PR domain [note 1] zinc finger protein 9 is a protein that in humans is encoded by the PRDM9 gene. [5] PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain. [6] PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome. [7] [8]
PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding). [9]
In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility. [10]
In 1982 a haplotype was identified controlling recombination rate wm7, [11] which would later be identified as PRDM9. [12]
In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3). [13] This would later turn out to be the same PRDM9 protein independently identified later. [14]
In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity. [15]
In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals. [16]
Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome. [9] [17]
In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice. [6] [18] [19] [20] [21]
in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters. [22]
In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro, [23] which was confirmed in vivo in 2016. [24]
In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks. [25] [26]
PRDM9 mediates the process of meiosis by directing the sites of homologous recombination. [27] In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called recombination hotspots. Hotspots are regions of DNA about 1-2kb in length. [28] There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50-100kb DNA on average. [28] In humans, the average number of crossover recombination events per hotspot is one per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses. [28] These hotspots are binding sites for the PRDM9 Zinc Finger array. [29] Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and lysine 36. [30] As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.
Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a cell with two copies of each chromosome again, the zygote.
Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.
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.
Repeated sequences are short or long patterns of nucleic acids that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genomic DNA is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.
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.
Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. This appellation can refer to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.
Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.
Spo11 is a protein that in humans is encoded by the SPO11 gene. Spo11, in a complex with mTopVIB, creates double strand breaks to initiate meiotic recombination. Its active site contains a tyrosine which ligates and dissociates with DNA to promote break formation. One Spo11 protein is involved per strand of DNA, thus two Spo11 proteins are involved in each double stranded break event.
Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.
Translin is a DNA-binding protein that in humans is encoded by the TSN gene. Together with translin-associated factor X, translin forms the component 3 of promoter of RISC (C3PO) complex which facilitates endonucleolytic cleavage of the passenger strand during microRNA loading into the RNA-induced silencing complex (RISC).
Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.
Synaptonemal complex protein 3 is a protein that in humans is encoded by the SYCP3 gene. It is a component of the synaptonemal complex formed between homologous chromosomes during the prophase of meiosis.
Protein boule-like is a protein that in humans is encoded by the BOLL gene.
RecQ-mediated genome instability protein 1 is a protein that in humans is encoded by the RMI1 gene.
DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.
Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.
The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.
Protein ZGRF1 is a protein encoded in the human by the ZGRF1 gene also known as C4orf21, that has a weight of 236.6 kDa. The ZGRF1 gene product localizes to the cell nucleus and promotes DNA repair by stimulating homologous recombination. This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. ZGRF1 is orthologous to nearly all eukaryotes. Functional domains of this protein link it to a series of helicases, most notably the AAA_12 and AAA_11 domains.
H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
