제 4 장 염색체

ㆍ염색체는 염색이 잘되는 물질이다.

ㆍ그 기본 구조는 DNA가 8개의 히스톤 단백질을 감고 있는 110 A의 직경을 갖는 구조인  뉴클레오좀이다(Fig. 4.1)

Figure 4.1 Nucleosome, chromatin fiber and chromatid

ㆍ이 구조가 다시 coil처럼 꼬여서 360A 직경의 chromatin을 형성한다..

ㆍ중기 염색체는 염색사의 반복서열이 부착하는 산성단백질인 scaffold가 있고 그 scaffold에 30-150 kb의 DNA가 고리형태(Lawmli loop)로 걸려 있는 형태의 0.6 micrometer 직경의 chromatin body를 형성한 것

ㆍ이러한 방법으로 2 meter 길이의 DNA가 2-10 micrometer 길이의 염색체에 들어가는 것이다.

kar·y·o·type

1. The characterization of the chromosomal complement of an individual or a species, including number, form, and size of the chromosomes.

2. A photomicrograph of chromosomes arranged according to a standard classification.

v.

To classify and array the chromosome complement of an organism or a species according to the arrangement, number, size, shape, or other characteristics of the chromosomes.

ㆍLaemmli loop 는 기능 단위라고 볼 수 있으며, 각각이 활성부위인 euchromatin만으로 되어 있거나 혹은 불활성인 heterochromatin으로만 되어 있는 것으로 보인다. 후자는 H1 histone이 부착하여 전사를 방해하고 있다.

ㆍheterochromatin은 활성 유전자가 거의 없으며, DNA 복제시에 늦게 복제한다.

Euchromatin

Euchromatin is a lightly packed form of chromatin (DNA, RNA and protein) that is rich in gene concentration, and is often (but not always) under active transcription. Euchromatin comprises the most active portion of the genome within the cell nucleus. 92% of the human genome is euchromatic.[1]

Contents

1 Structure

2 Appearance

3 Function

4 References

5 External links

Structure

The structure of euchromatin is reminiscent of an unfolded set of beads along a string, wherein those beads represent nucleosomes. Nucleosomes consist of eight proteins known as histones, with approximately 147 base pairs of DNA wound around them; in euchromatin, this wrapping is loose so that the raw DNA may be accessed. Each core histone possesses a `tail' structure, which can vary in several ways; it is thought that these variations act as "master control switches," which determine the overall arrangement of the chromatin. In particular, it is believed that the presence of methylated lysine 4 on the histone tails acts as a general marker for euchromatin.

Appearance

In general, euchromatin appears as light-colored bands when stained in G banding and observed under an optical microscope, in contrast to heterochromatin, which stains darkly. This lighter staining is due to the less compact structure of euchromatin. The basic structure of euchromatin is an elongated, open, 10 nm microfibril, as noted by electron microscopy. In prokaryotes, euchromatin is the only form of chromatin present; this indicates that the heterochromatin structure evolved later along with the nucleus, possibly as a mechanism to handle increasing genome size.

Function

Euchromatin participates in the active transcription of DNA to mRNA products. The unfolded structure allows gene regulatory proteins and RNA polymerase complexes to bind to the DNA sequence, which can then initiate the transcription process. Not all euchromatin is necessarily transcribed, but in general that which is not is transformed into heterochromatin to protect the genes while they are not in use. There is therefore a direct link to how actively productive a cell is and the amount of euchromatin that can be found in its nucleus. It is thought that the cell uses transformation from euchromatin into heterochromatin as a method of controlling gene expression and replication, since such processes behave differently on densely compacted chromatin, known as the `accessibility hypothesis'. One example of constitutive euchromatin that is 'always turned on' is housekeeping genes, which code for the proteins needed for basic functions of cell survival.

References

^ http://www.nature.com/nature/journal/v431/n7011/full/nature03001.html

출처: http://en.wikipedia.org/wiki/Euchromatin

Heterochromatin

From Wikipedia, the free encyclopedia

The nucleus of a human cell showing the location of heterochromatin

Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin. Both play a role in the expression of genes, where constitutive heterochromatin can affect the genes near them (position-effect variegation) and where facultative heterochromatin is the result of genes that are silenced through a mechanism such as histone methylation or siRNA through RNAi. Constitutive heterochromatin is usually repetitive and forms structural functions such as centromeres or telomeres, in addition to acting as an attractor for other gene-expression or repression signals. Facultative heterochromatin is not repetitive and although it shares the compact structure of constitutive heterochromatin, facultative heterochromatin can, under specific developmental or environmental signaling cues, lose its condensed structure and become transcriptionally active.[1] Heterochromatin is often associated with the di and tri-methylation of H3K9.[2]

Contents

1 Structure

2 Function

3 Constitutive heterochromatin

4 Facultative heterochromatin

5 Yeast heterochromatin

6 See also

7 External links

8 References

Structure

Chromatin is found in two varieties: euchromatin and heterochromatin.[3] Originally, the two forms were distinguished cytologically by how intensely they stained - the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin is usually localized to the periphery of the nucleus. Despite this early dichotomy, recent evidence in both animals [4] and plants [5] has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations of epigenetic marks.

Heterochromatin mainly consists of genetically inactive satellite sequences,[6] and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all.[7] Both centromeres and telomeres are heterochromatic, as is the Barr body of the second, inactivated X-chromosome in a female.

