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== Structure ==
== Structure ==
[[Telomere]]s are specialized [[protein]]–[[DNA]] constructs present at the ends of [[eukaryotic]] chromosomes, which prevent them from degradation and end-to-end [[chromosome|chromosomal]] fusion. Introductory biology courses often describe telomeres as a type of chromosomal [[aglet]]. Most [[vertebrate]] telomeric DNA consists of long ([[Thymine|T]][[Thymine|T]][[Adenine|A]][[Guanine|G]][[Guanine|G]][[Guanine|G]])n repeats of variable length, often around 3-20kb. ''Subtelomeres'' are segments of DNA between telomeric caps and [[chromatin]]. Each chromosome has two subtelomeres immediately adjacent to the long (TTAGGG)n repeats. Subtelomeres are considered to be the most distal (farthest from the [[centromere]]) region of unique DNA on a chromosome and they are unusually dynamic and variable mosaics of multichromosomal blocks of sequence. The subtelomeres of such diverse species as Humans, [[Plasmodium falciparum]], [[Drosophila melanogaster]] or [[Saccharomyces cerevisiae]], are structurally similar in that they are composed of various repeated elements, but the extent of the subtelomeres and the sequence of the elements vary greatly among organisms.<ref name="Mefford2002">{{cite journal |vauthors=Mefford HC, Trask BJ |title=[The complex structure and dynamic evolution of human subtelomeres] |journal=Nature Reviews Genetics |volume=3 |pages=91–102 |date=February 2002 |doi=10.1038/nrg727 |pmid=11836503}}</ref> In yeast (''S. cerevisiae''), subtelomeres are composed of two domains : the proximal and distal (telomeric) domains. The two domains differ in sequence content and extent of homology to other chromosome ends and they are often separated by a stretch of degenerate telomere repeats (TTAGGG) and an element called 'core X', which is found at all chromosome ends and contains an [[autonomously replicating sequence]] (ARS) and an ABF1 binding site.<ref name="Louis1994">{{cite journal |vauthors=Louis EJ, Naumova ES, Lee A, Naumov G, Haber JE |title=[The chromosome end in yeast: its mosaic nature and influence on recombinational dynamics] |journal=Genetics |volume=136 |pages=789–802 |date=1994 |PMC=1205885 |pmid=8005434}}</ref><ref name="Walmsley1984">{{cite journal |vauthors=Walmsley RW, Chan CS, Tye BK, Petes TD |title=[Unusual DNA sequences associated with the ends of yeast chromosomes] |journal=Nature |volume=310 |pages=157–160 |date=July 1984 |doi=10.1038/310157a0}}</ref> The proximal domain is composed of variable interchromosomal duplications (<1-30 [[kilobase|kb]]), this region can contain genes such ''Pho'', ''Mel'', ''Mal'' and [[open reading frames]] (ORFs).<ref name="Coissac1996">{{cite journal |vauthors=Coissac E, Maillier E, Robineau S, Netter P |title=[Sequence of a 39,411 bp DNA fragment covering the left end of chromosome VII of Saccharomyces cerevisiae] |journal=Yeast |volume=12 |issue=15 |pages=1555–1562 |date=December 1996 |doi=10.1002/(SICI)1097-0061(199612)12:15<1555::AID-YEA43>3.0.CO;2-Q}}</ref> The distal domain is composed of 0-4 tandem copies of the highly conserved Y' element which contains other ORFs, the number and chromosomal distribution of Y′ elements varies among yeast strains.<ref name="Louis1992">{{cite journal |vauthors=Louis EJ, Haber JE |title=[The structure and evolution of subtelomeric Y′ repeats in Saccharomyces cerevisiae] |journal=Genetics |volume=131 |pages=559–574 |date=1992 |PMC=1205030 |pmid=1628806}}</ref> Between the core X and the Y' element or the core X and TTAGGG sequence there is often a set of 4 'subtelomeric repeats elements' (STR) : STR-A, STR-B, STR-C and STR-D which consists of multiple copies of the vertebrate telomeric motif TTAGGG.<ref name="Louis1995">{{cite journal |author=Louis EJ |title=[The chromosome ends of Saccharomyces cerevisiae] |journal=Yeast |volume=11 |issue=16 |pages=1553–1573 |date=December 1995 |doi=10.1002/yea.320111604}}</ref> This two-domain structure is remarkably similar to the subtelomere structure in human chromosomes 20p, 4q and 18p in which proximal and distal subtelomeric domains are separated by a stretch of degenerate TTAGGG repeats, but, the picture that emerges from studies
[[Telomere]]s are specialized [[protein]]–[[DNA]] constructs present at the ends of [[eukaryotic]] chromosomes, which prevent them from degradation and end-to-end [[chromosome|chromosomal]] fusion. Introductory biology courses often describe telomeres as a type of chromosomal [[aglet]]. Most [[vertebrate]] telomeric DNA consists of long ([[Thymine|T]][[Thymine|T]][[Adenine|A]][[Guanine|G]][[Guanine|G]][[Guanine|G]])n repeats of variable length, often around 3-20kb. ''Subtelomeres'' are segments of DNA between telomeric caps and [[chromatin]]. Each chromosome has two subtelomeres immediately adjacent to the long (TTAGGG)n repeats. Subtelomeres are considered to be the most distal (farthest from the [[centromere]]) region of unique DNA on a chromosome and they are unusually dynamic and variable mosaics of multichromosomal blocks of sequence. The subtelomeres of such diverse species as Humans, [[Plasmodium falciparum]], [[Drosophila melanogaster]] or [[Saccharomyces cerevisiae]], are structurally similar in that they are composed of various repeated elements, but the extent of the subtelomeres and the sequence of the elements vary greatly among organisms.<ref name=pmid11836503/> In yeast (''S. cerevisiae''), subtelomeres are composed of two domains : the proximal and distal (telomeric) domains. The two domains differ in sequence content and extent of homology to other chromosome ends and they are often separated by a stretch of degenerate telomere repeats (TTAGGG) and an element called 'core X', which is found at all chromosome ends and contains an [[autonomously replicating sequence]] (ARS) and an ABF1 binding site.<ref name="Louis1994">{{cite journal |last1=Louis |first1=E. J. |last2=Naumova |first2=E. S. |last3=Lee |first3=A. |last4=Naumov |first4=G. |last5=Haber |first5=J. E. |title=The Chromosome End in Yeast: Its Mosaic Nature and Influence on Recombinational Dynamics |journal=Genetics |date=March 1994 |volume=136 |issue=3 |pages=789–802 |pmid=8005434 |pmc=1205885 }}</ref><ref name="Walmsley1984">{{cite journal |last1=Walmsley |first1=Richard W. |last2=Chan |first2=Clarence S. M. |last3=Tye |first3=Bik-Kwoon |last4=Petes |first4=Thomas D. |title=Unusual DNA sequences associated with the ends of yeast chromosomes |journal=Nature |date=July 1984 |volume=310 |issue=5973 |pages=157–160 |doi=10.1038/310157a0 }}</ref> The proximal domain is composed of variable interchromosomal duplications (<1-30 [[kilobase|kb]]), this region can contain genes such ''Pho'', ''Mel'', ''Mal'' and [[open reading frames]] (ORFs).<ref name="Coissac1996">{{cite journal |last1=Coissac |first1=Eric |last2=Maillier |first2=Evelyne |last3=Robineau |first3=Sylviane |last4=Netter |first4=Pierre |title=Sequence of a 39 411 bp DNA fragment covering the left end of chromosome VII of Saccharomyces cerevisiae |journal=Yeast |date=December 1996 |volume=12 |issue=15 |pages=1555–1562 |doi=10.1002/(SICI)1097-0061(199612)12:15<1555::AID-YEA43>3.0.CO;2-Q }}</ref> The distal domain is composed of 0-4 tandem copies of the highly conserved Y' element which contains other ORFs, the number and chromosomal distribution of Y′ elements varies among yeast strains.<ref name="Louis1992">{{cite journal |last1=Louis |first1=E. J. |last2=Haber |first2=J. E. |title=The Structure and Evolution of Subtelomeric Y' Repeats in Saccharomyces Cerevisiae |journal=Genetics |date=July 1992 |volume=131 |issue=3 |pages=559–574 |pmid=1628806 |pmc=1205030 }}</ref> Between the core X and the Y' element or the core X and TTAGGG sequence there is often a set of 4 'subtelomeric repeats elements' (STR) : STR-A, STR-B, STR-C and STR-D which consists of multiple copies of the vertebrate telomeric motif TTAGGG.<ref name="Louis1995">{{cite journal |last1=Louis |first1=Edward J. |title=The chromosome ends ofSaccharomyces cerevisiae |journal=Yeast |date=December 1995 |volume=11 |issue=16 |pages=1553–1573 |doi=10.1002/yea.320111604 }}</ref> This two-domain structure is remarkably similar to the subtelomere structure in human chromosomes 20p, 4q and 18p in which proximal and distal subtelomeric domains are separated by a stretch of degenerate TTAGGG repeats, but, the picture that emerges from studies of the subtelomeres of other human chromosomes indicates that the two-domain model does not apply universally.<ref name=pmid11836503/>
of the subtelomeres of other human chromosomes indicates that the two-domain model does not apply universally.<ref name="Mefford2002"/>


