Gene duplication

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Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. Gene duplications can arise as products of several types of errors in DNA replication and repair machinery as well as through fortuitous capture by selfish genetic elements. Common sources of gene duplications include ectopic recombination, retrotransposition event, aneuploidy, polyploidy, and replication slippage. [1]

Contents

Mechanisms of duplication

Ectopic recombination

Duplications arise from an event termed unequal crossing-over that occurs during meiosis between misaligned homologous chromosomes. The chance of it happening is a function of the degree of sharing of repetitive elements between two chromosomes. The products of this recombination are a duplication at the site of the exchange and a reciprocal deletion. Ectopic recombination is typically mediated by sequence similarity at the duplicate breakpoints, which form direct repeats. Repetitive genetic elements such as transposable elements offer one source of repetitive DNA that can facilitate recombination, and they are often found at duplication breakpoints in plants and mammals. [2]

Schematic of a region of a chromosome before and after a duplication event Gene-duplication.png
Schematic of a region of a chromosome before and after a duplication event

Replication slippage

Replication slippage is an error in DNA replication that can produce duplications of short genetic sequences. During replication DNA polymerase begins to copy the DNA. At some point during the replication process, the polymerase dissociates from the DNA and replication stalls. When the polymerase reattaches to the DNA strand, it aligns the replicating strand to an incorrect position and incidentally copies the same section more than once. Replication slippage is also often facilitated by repetitive sequences, but requires only a few bases of similarity.[ citation needed ]

Retrotransposition

Retrotransposons, mainly L1, can occasionally act on cellular mRNA. Transcripts are reverse transcribed to DNA and inserted into random place in the genome, creating retrogenes. Resulting sequence usually lack introns and often contain poly(A) sequences that are also integrated into the genome. Many retrogenes display changes in gene regulation in comparison to their parental gene sequences, which sometimes results in novel functions. Retrogenes can move between different chromosomes to shape chromosomal evolution. [3]

Aneuploidy

Aneuploidy occurs when nondisjunction at a single chromosome results in an abnormal number of chromosomes. Aneuploidy is often harmful and in mammals regularly leads to spontaneous abortions (miscarriages). Some aneuploid individuals are viable, for example trisomy 21 in humans, which leads to Down syndrome. Aneuploidy often alters gene dosage in ways that are detrimental to the organism; therefore, it is unlikely to spread through populations.

Polyploidy

Polyploidy, or whole genome duplication is a product of nondisjunction during meiosis which results in additional copies of the entire genome. Polyploidy is common in plants, but it has also occurred in animals, with two rounds of whole genome duplication (2R event) in the vertebrate lineage leading to humans. [4] It has also occurred in the hemiascomycete yeasts ~100 mya. [5] [6]

After a whole genome duplication, there is a relatively short period of genome instability, extensive gene loss, elevated levels of nucleotide substitution and regulatory network rewiring. [7] [8] In addition, gene dosage effects play a significant role. [9] Thus, most duplicates are lost within a short period, however, a considerable fraction of duplicates survive. [10] Interestingly, genes involved in regulation are preferentially retained. [11] [12] Furthermore, retention of regulatory genes, most notably the Hox genes, has led to adaptive innovation.

Rapid evolution and functional divergence have been observed at the level of the transcription of duplicated genes, usually by point mutations in short transcription factor binding motifs. [13] [14] Furthermore, rapid evolution of protein phosphorylation motifs, usually embedded within rapidly evolving intrinsically disordered regions is another contributing factor for survival and rapid adaptation/neofunctionalization of duplicate genes. [15] Thus, a link seems to exist between gene regulation (at least at the post-translational level) and genome evolution. [15]

Polyploidy is also a well known source of speciation, as offspring, which have different numbers of chromosomes compared to parent species, are often unable to interbreed with non-polyploid organisms. Whole genome duplications are thought to be less detrimental than aneuploidy as the relative dosage of individual genes should be the same.

