal RNA genes. The information flow is
sometimes called homogenization. The resultant phenomenon
such that gene members show higher identity when compared
in the same species than when compared between the species is
called concerted evolution. Gene conversion and unequal
crossing-over are thought to contribute to the concerted evolu­
tion. Note that duplication and deletion of gene members by
unequal crossing-over results in chance fluctuation of copy
number of gene members within a family. In theory, repeated
duplication and deletion of gene members of a family have
similar effects on increasing gene identity within a family just as
random genetic drift has the effect on alleles within a finite
population.

Interplay between Gene Conversion and Natural
Selection
While concerted evolution is beneficial for gene families when
large amount of gene products with uniform function is
needed, it may bring different effects in other occasions. In
principle, gene conversion between gene members of a family
is a kind of mutation whose effects are either deleterious or
advantageous. Harmful effects of gene conversion have been
studied in relation to human diseases. Various cases have been
reported that occur by gene conversion, such as congenital
adrenal hyperplasia or neural tube defects.
Gene conversion also generates useful variations. Examples
are found in gene families with diverse functions of gene pro­
ducts, such as those found in the major histocompatibility
complex (MHC) and those of immunoglobulins, proteolytic
enzymes, and their inhibitors. These proteins are often charac­
terized by high variability at the active sites, where functional
diversity is needed as compared with the remaining regions.
This high variability is important for the organisms and is
thought to be attained by the interplay between diversity
enhancing selection and gene conversion. In case of human
leukocyte antigen families at the MHC, the active sites are the
antigen recognition sites, where unusually high polymorph­
isms have been much of interest from the standpoint of both
Evolution of Gene Families 565
medicine and evolutionary biology. Here, the interplay of
diversity enhancing selection and generation of new alleles by
gene conversion is thought to be responsible for the high
polymorphisms.
See also: Concerted Evolution; Crossing-Over; Gene
Conversion; Gene Duplication; Gene Family; Genetic
Recombination; Illegitimate Recombination; Immunoglobin
Superfamily; Pseudogene; Retrotransposons; Unequal
Crossing Over.
Further Reading
Eickbush TH and Eickbush DG (2007) Finely orchestrated movements: Evolution of
the ribosomal RNA genes. Genetics 175: 477–485. doi:10.1534/
genetics.107.071399.
Innan H and Kondrashov F (2010) The evolution of gene duplications: Classifying and
distinguishing between models. Nature Reviews Genetics 11: 97–108. doi:10.1038/
nrg2689.
Lynch M and Force A (2000) The probability of duplicate gene preservation by
subfunctionalization. Genetics 154: 459–473.
Ohta T (1983) On the evolution of multigene families. Theoretical Population Biology 23:
216–240.
Ohta T (2010) Gene conversion and evolution of gene families: An overview. Genes 1:
349–356. doi:10.3390/genes1030349.