== Properties ==
== Properties ==
This structure with repeated sequences is responsible for frequent duplication events (which create new genes) and recombination events, at the origin of combination diversity. These peculiar properties are mechanisms that generate diversity at an individual scale and therefore contribute to adaptation of organisms to their environments. For example, in ''Plasmodium falciparum'' during [[interphase]] of [[Plasmodium falciparum biology|erythrocytic stage]], the chromosomic extremities are gathered at the cell nucleus periphery, where they undergo frequent [[deletion (genetics)|deletion]] and telomere [[position effect]] (TPE). This event in addition to expansion and deletion of subtelomeric repeats, give rise to chromosome size polymorphisms and so, subtelomeres undergo [[epigenetics|epigenetic]] and genetic controls. Thanks to the properties of subtelomeres, ''Plasmodium falciparum'' evades host immunity by varying the antigenic and adhesive character of infected erythrocytes (see Subtelomeric transcripts).<ref name="Rubio1996">{{cite journal |vauthors=Rubio JP, Thompson JK, Cowman AF |title=[The var genes of Plasmodium falciparum are located in the subtelomeric region of most chromosomes] |journal=The EMBO Journal |volume=15 |issue=15 |pages=4069–4077 |date=1996 |PMC=452127 |pmid=8670911}}</ref><ref name="Su1995">{{cite journal |vauthors=Su XR, Heatwoie VM, Wertheimer SP, Guinet F, Hertfeldt JA, Peterson DS, Ravetch JA, Weilems TE |title=[The Large Diverse Gene Family var Encodes Proteins Involved in Cytoadherence and Antigenic Variation of Plasmodium falciparum-Infected Erythrocytes] |journal=Cell |volume=82 |pages=89–100 |date=July 1994 |doi=10.1016/0092-8674(95)90055-1 |pmid=7606788}}</ref>
This structure with repeated sequences is responsible for frequent duplication events (which create new genes) and recombination events, at the origin of combination diversity. These peculiar properties are mechanisms that generate diversity at an individual scale and therefore contribute to adaptation of organisms to their environments. For example, in ''Plasmodium falciparum'' during [[interphase]] of [[Plasmodium falciparum biology|erythrocytic stage]], the chromosomic extremities are gathered at the cell nucleus periphery, where they undergo frequent [[deletion (genetics)|deletion]] and telomere [[position effect]] (TPE). This event in addition to expansion and deletion of subtelomeric repeats, give rise to chromosome size polymorphisms and so, subtelomeres undergo [[epigenetics|epigenetic]] and genetic controls. Thanks to the properties of subtelomeres, ''Plasmodium falciparum'' evades host immunity by varying the antigenic and adhesive character of infected erythrocytes (see Subtelomeric transcripts).<ref name="Rubio1996">{{cite journal |last1=Rubio |first1=J P |last2=Thompson |first2=J K |last3=Cowman |first3=A F |title=The var genes of Plasmodium falciparum are located in the subtelomeric region of most chromosomes. |journal=The EMBO Journal |date=1 August 1996 |volume=15 |issue=15 |pages=4069–4077 |pmid=8670911 |pmc=452127 }}</ref><ref name="Su1995">{{cite journal |last1=Su |first1=Xin-zhuan |last2=Heatwole |first2=Virginia M. |last3=Wertheimer |first3=Samuel P. |last4=Guinet |first4=Frangoise |last5=Herrfeldt |first5=Jacqueline A. |last6=Peterson |first6=David S. |last7=Ravetch |first7=Jeffrey A. |last8=Wellems |first8=Thomas E. |title=The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes |journal=Cell |date=July 1995 |volume=82 |issue=1 |pages=89–100 |doi=10.1016/0092-8674(95)90055-1 |pmid=7606788 }}</ref>