As an evolutionary event

Evolutionary fate of duplicate genes Evolution fate duplicate genes - vector.svg
Evolutionary fate of duplicate genes

Rate of gene duplication

Comparisons of genomes demonstrate that gene duplications are common in most species investigated. This is indicated by variable copy numbers (copy number variation) in the genome of humans [16] [17] or fruit flies. [18] However, it has been difficult to measure the rate at which such duplications occur. Recent studies yielded a first direct estimate of the genome-wide rate of gene duplication in C. elegans , the first multicellular eukaryote for which such as estimate became available. The gene duplication rate in C. elegans is on the order of 10−7 duplications/gene/generation, that is, in a population of 10 million worms, one will have a gene duplication per generation. This rate is two orders of magnitude greater than the spontaneous rate of point mutation per nucleotide site in this species. [19] Older (indirect) studies reported locus-specific duplication rates in bacteria, Drosophila, and humans ranging from 10−3 to 10−7/gene/generation. [20] [21] [22]

Neofunctionalization

Gene duplications are an essential source of genetic novelty that can lead to evolutionary innovation. Duplication creates genetic redundancy, where the second copy of the gene is often free from selective pressure—that is, mutations of it have no deleterious effects to its host organism. If one copy of a gene experiences a mutation that affects its original function, the second copy can serve as a 'spare part' and continue to function correctly. Thus, duplicate genes accumulate mutations faster than a functional single-copy gene, over generations of organisms, and it is possible for one of the two copies to develop a new and different function. Some examples of such neofunctionalization is the apparent mutation of a duplicated digestive gene in a family of ice fish into an antifreeze gene and duplication leading to a novel snake venom gene [23] and the synthesis of 1 beta-hydroxytestosterone in pigs. [24]

Gene duplication is believed to play a major role in evolution; this stance has been held by members of the scientific community for over 100 years. [25] Susumu Ohno was one of the most famous developers of this theory in his classic book Evolution by gene duplication (1970). [26] Ohno argued that gene duplication is the most important evolutionary force since the emergence of the universal common ancestor. [27] Major genome duplication events can be quite common. It is believed that the entire yeast genome underwent duplication about 100 million years ago. [28] Plants are the most prolific genome duplicators. For example, wheat is hexaploid (a kind of polyploid), meaning that it has six copies of its genome.

Subfunctionalization

Another possible fate for duplicate genes is that both copies are equally free to accumulate degenerative mutations, so long as any defects are complemented by the other copy. This leads to a neutral "subfunctionalization" (a process of constructive neutral evolution) or DDC (duplication-degeneration-complementation) model, [29] [30] in which the functionality of the original gene is distributed among the two copies. Neither gene can be lost, as both now perform important non-redundant functions, but ultimately neither is able to achieve novel functionality.

Subfunctionalization can occur through neutral processes in which mutations accumulate with no detrimental or beneficial effects. However, in some cases subfunctionalization can occur with clear adaptive benefits. If an ancestral gene is pleiotropic and performs two functions, often neither one of these two functions can be changed without affecting the other function. In this way, partitioning the ancestral functions into two separate genes can allow for adaptive specialization of subfunctions, thereby providing an adaptive benefit. [31]

Loss

Often the resulting genomic variation leads to gene dosage dependent neurological disorders such as Rett-like syndrome and Pelizaeus–Merzbacher disease. [32] Such detrimental mutations are likely to be lost from the population and will not be preserved or develop novel functions. However, many duplications are, in fact, not detrimental or beneficial, and these neutral sequences may be lost or may spread through the population through random fluctuations via genetic drift.

Identifying duplications in sequenced genomes

Criteria and single genome scans

The two genes that exist after a gene duplication event are called paralogs and usually code for proteins with a similar function and/or structure. By contrast, orthologous genes present in different species which are each originally derived from the same ancestral sequence. (See Homology of sequences in genetics).

It is important (but often difficult) to differentiate between paralogs and orthologs in biological research. Experiments on human gene function can often be carried out on other species if a homolog to a human gene can be found in the genome of that species, but only if the homolog is orthologous. If they are paralogs and resulted from a gene duplication event, their functions are likely to be too different. One or more copies of duplicated genes that constitute a gene family may be affected by insertion of transposable elements that causes significant variation between them in their sequence and finally may become responsible for divergent evolution. This may also render the chances and the rate of gene conversion between the homologs of gene duplicates due to less or no similarity in their sequences.