==Variations of subtelomere==
==Variations of subtelomere==
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== Subtelomeric transcripts ==
== Subtelomeric transcripts ==
Subtelomeric transcripts are [[pseudogene]]s (transcribed genes producing RNA sequences not translated into protein) and [[gene families]]. In humans, they code for [[olfactory receptor]]s, [[immunoglobulin heavy chain]]s, and [[zinc-finger protein]]s. In other species, several parasites such as [[Plasmodium]] and [[Trypanosoma brucei]] have developed sophisticated evasion mechanisms to adapt to the hostile environment posed by the host, such as exposing variable surface [[antigen]]s to escape the immune system. Genes coding for surface antigens in these organisms are located at subtelomeric regions, and it has been speculated that this preferred location facilitates gene switching and expression, and the generation of new variants.<ref name="Cano2001">{{cite journal |author=Cano MIN |title=[Telomere biology of Trypanosomatids: more questions than answers] |journal=Trends in Parasitology |volume=17 |issue=9,1 |pages=425–429 |date=September 2001 |DOI=10.1016/S1471-4922(01)02014-1 }}</ref><ref name="Barry2003">{{cite journal |vauthors=Barry JD, Ginger ML, Burton P, McCulloch R |title=[Why are parasite contingency genes often associated with telomeres?] |journal=International Journal for Parasitology |volume=33 |issue=1 |pages=29–45 |date=January 2003 |DOI=10.1016/S0020-7519(02)00247-3}}</ref> For example, the genes belonging to the ''var'' family in [[Plasmodium falciparum]] (agent of malaria) code for the PfEMP1 ([[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' erythrocyte membrane protein 1]]), a major virulence factor of [[erythrocyte|erythrocytic]] stages, ''var'' genes are mostly localized in subtelomeric regions. Antigenic variation is orchestrated by epigenetic factors including monoallelic var transcription at separate spatial domains at the nuclear periphery ([[nuclear pore]]), differential [[histone]] marks on otherwise identical var genes, and var [[Gene silencing|silencing]] mediated by telomeric [[heterochromatin]]. Other factors such as non-coding RNA produced in subtelomeric regions adjacent or within ''var'' genes may contribute as well to [[antigenic variation]].<ref name="Scherf2008">{{cite journal |vauthors=Scherf A, Lopez-Rubio JJ, Riviere L |title=[Antigenic Variation in Plasmodium falciparum] |journal=Annual Review of Microbiology |volume=62 |pages=445–470 |date=October 2008 |DOI=10.1146/annurev.micro.61.080706.093134 |pmid=18785843}}</ref><ref name="Guizetti2013">{{cite journal |vauthors=Guizetti J, Scherf A |title=[Silence, activate, poise and switch! Mechanisms of antigenic variation in Plasmodium falciparum] |journal=Cellular Microbiology |volume=15 |issue=5 |pages=718–726 |date=February 2013 |DOI=10.1111/cmi.12115|pmc=3654561 |pmid=23351305}}</ref> In ''Trypanosoma brucei'' (agent of sleeping sickness), [[variable surface glycoprotein]] (VSG) antigenic variation is a relevant mechanism used by the parasite to evade the host immune system. VSG expression is exclusively subtelomeric and occurs either by in situ activation of a silent VSG gene or by DNA rearrangement that inserts an internal silent copy of a VSG gene into an active telomeric expression site. To contrast with ''Plasmodium falciparum'', in ''Trypanosoma brucei'', antigenic variation is orchestrated by epigenetic and genetic factors.<ref name="Cross2005">{{cite journal |author=Cross GAM|title=[Antigenic variation in trypansosomes: Secrets surface slowly] |journal=BioEssays |volume=18 |issue=4 |pages=283–291 |date=February 2005 |DOI=10.1002/bies.950180406 |pmid=8967896}}</ref><ref name="Rudenko2000">{{cite journal |author=Rudenko G|title=[The polymorphic telomeres of the African trypanosome Trypanosoma brucei] |journal=Biochemical Society Transactions |volume=28 |issue=5 |pages=536–540 |date=October 2000 |pmid=11044370 | doi = 10.1042/bst0280536 |pmc=3375589 }}</ref> In [[Pneumocystis jirovecii]] major surface glycoprotein (MSG) gene family cause antigenic variation. MSG genes are like boxes at chromosome ends and only the MSG gene at the unique [[locus (genetics)|locus]] UCS (upstream conserved sequence) is [[Transcription (genetics)|transcribed]]. Different MSG genes can occupy the expression site (UCS), suggesting that [[Genetic recombination|recombination]] can take a gene from a pool of silent donors and install it at the expression site, possibly via [[Chromosomal crossover|crossovers]], activating transcription of a new MSG gene, and changing the surface antigen of ''Pneumocystis jirovecii''. Switching at the expression site is probably facilitated by the subtelomeric locations of expressed and silent MSG genes. A second subtelomeric gene family, MSR, is not strictly regulated at the transcriptional level, but may contribute to phenotypic diversity. Antigenic variation in ''P. jirovecii'' is dominated by genetic regulation.<ref name="Stringer2014">{{cite book |author=Stringer JR |veditors=Edward JL, Becker MM |title=[Pneumocystis carinii Subtelomeres] |pages=101–115 |date=2014 |doi=10.1007/978-3-642-41566-1_5}}</ref><ref name="Stringer2001">{{cite journal |vauthors=Stringer JR, Keely SP |title=[Genetics of Surface Antigen Expression in Pneumocystis carinii] |journal=Infection and Immunity |volume=69 |issue=2 |pages=627–639 |date=February 2001 |doi=10.1128/iai.69.2.627-639.2001 |pmid=11159949|pmc=97933 }}</ref>
Subtelomeric transcripts are [[pseudogene]]s (transcribed genes producing RNA sequences not translated into protein) and [[gene families]]. In humans, they code for [[olfactory receptor]]s, [[immunoglobulin heavy chain]]s, and [[zinc-finger protein]]s. In other species, several parasites such as [[Plasmodium]] and [[Trypanosoma brucei]] have developed sophisticated evasion mechanisms to adapt to the hostile environment posed by the host, such as exposing variable surface [[antigen]]s to escape the immune system. Genes coding for surface antigens in these organisms are located at subtelomeric regions, and it has been speculated that this preferred location facilitates gene switching and expression, and the generation of new variants.<ref name="Cano2001">{{cite journal |last1=Cano |first1=Maria Isabel N |title=Telomere biology of Trypanosomatids: more questions than answers |journal=Trends in Parasitology |date=September 2001 |volume=17 |issue=9 |pages=425–429 |doi=10.1016/S1471-4922(01)02014-1 }}</ref><ref name="Barry2003">{{cite journal |last1=Barry |first1=J.D. |last2=Ginger |first2=M.L. |last3=Burton |first3=P. |last4=McCulloch |first4=R. |title=Why are parasite contingency genes often associated with telomeres? |journal=International Journal for Parasitology |date=January 2003 |volume=33 |issue=1 |pages=29–45 |doi=10.1016/S0020-7519(02)00247-3 }}</ref> For example, the genes belonging to the ''var'' family in [[Plasmodium falciparum]] (agent of malaria) code for the PfEMP1 ([[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' erythrocyte membrane protein 1]]), a major virulence factor of [[erythrocyte|erythrocytic]] stages, ''var'' genes are mostly localized in subtelomeric regions. Antigenic variation is orchestrated by epigenetic factors including monoallelic var transcription at separate spatial domains at the nuclear periphery ([[nuclear pore]]), differential [[histone]] marks on otherwise identical var genes, and var [[Gene silencing|silencing]] mediated by telomeric [[heterochromatin]]. Other factors such as non-coding RNA produced in subtelomeric regions adjacent or within ''var'' genes may contribute as well to [[antigenic variation]].<ref name="Scherf2008">{{cite journal |last1=Scherf |first1=Artur |last2=Lopez-Rubio |first2=Jose Juan |last3=Riviere |first3=Loïc |title=Antigenic Variation in Plasmodium falciparum |journal=Annual Review of Microbiology |date=October 2008 |volume=62 |issue=1 |pages=445–470 |doi=10.1146/annurev.micro.61.080706.093134 |pmid=18785843 }}</ref><ref name="Guizetti2013">{{cite journal |last1=Guizetti |first1=Julien |last2=Scherf |first2=Artur |title=Silence, activate, poise and switch! Mechanisms of antigenic variation in |journal=Cellular Microbiology |date=May 2013 |volume=15 |issue=5 |pages=718–726 |doi=10.1111/cmi.12115 |pmid=23351305 |pmc=3654561 }}</ref> In ''Trypanosoma brucei'' (agent of sleeping sickness), [[variable surface glycoprotein]] (VSG) antigenic variation is a relevant mechanism used by the parasite to evade the host immune system. VSG expression is exclusively subtelomeric and occurs either by in situ activation of a silent VSG gene or by DNA rearrangement that inserts an internal silent copy of a VSG gene into an active telomeric expression site. To contrast with ''Plasmodium falciparum'', in ''Trypanosoma brucei'', antigenic variation is orchestrated by epigenetic and genetic factors.<ref name="Cross2005">{{cite journal |last1=Cross |first1=George A. M. |title=Antigenic variation in trypansosomes: Secrets surface slowly |journal=BioEssays |date=April 1996 |volume=18 |issue=4 |pages=283–291 |doi=10.1002/bies.950180406 |pmid=8967896 }}</ref><ref name="Rudenko2000">{{cite journal |last1=Rudenko |first1=G. |title=The polymorphic telomeres of the African trypanosome Trypanosoma brucei |journal=Biochemical Society Transactions |date=1 October 2000 |volume=28 |issue=5 |pages=536–540 |doi=10.1042/bst0280536 |pmid=11044370 |pmc=3375589 }}</ref> In [[Pneumocystis jirovecii]] major surface glycoprotein (MSG) gene family cause antigenic variation. MSG genes are like boxes at chromosome ends and only the MSG gene at the unique [[locus (genetics)|locus]] UCS (upstream conserved sequence) is [[Transcription (genetics)|transcribed]]. Different MSG genes can occupy the expression site (UCS), suggesting that [[Genetic recombination|recombination]] can take a gene from a pool of silent donors and install it at the expression site, possibly via [[Chromosomal crossover|crossovers]], activating transcription of a new MSG gene, and changing the surface antigen of ''Pneumocystis jirovecii''. Switching at the expression site is probably facilitated by the subtelomeric locations of expressed and silent MSG genes. A second subtelomeric gene family, MSR, is not strictly regulated at the transcriptional level, but may contribute to phenotypic diversity. Antigenic variation in ''P. jirovecii'' is dominated by genetic regulation.<ref name="Stringer2014">{{cite journal |doi=10.1007/978-3-642-41566-1_5 }}</ref><ref name="Stringer2001">{{cite journal |last1=Portnoy |first1=D. A. |last2=Stringer |first2=James R. |last3=Keely |first3=Scott P. |title=Genetics of Surface Antigen Expression inPneumocystis carinii |journal=Infection and Immunity |date=1 February 2001 |volume=69 |issue=2 |pages=627–639 |doi=10.1128/IAI.69.2.627-639.2001 |pmid=11159949 |pmc=97933 }}</ref>


==Pathologic implication==
==Pathologic implication==
Loss of telomeric DNA through repeated cycles of cell division is associated with [[senescence]] or somatic cell aging. In contrast, [[germ line]] and [[cancer]] cells possess an enzyme, [[telomerase]], which prevents telomere degradation and maintains telomere integrity, causing these types of cells to be very long-lived.
Loss of telomeric DNA through repeated cycles of cell division is associated with [[senescence]] or somatic cell aging. In contrast, [[germ line]] and [[cancer]] cells possess an enzyme, [[telomerase]], which prevents telomere degradation and maintains telomere integrity, causing these types of cells to be very long-lived.


In humans, the role of subtelomere disorders is demonstrated in [[facioscapulohumeral muscular dystrophy]] (FSHD), [[Alzheimer's disease]], and peculiar syndromic diseases ([[malformation]] and mental retardation). For example, FSHD is associated with a deletion in the subtelomeric region of chromosome 4q. A series of 10 to >100 kb repeats is located in the normal 4q subtelomere, but FSHD patients have only 1–10 repeat units. This deletion is thought to cause disease owing to a position effect that influences the transcription of
In humans, the role of subtelomere disorders is demonstrated in [[facioscapulohumeral muscular dystrophy]] (FSHD), [[Alzheimer's disease]], and peculiar syndromic diseases ([[malformation]] and mental retardation). For example, FSHD is associated with a deletion in the subtelomeric region of chromosome 4q. A series of 10 to >100 kb repeats is located in the normal 4q subtelomere, but FSHD patients have only 1–10 repeat units. This deletion is thought to cause disease owing to a position effect that influences the transcription of nearby genes, rather than through the loss of the repeat array itself.<ref name=pmid11836503/>
nearby genes, rather than through the loss of the repeat array itself.<ref name="Mefford2002"/>