Paralogs can be identified in single genomes through a sequence comparison of all annotated gene models to one another. Such a comparison can be performed on translated amino acid sequences (e.g. BLASTp, tBLASTx) to identify ancient duplications or on DNA nucleotide sequences (e.g. BLASTn, megablast) to identify more recent duplications. Most studies to identify gene duplications require reciprocal-best-hits or fuzzy reciprocal-best-hits, where each paralog must be the other's single best match in a sequence comparison. [33]

Most gene duplications exist as low copy repeats (LCRs), rather highly repetitive sequences like transposable elements. They are mostly found in pericentronomic, subtelomeric and interstitial regions of a chromosome. Many LCRs, due to their size (>1Kb), similarity, and orientation, are highly susceptible to duplications and deletions.

Genomic microarrays detect duplications

Technologies such as genomic microarrays, also called array comparative genomic hybridization (array CGH), are used to detect chromosomal abnormalities, such as microduplications, in a high throughput fashion from genomic DNA samples. In particular, DNA microarray technology can simultaneously monitor the expression levels of thousands of genes across many treatments or experimental conditions, greatly facilitating the evolutionary studies of gene regulation after gene duplication or speciation. [34] [35]

Next generation sequencing

Gene duplications can also be identified through the use of next-generation sequencing platforms. The simplest means to identify duplications in genomic resequencing data is through the use of paired-end sequencing reads. Tandem duplications are indicated by sequencing read pairs which map in abnormal orientations. Through a combination of increased sequence coverage and abnormal mapping orientation, it is possible to identify duplications in genomic sequencing data.

Nomenclature

Human karyotype with annotated bands and sub-bands as used for the nomenclature of chromosome abnormalities. It shows dark and white regions as seen on G banding. Each row is vertically aligned at centromere level. It shows 22 homologous autosomal chromosome pairs, both the female (XX) and male (XY) versions of the two sex chromosomes, as well as the mitochondrial genome (at bottom left). Further information: Karyotype Human karyotype with bands and sub-bands.png
Human karyotype with annotated bands and sub-bands as used for the nomenclature of chromosome abnormalities. It shows dark and white regions as seen on G banding. Each row is vertically aligned at centromere level. It shows 22 homologous autosomal chromosome pairs, both the female (XX) and male (XY) versions of the two sex chromosomes, as well as the mitochondrial genome (at bottom left).

The International System for Human Cytogenomic Nomenclature (ISCN) is an international standard for human chromosome nomenclature, which includes band names, symbols and abbreviated terms used in the description of human chromosome and chromosome abnormalities. Abbreviations include dup for duplications of parts of a chromosome. [36] For example, dup(17p12) causes Charcot–Marie–Tooth disease type 1A. [37]

As amplification

Gene duplication does not necessarily constitute a lasting change in a species' genome. In fact, such changes often don't last past the initial host organism. From the perspective of molecular genetics, gene amplification is one of many ways in which a gene can be overexpressed. Genetic amplification can occur artificially, as with the use of the polymerase chain reaction technique to amplify short strands of DNA in vitro using enzymes, or it can occur naturally, as described above. If it's a natural duplication, it can still take place in a somatic cell, rather than a germline cell (which would be necessary for a lasting evolutionary change).

Role in cancer

Duplications of oncogenes are a common cause of many types of cancer. In such cases the genetic duplication occurs in a somatic cell and affects only the genome of the cancer cells themselves, not the entire organism, much less any subsequent offspring. Recent comprehensive patient-level classification and quantification of driver events in TCGA cohorts revealed that there are on average 12 driver events per tumor, of which 1.5 are amplifications of oncogenes. [38]