==Advantages and effects==
==Advantages and effects==
Subtelomeres are DNA segments located before [https://en.wikipedia.org/wiki/Telomere telomeres] and after [https://en.wikipedia.org/wiki/Chromatin chromatin]. Subtelomeres are homologous to other subtelomeres that are located at different chromosomes and are a type of [https://en.wikipedia.org/wiki/Transposable_element transposable element]; DNA segments that can move around the genome. Although subtelomeres are [https://en.wikipedia.org/wiki/Pseudogene pseudogenes] and do not code for protein, they provide an evolutionary advantage by diversifying genes. The duplication, recombination, and deletion of subtelomeres allows for the creation of new genes and new chromosomal properties.<ref> Gale OneFile: Health and Medicine - Document - The complex structure and dynamic evolution of human subtelomeres. https://go.gale.com/ps/retrieve.do?tabID=T002&resultListType=RESULT_LIST&searchResultsType=SingleTab&searchType=AdvancedSearchForm&currentPosition=1&docId=GALE%7CA188858734&docType=Article&sort=RELEVANCE&contentSegment=ZHCC&prodId=HRCA&contentSet=GALE%7CA188858734&searchId=R1&userGroupName=s8888903&inPS=true.</ref> The advantages of subtelomeres have been studied in different species such as [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum],<ref> Mefford HC, Trask BJ (February 2002). "[The complex structure and dynamic evolution of human subtelomeres]". Nature Reviews Genetics. 3: 91–102. doi:10.1038/nrg727. PMID 11836503.</ref>[https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster],<ref> Mefford HC, Trask BJ (February 2002). "[The complex structure and dynamic evolution of human subtelomeres]". Nature Reviews Genetics. 3: 91–102. doi:10.1038/nrg727. PMID 11836503.</ref> [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae],<ref> Mefford HC, Trask BJ (February 2002). "[The complex structure and dynamic evolution of human subtelomeres]". Nature Reviews Genetics. 3: 91–102. doi:10.1038/nrg727. PMID 11836503.</ref> since they have similar genetic elements to humans, not accounting for length and sequence.<ref> Mefford HC, Trask BJ (February 2002). "[The complex structure and dynamic evolution of human subtelomeres]". Nature Reviews Genetics. 3: 91–102. doi:10.1038/nrg727. PMID 11836503.</ref> Subtelomeres might have the same role in plants since the same advantage have been found in a common bean plant known as [https://en.wikipedia.org/wiki/Phaseolus_vulgaris Phaseolus vulgaris].<ref> Common Bean Subtelomeres Are Hot Spots of Recombination and Favor Resistance Gene Evolution. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/30154814.</ref>
Subtelomeres are DNA segments located before [[Telomere telomeres]] and after [[Chromatin chromatin]]. Subtelomeres are homologous to other subtelomeres that are located at different chromosomes and are a type of [[transposable element]]; DNA segments that can move around the genome. Although subtelomeres are [[Pseudogene pseudogenes]] and do not code for protein, they provide an evolutionary advantage by diversifying genes. The duplication, recombination, and deletion of subtelomeres allows for the creation of new genes and new chromosomal properties.<ref name=pmid11836503>{{cite journal |last1=Mefford |first1=Heather C. |last2=Trask |first2=Barbara J. |title=The complex structure and dynamic evolution of human subtelomeres |journal=Nature Reviews Genetics |date=February 2002 |volume=3 |issue=2 |pages=91–102 |doi=10.1038/nrg727 |pmid=11836503 }}</ref> The advantages of subtelomeres have been studied in different species such as [[Plasmodium_falciparum]],<ref name=pmid11836503/> [[Drosophila melanogaster]],<ref name=pmid11836503/> [[Saccharomyces cerevisiae]],<ref name=pmid11836503/> since they have similar genetic elements to humans, not accounting for length and sequence.<ref name=pmid11836503/> Subtelomeres might have the same role in plants since the same advantage have been found in a common bean plant known as [[Phaseolus vulgaris]].<ref>{{cite journal |last1=Chen |first1=Nicolas W. G. |last2=Thareau |first2=Vincent |last3=Ribeiro |first3=Tiago |last4=Magdelenat |first4=Ghislaine |last5=Ashfield |first5=Tom |last6=Innes |first6=Roger W. |last7=Pedrosa-Harand |first7=Andrea |last8=Geffroy |first8=Valérie |title=Common Bean Subtelomeres Are Hot Spots of Recombination and Favor Resistance Gene Evolution |journal=Frontiers in Plant Science |date=14 August 2018 |volume=9 |doi=10.3389/fpls.2018.01185 |pmid=30154814 }}</ref>

⚫
Different varieties of subtelomeres are frequently rearranging during meiotic and mitotic recombination, indicating that subtelomeres are frequently shuffling, which causes new and rapid genetic changes in chromosomes.<ref> Gale OneFile: Health and Medicine - Document - The complex structure and dynamic evolution of human subtelomeres. https://go.gale.com/ps/retrieve.do?tabID=T002&resultListType=RESULT_LIST&searchResultsType=SingleTab&searchType=AdvancedSearchForm&currentPosition=1&docId=GALE%7CA188858734&docType=Article&sort=RELEVANCE&contentSegment=ZHCC&prodId=HRCA&contentSet=GALE%7CA188858734&searchId=R1&userGroupName=s8888903&inPS=true.</ref> In Saccharomyces cerevisiae, 15kb region of chromosome 7L in subtelomeres maintained cell viability in the removal of telomerase, while the removal of the last 15kb increased chromosome [https://en.wikipedia.org/wiki/Senescence senescence].<ref> A subtelomeric region affects telomerase-negative replicative senescence in Saccharomyces cerevisiae. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/30755624.</ref> The knockout of subtelomeres in fission yeast, [https://en.wikipedia.org/wiki/Schizosaccharomyces_pombe Schizosaccharomyces pombe] cells does not impede mitosis and meiosis from occurring, indicating that subtelomeres are not necessary for cell division.<ref> Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/28981863.</ref> They are not needed for the procession of mitosis and meiosis yet, subtelomeres take advantage of cellular DNA recombination. The knockout of subtelomeres in Schizosaccharomyces pombe cells does not affect the regulation of multiple stress responses, when treated with high doses of [https://en.wikipedia.org/wiki/Hydroxycarbamide hydroxyurea], [https://en.wikipedia.org/wiki/Camptothecin camptothecin], [https://en.wikipedia.org/wiki/Ultraviolet ultraviolet radiation], and [https://en.wikipedia.org/wiki/Tiabendazole thiabendazole].<ref> Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/28981863.</ref> Knockout of Subtelomeres in Schizosaccharomyces pombe cells did not affect the length of telomeres, indicating that they play no role it the regulation of length. <ref> Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/28981863.</ref> However, subtelomeres strongly influences the replication timing of telomeres.<ref> Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres | Scientific Reports. https://www.nature.com/articles/srep32510.</ref> Knockout of subtelomeres in Schizosaccharomyces pombe cells after the loss of telomerase does not affect cell survival, indicating that subtelomeres are not necessary for cell survival. <ref> Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/28981863.</ref> An explanation as to why subtelomeres are not necessary after the loss of telomerase is because the chromosomes can use [https://www.sciencedirect.com/science/article/pii/S1097276508004590 intra or inter-chromosomal circularization] or [https://www.researchgate.net/publication/46191823_HAATI_survivors_replace_canonical_telomeres_with_blocks_of_generic_heterochromatin HAATI] to maintain chromosomal stabilization. However, the use of inter-chromosomal circularization engenders chromosome instability by creating two [https://en.wikipedia.org/wiki/Centromere centromeres] in a single chromosome, causing chromosomal breakage during mitosis. In response to this, the chromosome could induce centromere inactivation to impede the formation of two centromeres but, this would induce [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] formation in centromeres. Heterochromatin can be deleterious if it gets into a location that it is not supposed to be in. Subtelomeres are responsible to block heterochromatin from getting into the [https://en.wikipedia.org/wiki/Euchromatin euchromatin] region. Subtelomeres can mitigate the effects of heterochromatin invasion, by distributing heterochromatin around the ends of the subtelomeres. Without subtelomeres, heterochromatin would spread around the region of subtelomeres, getting too close to important genes. At this distance, heterochromatin can silence genes that are nearby, resulting in a higher sensitivity to [https://en.wikipedia.org/wiki/Osmotic_shock osmotic stress]. <ref> Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/28981863.</ref>

⚫
Subtelomeres carry out essential functions with [https://en.wikipedia.org/wiki/Shugoshin_N_terminal_protein_domain Shugonshi protein]. Shugonshi is a centromere protein for chromosome segregation during meiosis and mitosis. There are two types of Shugonshi protein: [https://en.wikipedia.org/wiki/SGOL1 Sgo1] and [https://en.wikipedia.org/wiki/SGOL2 Sgo2]. Sgo1 is only expressed in meiosis 1 for [https://www.cell.com/trends/genetics/pdf/S0168-9525(05)00139-3.pdf centromeric cohesion] of the sister chromosomes, while Sgo2 is expressed in both cell cycles and is responsible for the segregation of chromosomes in the M phase. Not only is Sgo2 expressed in centromeres, but it is also expressed in subtelomeres. Sgo2 interacts with subtelomeres during interphase; middle of the G2 phase. Sgo2 remains in subtelomeres, whose cells lack telomere DNA and plays a major role in creating knobs, which is a highly concentrated chromatin body. Sog2 increases the gene expression of subtelomeres, but it does not increase gene expression in other Sog2 cells. Sog2 increases gene expressions that have to do with transcription and [https://en.wikipedia.org/wiki/Histone histone] configurations by Sgo2 forms a new chromatin repressor for telomere gene expression that is different from the [https://en.wikipedia.org/wiki/H3K9me3 H3K9me]-[https://en.wikipedia.org/wiki/Heterochromatin_protein_1 Swi6]-mediated heterochromatin. Sgo2 represses subtelomeres replication by suppressing [https://www.jbc.org/content/290/45/27414 Sld3], a replication factor, at the start of the replication. <ref> Tashiro, S. et al. Shugonshi forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing. Nat Commun 7, 10393 (2016).</ref>


⚫
Different varieties of subtelomeres are frequently rearranging during meiotic and mitotic recombination, indicating that subtelomeres are frequently shuffling, which causes new and rapid genetic changes in chromosomes.<ref name=pmid11836503/> In Saccharomyces cerevisiae, 15kb region of chromosome 7L in subtelomeres maintained cell viability in the removal of telomerase, while the removal of the last 15kb increased chromosome [[senescence]].<ref>{{cite journal |last1=Jolivet |first1=Pascale |last2=Serhal |first2=Kamar |last3=Graf |first3=Marco |last4=Eberhard |first4=Stephan |last5=Xu |first5=Zhou |last6=Luke |first6=Brian |last7=Teixeira |first7=Maria Teresa |title=A subtelomeric region affects telomerase-negative replicative senescence in Saccharomyces cerevisiae |journal=Scientific Reports |date=12 February 2019 |volume=9 |issue=1 |doi=10.1038/s41598-018-38000-9 |pmid=30755624 }}</ref> The knockout of subtelomeres in fission yeast, [[Schizosaccharomyces pombe]] cells does not impede mitosis and meiosis from occurring, indicating that subtelomeres are not necessary for cell division.<ref name=pmid28981863>{{cite journal |last1=Tashiro |first1=Sanki |last2=Nishihara |first2=Yuki |last3=Kugou |first3=Kazuto |last4=Ohta |first4=Kunihiro |last5=Kanoh |first5=Junko |title=Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis |journal=Nucleic Acids Research |date=13 October 2017 |volume=45 |issue=18 |pages=10333–10349 |doi=10.1093/nar/gkx780 |pmid=28981863 }}</ref> They are not needed for the procession of mitosis and meiosis yet, subtelomeres take advantage of cellular DNA recombination. The knockout of subtelomeres in Schizosaccharomyces pombe cells does not affect the regulation of multiple stress responses, when treated with high doses of [[hydroxyurea]], [[camptothecin]], [[ultraviolet radiation]], and [[thiabendazole]].<ref name=pmid28981863/> Knockout of Subtelomeres in Schizosaccharomyces pombe cells did not affect the length of telomeres, indicating that they play no role it the regulation of length.<ref name=pmid28981863/> However, subtelomeres strongly influences the replication timing of telomeres.<ref>{{cite journal |last1=Piqueret-Stephan |first1=Laure |last2=Ricoul |first2=Michelle |last3=Hempel |first3=William M. |last4=Sabatier |first4=Laure |title=Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres |journal=Scientific Reports |date=2 September 2016 |volume=6 |issue=1 |pages=1–13 |doi=10.1038/srep32510 }}</ref> Knockout of subtelomeres in Schizosaccharomyces pombe cells after the loss of telomerase does not affect cell survival, indicating that subtelomeres are not necessary for cell survival.<ref name=pmid28981863/> An explanation as to why subtelomeres are not necessary after the loss of telomerase is because the chromosomes can use intra or inter-chromosomal circularization<ref>{{cite journal |last1=Wang |first1=Xiaorong |last2=Baumann |first2=Peter |title=Chromosome Fusions following Telomere Loss Are Mediated by Single-Strand Annealing |journal=Molecular Cell |date=22 August 2008 |volume=31 |issue=4 |pages=463–473 |doi=10.1016/j.molcel.2008.05.028 }}</ref> or HAATI<ref>{{cite journal |last1=Jain |first1=Devanshi |last2=Hebden |first2=Anna K. |last3=Nakamura |first3=Toru M. |last4=Miller |first4=Kyle M. |last5=Cooper |first5=Julia Promisel |title=HAATI survivors replace canonical telomeres with blocks of generic heterochromatin |journal=Nature |date=September 2010 |volume=467 |issue=7312 |pages=223–227 |doi=10.1038/nature09374 }}</ref> to maintain chromosomal stabilization. However, the use of inter-chromosomal circularization engenders chromosome instability by creating two [[centromeres]] in a single chromosome, causing chromosomal breakage during mitosis. In response to this, the chromosome could induce centromere inactivation to impede the formation of two centromeres but, this would induce [[heterochromatin]] formation in centromeres. Heterochromatin can be deleterious if it gets into a location that it is not supposed to be in. Subtelomeres are responsible to block heterochromatin from getting into the [[euchromatin]] region. Subtelomeres can mitigate the effects of heterochromatin invasion, by distributing heterochromatin around the ends of the subtelomeres. Without subtelomeres, heterochromatin would spread around the region of subtelomeres, getting too close to important genes. At this distance, heterochromatin can silence genes that are nearby, resulting in a higher sensitivity to [[osmotic stress]].<ref name=pmid28981863/>


⚫
Subtelomeres carry out essential functions with [[Shugonshi protein]]. Shugonshi is a centromere protein for chromosome segregation during meiosis and mitosis. There are two types of Shugonshi protein: [[SGOL1]] and [[SGOL2]]. Sgo1 is only expressed in meiosis 1 for centromeric cohesion of the sister chromosomes,<ref>{{cite journal |last1=Watanabe |first1=Yoshinori |title=Sister chromatid cohesion along arms and at centromeres |journal=Trends in Genetics |date=July 2005 |volume=21 |issue=7 |pages=405–412 |doi=10.1016/j.tig.2005.05.009 }}</ref> while Sgo2 is expressed in both cell cycles and is responsible for the segregation of chromosomes in the M phase. Not only is Sgo2 expressed in centromeres, but it is also expressed in subtelomeres. Sgo2 interacts with subtelomeres during interphase; middle of the G2 phase. Sgo2 remains in subtelomeres, whose cells lack telomere DNA and plays a major role in creating knobs, which is a highly concentrated chromatin body. Sog2 increases the gene expression of subtelomeres, but it does not increase gene expression in other Sog2 cells. Sog2 increases gene expressions that have to do with transcription and [[histone]] configurations by Sgo2 forms a new chromatin repressor for telomere gene expression that is different from the [[H3K9me3]]- Swi6-mediated heterochromatin. Sgo2 represses subtelomeres replication by suppressing Sld3,<ref>{{cite journal |last1=Bruck |first1=Irina |last2=Kaplan |first2=Daniel L. |title=The Replication Initiation Protein Sld3/Treslin Orchestrates the Assembly of the Replication Fork Helicase during S Phase |journal=Journal of Biological Chemistry |date=6 November 2015 |volume=290 |issue=45 |pages=27414–27424 |doi=10.1074/jbc.M115.688424 }}</ref> a replication factor, at the start of the replication.<ref>{{cite journal |last1=Tashiro |first1=Sanki |last2=Handa |first2=Tetsuya |last3=Matsuda |first3=Atsushi |last4=Ban |first4=Takuto |last5=Takigawa |first5=Toru |last6=Miyasato |first6=Kazumi |last7=Ishii |first7=Kojiro |last8=Kugou |first8=Kazuto |last9=Ohta |first9=Kunihiro |last10=Hiraoka |first10=Yasushi |last11=Masukata |first11=Hisao |last12=Kanoh |first12=Junko |title=Shugoshin forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing |journal=Nature Communications |date=25 January 2016 |volume=7 |issue=1 |pages=1–12 |doi=10.1038/ncomms10393 }}</ref>