Common oncogene amplifications in human cancers
Cancer typeAssociated gene
amplifications		Prevalence of
amplification
in cancer type
(percent)
Breast cancer MYC 20% [39]
ERBB2 (HER2)20% [39]
CCND1 (Cyclin D1)15–20% [39]
FGFR1 12% [39]
FGFR2 12% [39]
Cervical cancer MYC 25–50% [39]
ERBB2 20% [39]
Colorectal cancer HRAS 30% [39]
KRAS 20% [39]
MYB 15–20% [39]
Esophageal cancer MYC 40% [39]
CCND1 25% [39]
MDM2 13% [39]
Gastric cancer CCNE (Cyclin E)15% [39]
KRAS 10% [39]
MET 10% [39]
Glioblastoma ERBB1 (EGFR)33–50% [39]
CDK4 15% [39]
Head and neck cancer CCND1 50% [39]
ERBB1 10% [39]
MYC 7–10% [39]
Hepatocellular cancer CCND1 13% [39]
Neuroblastoma MYCN 20–25% [39]
Ovarian cancer MYC 20–30% [39]
ERBB2 15–30% [39]
AKT2 12% [39]
Sarcoma MDM2 10–30% [39]
CDK4 10% [39]
Small cell lung cancer MYC 15–20% [39]


Whole-genome duplications are also frequent in cancers, detected in 30% to 36% of tumors from the most common cancer types. [40] [41] Their exact role in carcinogenesis is unclear, but they in some cases lead to loss of chromatin segregation leading to chromatin conformation changes that in turn lead to oncogenic epigenetic and transcriptional modifications. [42]

See also

Related Research Articles

<span class="mw-page-title-main">Genome</span> All genetic material of an organism

In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA. The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as regulatory sequences, and often a substantial fraction of junk DNA with no evident function. Almost all eukaryotes have mitochondria and a small mitochondrial genome. Algae and plants also contain chloroplasts with a chloroplast genome.

Microevolution is the change in allele frequencies that occurs over time within a population. This change is due to four different processes: mutation, selection, gene flow and genetic drift. This change happens over a relatively short amount of time compared to the changes termed macroevolution.

<span class="mw-page-title-main">Mutation</span> Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

<span class="mw-page-title-main">Human genome</span> Complete set of nucleic acid sequences for humans

The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.

A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.

<span class="mw-page-title-main">Polyploidy</span> Condition where cells of an organism have more than two paired sets of chromosomes

Polyploidy is a condition in which the cells of an organism have more than one pair of (homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two complete sets of chromosomes, one from each of two parents; each set contains the same number of chromosomes, and the chromosomes are joined in pairs of homologous chromosomes. However, some organisms are polyploid. Polyploidy is especially common in plants. Most eukaryotes have diploid somatic cells, but produce haploid gametes by meiosis. A monoploid has only one set of chromosomes, and the term is usually only applied to cells or organisms that are normally diploid. Males of bees and other Hymenoptera, for example, are monoploid. Unlike animals, plants and multicellular algae have life cycles with two alternating multicellular generations. The gametophyte generation is haploid, and produces gametes by mitosis; the sporophyte generation is diploid and produces spores by meiosis.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

Molecular evolution describes how inherited DNA and/or RNA change over evolutionary time, and the consequences of this for proteins and other components of cells and organisms. Molecular evolution is the basis of phylogenetic approaches to describing the tree of life. Molecular evolution overlaps with population genetics, especially on shorter timescales. Topics in molecular evolution include the origins of new genes, the genetic nature of complex traits, the genetic basis of adaptation and speciation, the evolution of development, and patterns and processes underlying genomic changes during evolution.

<span class="mw-page-title-main">Pseudogene</span> Functionless relative of a gene

Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by gene duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are usually identified when genome sequence analysis finds gene-like sequences that lack regulatory sequences needed for transcription or translation, or whose coding sequences are obviously defective due to frameshifts or premature stop codons. Pseudogenes are a type of junk DNA.

<span class="mw-page-title-main">Molecular genetics</span> Scientific study of genes at the molecular level

Molecular genetics is a branch of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the structure and/or function of genes in an organism's genome using genetic screens. 