==Analysis==
==Analysis==
Subtelomere analysis, especially sequencing and profiling of patient subtelomeres, is difficult because of the repeated sequences, length of stretches, and lack of databases on the topic.
Subtelomere analysis, especially sequencing and profiling of patient subtelomeres, is difficult because of the repeated sequences, length of stretches, and lack of databases on the topic.


[[File:subtelomere copy.jpg]]
[[File:subtelomere copy.jpg]]


==References==
==References==
Line 40: Line 36:


== External links ==
== External links ==
* [http://estore.asm.org/estore/files/ccLibraryFiles/FILENAME/000000000581/Coop05.pdf The flow of genetic information]—PDF file. See Table 5.5
* [http://estore.asm.org/estore/files/ccLibraryFiles/FILENAME/000000000581/Coop05.pdf The flow of genetic information]{{dead link}}—PDF file. See Table 5.5


[[Category:Repetitive DNA sequences]]
[[Category:Repetitive DNA sequences]]

Revision as of 15:43, 16 April 2020

Subtelomeres are segments of DNA between telomeric caps and chromatin.

Structure

Telomeres are specialized protein–DNA constructs present at the ends of eukaryotic chromosomes, which prevent them from degradation and end-to-end chromosomal fusion. Introductory biology courses often describe telomeres as a type of chromosomal aglet. Most vertebrate telomeric DNA consists of long (TTAGGG)n repeats of variable length, often around 3-20kb. Subtelomeres are segments of DNA between telomeric caps and chromatin. Each chromosome has two subtelomeres immediately adjacent to the long (TTAGGG)n repeats. Subtelomeres are considered to be the most distal (farthest from the centromere) region of unique DNA on a chromosome and they are unusually dynamic and variable mosaics of multichromosomal blocks of sequence. The subtelomeres of such diverse species as Humans, Plasmodium falciparum, Drosophila melanogaster or Saccharomyces cerevisiae, are structurally similar in that they are composed of various repeated elements, but the extent of the subtelomeres and the sequence of the elements vary greatly among organisms.[1] In yeast (S. cerevisiae), subtelomeres are composed of two domains : the proximal and distal (telomeric) domains. The two domains differ in sequence content and extent of homology to other chromosome ends and they are often separated by a stretch of degenerate telomere repeats (TTAGGG) and an element called 'core X', which is found at all chromosome ends and contains an autonomously replicating sequence (ARS) and an ABF1 binding site.[2][3] The proximal domain is composed of variable interchromosomal duplications (<1-30 kb), this region can contain genes such Pho, Mel, Mal and open reading frames (ORFs).[4] The distal domain is composed of 0-4 tandem copies of the highly conserved Y' element which contains other ORFs, the number and chromosomal distribution of Y′ elements varies among yeast strains.[5] Between the core X and the Y' element or the core X and TTAGGG sequence there is often a set of 4 'subtelomeric repeats elements' (STR) : STR-A, STR-B, STR-C and STR-D which consists of multiple copies of the vertebrate telomeric motif TTAGGG.[6] This two-domain structure is remarkably similar to the subtelomere structure in human chromosomes 20p, 4q and 18p in which proximal and distal subtelomeric domains are separated by a stretch of degenerate TTAGGG repeats, but, the picture that emerges from studies of the subtelomeres of other human chromosomes indicates that the two-domain model does not apply universally.[1]

Properties

This structure with repeated sequences is responsible for frequent duplication events (which create new genes) and recombination events, at the origin of combination diversity. These peculiar properties are mechanisms that generate diversity at an individual scale and therefore contribute to adaptation of organisms to their environments. For example, in Plasmodium falciparum during interphase of erythrocytic stage, the chromosomic extremities are gathered at the cell nucleus periphery, where they undergo frequent deletion and telomere position effect (TPE). This event in addition to expansion and deletion of subtelomeric repeats, give rise to chromosome size polymorphisms and so, subtelomeres undergo epigenetic and genetic controls. Thanks to the properties of subtelomeres, Plasmodium falciparum evades host immunity by varying the antigenic and adhesive character of infected erythrocytes (see Subtelomeric transcripts).[7][8]

Variations of subtelomere

Variation of subtelomeric regions are mostly variation on STRs, due to recombination of large-scale stretches delimited by (TTAGGG)n-like repeated sequences, which play an important role in recombination and transcription. Haplotype (DNA sequence variants) and length differences are therefore observed between individuals.

Subtelomeric transcripts

Subtelomeric transcripts are pseudogenes (transcribed genes producing RNA sequences not translated into protein) and gene families. In humans, they code for olfactory receptors, immunoglobulin heavy chains, and zinc-finger proteins. In other species, several parasites such as Plasmodium and Trypanosoma brucei have developed sophisticated evasion mechanisms to adapt to the hostile environment posed by the host, such as exposing variable surface antigens to escape the immune system. Genes coding for surface antigens in these organisms are located at subtelomeric regions, and it has been speculated that this preferred location facilitates gene switching and expression, and the generation of new variants.[9][10] For example, the genes belonging to the var family in Plasmodium falciparum (agent of malaria) code for the PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), a major virulence factor of erythrocytic stages, var genes are mostly localized in subtelomeric regions. Antigenic variation is orchestrated by epigenetic factors including monoallelic var transcription at separate spatial domains at the nuclear periphery (nuclear pore), differential histone marks on otherwise identical var genes, and var silencing mediated by telomeric heterochromatin. Other factors such as non-coding RNA produced in subtelomeric regions adjacent or within var genes may contribute as well to antigenic variation.[11][12] In Trypanosoma brucei (agent of sleeping sickness), variable surface glycoprotein (VSG) antigenic variation is a relevant mechanism used by the parasite to evade the host immune system. VSG expression is exclusively subtelomeric and occurs either by in situ activation of a silent VSG gene or by DNA rearrangement that inserts an internal silent copy of a VSG gene into an active telomeric expression site. To contrast with Plasmodium falciparum, in Trypanosoma brucei, antigenic variation is orchestrated by epigenetic and genetic factors.[13][14] In Pneumocystis jirovecii major surface glycoprotein (MSG) gene family cause antigenic variation. MSG genes are like boxes at chromosome ends and only the MSG gene at the unique locus UCS (upstream conserved sequence) is transcribed. Different MSG genes can occupy the expression site (UCS), suggesting that recombination can take a gene from a pool of silent donors and install it at the expression site, possibly via crossovers, activating transcription of a new MSG gene, and changing the surface antigen of Pneumocystis jirovecii. Switching at the expression site is probably facilitated by the subtelomeric locations of expressed and silent MSG genes. A second subtelomeric gene family, MSR, is not strictly regulated at the transcriptional level, but may contribute to phenotypic diversity. Antigenic variation in P. jirovecii is dominated by genetic regulation.[15][16]

Pathologic implication

Loss of telomeric DNA through repeated cycles of cell division is associated with senescence or somatic cell aging. In contrast, germ line and cancer cells possess an enzyme, telomerase, which prevents telomere degradation and maintains telomere integrity, causing these types of cells to be very long-lived.

In humans, the role of subtelomere disorders is demonstrated in facioscapulohumeral muscular dystrophy (FSHD), Alzheimer's disease, and peculiar syndromic diseases (malformation and mental retardation). For example, FSHD is associated with a deletion in the subtelomeric region of chromosome 4q. A series of 10 to >100 kb repeats is located in the normal 4q subtelomere, but FSHD patients have only 1–10 repeat units. This deletion is thought to cause disease owing to a position effect that influences the transcription of nearby genes, rather than through the loss of the repeat array itself.[1]

Advantages and effects

Subtelomeres are DNA segments located before Telomere telomeres and after Chromatin chromatin. Subtelomeres are homologous to other subtelomeres that are located at different chromosomes and are a type of transposable element; DNA segments that can move around the genome. Although subtelomeres are Pseudogene pseudogenes and do not code for protein, they provide an evolutionary advantage by diversifying genes. The duplication, recombination, and deletion of subtelomeres allows for the creation of new genes and new chromosomal properties.[1] The advantages of subtelomeres have been studied in different species such as Plasmodium_falciparum,[1] Drosophila melanogaster,[1] Saccharomyces cerevisiae,[1] since they have similar genetic elements to humans, not accounting for length and sequence.[1] Subtelomeres might have the same role in plants since the same advantage have been found in a common bean plant known as Phaseolus vulgaris.[17]

Different varieties of subtelomeres are frequently rearranging during meiotic and mitotic recombination, indicating that subtelomeres are frequently shuffling, which causes new and rapid genetic changes in chromosomes.[1] In Saccharomyces cerevisiae, 15kb region of chromosome 7L in subtelomeres maintained cell viability in the removal of telomerase, while the removal of the last 15kb increased chromosome senescence.[18] The knockout of subtelomeres in fission yeast, Schizosaccharomyces pombe cells does not impede mitosis and meiosis from occurring, indicating that subtelomeres are not necessary for cell division.[19] They are not needed for the procession of mitosis and meiosis yet, subtelomeres take advantage of cellular DNA recombination. The knockout of subtelomeres in Schizosaccharomyces pombe cells does not affect the regulation of multiple stress responses, when treated with high doses of hydroxyurea, camptothecin, ultraviolet radiation, and thiabendazole.[19] Knockout of Subtelomeres in Schizosaccharomyces pombe cells did not affect the length of telomeres, indicating that they play no role it the regulation of length.[19] However, subtelomeres strongly influences the replication timing of telomeres.[20] Knockout of subtelomeres in Schizosaccharomyces pombe cells after the loss of telomerase does not affect cell survival, indicating that subtelomeres are not necessary for cell survival.[19] An explanation as to why subtelomeres are not necessary after the loss of telomerase is because the chromosomes can use intra or inter-chromosomal circularization[21] or HAATI[22] to maintain chromosomal stabilization. However, the use of inter-chromosomal circularization engenders chromosome instability by creating two centromeres in a single chromosome, causing chromosomal breakage during mitosis. In response to this, the chromosome could induce centromere inactivation to impede the formation of two centromeres but, this would induce heterochromatin formation in centromeres. Heterochromatin can be deleterious if it gets into a location that it is not supposed to be in. Subtelomeres are responsible to block heterochromatin from getting into the euchromatin region. Subtelomeres can mitigate the effects of heterochromatin invasion, by distributing heterochromatin around the ends of the subtelomeres. Without subtelomeres, heterochromatin would spread around the region of subtelomeres, getting too close to important genes. At this distance, heterochromatin can silence genes that are nearby, resulting in a higher sensitivity to osmotic stress.[19]

Subtelomeres carry out essential functions with Shugonshi protein. Shugonshi is a centromere protein for chromosome segregation during meiosis and mitosis. There are two types of Shugonshi protein: SGOL1 and SGOL2. Sgo1 is only expressed in meiosis 1 for centromeric cohesion of the sister chromosomes,[23] while Sgo2 is expressed in both cell cycles and is responsible for the segregation of chromosomes in the M phase. Not only is Sgo2 expressed in centromeres, but it is also expressed in subtelomeres. Sgo2 interacts with subtelomeres during interphase; middle of the G2 phase. Sgo2 remains in subtelomeres, whose cells lack telomere DNA and plays a major role in creating knobs, which is a highly concentrated chromatin body. Sog2 increases the gene expression of subtelomeres, but it does not increase gene expression in other Sog2 cells. Sog2 increases gene expressions that have to do with transcription and histone configurations by Sgo2 forms a new chromatin repressor for telomere gene expression that is different from the H3K9me3- Swi6-mediated heterochromatin. Sgo2 represses subtelomeres replication by suppressing Sld3,[24] a replication factor, at the start of the replication.[25]

Analysis

Subtelomere analysis, especially sequencing and profiling of patient subtelomeres, is difficult because of the repeated sequences, length of stretches, and lack of databases on the topic.

References

  1. ^ a b c d e f g h i Mefford, Heather C.; Trask, Barbara J. (February 2002). "The complex structure and dynamic evolution of human subtelomeres". Nature Reviews Genetics. 3 (2): 91–102. doi:10.1038/nrg727. PMID 11836503.
  2. ^ Louis, E. J.; Naumova, E. S.; Lee, A.; Naumov, G.; Haber, J. E. (March 1994). "The Chromosome End in Yeast: Its Mosaic Nature and Influence on Recombinational Dynamics". Genetics. 136 (3): 789–802. PMC 1205885. PMID 8005434.
  3. ^ Walmsley, Richard W.; Chan, Clarence S. M.; Tye, Bik-Kwoon; Petes, Thomas D. (July 1984). "Unusual DNA sequences associated with the ends of yeast chromosomes". Nature. 310 (5973): 157–160. doi:10.1038/310157a0.
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