<span class="mw-page-title-main">Yeast artificial chromosome</span> Genetically engineered chromosome derived from the DNA of yeast

Yeast artificial chromosomes (YACs) are genetically engineered chromosomes derived from the DNA of the yeast, Saccharomyces cerevisiae, which is then ligated into a bacterial plasmid. By inserting large fragments of DNA, from 100–1000 kb, the inserted sequences can be cloned and physically mapped using a process called chromosome walking. This is the process that was initially used for the Human Genome Project, however due to stability issues, YACs were abandoned for the use of bacterial artificial chromosome

<span class="mw-page-title-main">Comparative genomics</span> Field of biological research

Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach compares two or more genomes to discover the similarities and differences between the genomes and to study the biology of the individual genomes. Comparison of whole genome sequences provides a highly detailed view of how organisms are related to each other at the gene level. By comparing whole genome sequences, researchers gain insights into genetic relationships between organisms and study evolutionary changes. The major principle of comparative genomics is that common features of two organisms will often be encoded within the DNA that is evolutionarily conserved between them. Therefore, Comparative genomics provides a powerful tool for studying evolutionary changes among organisms, helping to identify genes that are conserved or common among species, as well as genes that give unique characteristics of each organism. Moreover, these studies can be performed at different levels of the genomes to obtain multiple perspectives about the organisms.

<span class="mw-page-title-main">Sequence homology</span> Shared ancestry between DNA, RNA or protein sequences

Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speciation event (orthologs), or a duplication event (paralogs), or else a horizontal gene transfer event (xenologs).

<span class="mw-page-title-main">Paleopolyploidy</span> State of having undergone whole genome duplication in deep evolutionary time

Paleopolyploidy is the result of genome duplications which occurred at least several million years ago (MYA). Such an event could either double the genome of a single species (autopolyploidy) or combine those of two species (allopolyploidy). Because of functional redundancy, genes are rapidly silenced or lost from the duplicated genomes. Most paleopolyploids, through evolutionary time, have lost their polyploid status through a process called diploidization, and are currently considered diploids, e.g., baker's yeast, Arabidopsis thaliana, and perhaps humans.

<span class="mw-page-title-main">Copy number variation</span> Repeated DNA variation between individuals

Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of duplication or deletion event that affects a considerable number of base pairs. Approximately two-thirds of the entire human genome may be composed of repeats and 4.8–9.5% of the human genome can be classified as copy number variations. In mammals, copy number variations play an important role in generating necessary variation in the population as well as disease phenotype.

<span class="mw-page-title-main">Gene</span> Sequence of DNA or RNA that codes for an RNA or protein product

In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA, that is transcribed to produce a functional RNA. There are two types of molecular genes: protein-coding genes and non-coding genes.

Nuclear mitochondrial DNA (NUMT) segments or genetic loci describe a transposition of any type of cytoplasmic mitochondrial DNA into the nuclear genome of eukaryotic organisms.

<span class="mw-page-title-main">Gene redundancy</span>

Gene redundancy is the existence of multiple genes in the genome of an organism that perform the same function. Gene redundancy can result from gene duplication. Such duplication events are responsible for many sets of paralogous genes. When an individual gene in such a set is disrupted by mutation or targeted knockout, there can be little effect on phenotype as a result of gene redundancy, whereas the effect is large for the knockout of a gene with only one copy. Gene knockout is a method utilized in some studies aiming to characterize the maintenance and fitness effects functional overlap.

<span class="mw-page-title-main">Genome evolution</span> Process by which a genome changes in structure or size over time

Genome evolution is the process by which a genome changes in structure (sequence) or size over time. The study of genome evolution involves multiple fields such as structural analysis of the genome, the study of genomic parasites, gene and ancient genome duplications, polyploidy, and comparative genomics. Genome evolution is a constantly changing and evolving field due to the steadily growing number of sequenced genomes, both prokaryotic and eukaryotic, available to the scientific community and the public at large.

DNA transposons are DNA sequences, sometimes referred to "jumping genes", that can move and integrate to different locations within the genome. They are class II transposable elements (TEs) that move through a DNA intermediate, as opposed to class I TEs, retrotransposons, that move through an RNA intermediate. DNA transposons can move in the DNA of an organism via a single-or double-stranded DNA intermediate. DNA transposons have been found in both prokaryotic and eukaryotic organisms. They can make up a significant portion of an organism's genome, particularly in eukaryotes. In prokaryotes, TE's can facilitate the horizontal transfer of antibiotic resistance or other genes associated with virulence. After replicating and propagating in a host, all transposon copies become inactivated and are lost unless the transposon passes to a genome by starting a new life cycle with horizontal transfer. It is important to note that DNA transposons do not randomly insert themselves into the genome, but rather show preference for specific sites.

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