Function

Heterochromatin has been associated with several functions, from gene regulation to the protection of the integrity of chromosomes;[8] some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by the cell as damaged or viral DNA, triggering cell cycle arrest, DNA repair, or destruction of the DNA fragment such as by endonucleases in bacteria.

Some regions of chromatin are very densely packed with fibers displaying a condition comparable to that of the chromosome at mitosis. Heterochromatin is generally clonally inherited; when a cell divides the two daughter cells will typically contain heterochromatin within the same regions of DNA, resulting in epigenetic inheritance. Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (in cis) at these boundary domains. This gives rise to different levels of expression from cell to cell,[9] which may be demonstrated by position-effect variegation.[10] Insulator sequences may act as a barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus,[11] and loci in two Saccharomyces spp.[12][13]).

Constitutive heterochromatin

All cells of a given species will package the same regions of DNA in constitutive heterochromatin, and thus in all cells any genes contained within the constitutive heterochromatin will be poorly expressed. For example, all human chromosomes 1, 9, 16, and the Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.

[edit] Facultative heterochromatin

The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within poorly expressed) may be packaged in euchromatin in another cell (and the genes within no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with morphogenesis or differentiation. An example of facultative heterochromatin is X-chromosome inactivation in female mammals: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed.

Among the molecular components that appear to regulate the spreading of heterochromatin include the Polycomb-group proteins and non-coding genes such as Xist. The mechanism for such spreading is still a matter of controversy.[14]

[edit] Yeast heterochromatin

Saccharomyces cerevisiae, or budding yeast, is a model eukaryote and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin, S. cerevisiae has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR), the rDNA (encoding ribosomal RNA), and the sub-telomeric regions. Fission yeast (Schizosaccharomyces pombe) uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the RNAi pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.

In the fission yeast Schizosaccharomyces pombe two RNAi complexes, the RNAi-induced transcriptional gene silencing (RITS) complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in a siRNA-dependent manner on chromosomes, at the site of heterochromatin assembly. RNA polymerase II synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly. Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of Schizosaccharomyces pombe may occur in other eukaryotes.[15] A large RNA structure called RevCen has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.[16]

[edit] See also

Centric Heterochromatin

[edit] External links

BU Histology Learning System: 20102loa

[edit] References

^ Oberdoerffer P &Sinclair D. The role of nuclear architecture in genomic instability and ageing. Nature Reviews Molecular Cell Biology 8, 692-702 (September 2007). doi:10.1038/nrm2238

^ Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome". BMC Genomics 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539/.

^ Elgin, S.C. (1996). "Heterochromatin and gene regulation in Drosophila". Curr. Opin. Genet. Dev. 6 (2): 193–202. doi:10.1016/S0959-437X(96)80050-5. ISSN 0959-437X.

^ van Steensel, B. (2011). "Chromatin: constructing the big picture.". The EMBO Journal 30 (10): 1885-95. PMC 3098493. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3098493/.

^ Roudier, François "et al." (2011). "Integrative epigenomic mapping defines four main chromatin states in Arabidopsis.". EMBO Open 30 (10): 1928-1938. PMC 3098477. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3098477/.

^ Lohe, A.R., et al. (August 1, 1993). "Mapping Simple Repeated DNA Sequences in Heterochromatin of Drosophila Melanogaster". Genetics 134 (4): 1149–74. ISSN 0016-6731. PMC 1205583. PMID 8375654. http://www.genetics.org/cgi/content/full/134/4/1149.

^ Lu, B.Y., et al. (June 1, 2000). "Heterochromatin protein 1 is required for the normal expression of two heterochromatin genes in Drosophila". Genetics 155 (2): 699–708. ISSN 0016-6731. PMC 1461102. PMID 10835392. http://www.genetics.org/cgi/content/full/155/2/699.

^ Grewal SIS &Jia S (January 2007). "Heterochromatin revisited". Nature Reviews Genetics 8 (1): 35–. doi:10.1038/nrg2008. PMID 17173056. http://www.nature.com/nrg/journal/v8/n1/abs/nrg2008.html. [An up-to-date account of the current understanding of repetitive DNA, which usually doesn't contain genetic information. Lay summary]. "If evolution makes sense only in the context of the regulatory control of genes, we propose that heterochromatin, which is the main form of chromatin in higher eukaryotes, is positioned to be a deeply effective target for evolutionary change. Future investigations into assembly, maintenance and the many other functions of heterochromatin will shed light on the processes of gene and chromosome regulation."

^ Fisher, Amanda G.; Matthias Merkenschlager (April 2002). "Gene silencing, cell fate and nuclear organisation". Curr. Opin. Genet. Dev. 12 (2): 193–7. doi:10.1016/S0959-437X(02)00286-1. ISSN 0959-437X. PMID 11893493.

^ Zhimulev, I.F., et al. (December 1986). "Cytogenetic and molecular aspects of position effect variegation in Drosophila melanogaster". Chromosoma 94 (6): 492–504. doi:10.1007/BF00292759. ISSN 1432-0886.

^ Burgess-Beusse, B, et al. (December 2002). "The insulation of genes from external enhancers and silencing chromatin". Proc. Natl Acad. Sci. USA 9 (Suppl 4): 16433–7. doi:10.1073/pnas.162342499. PMC 139905. PMID 12154228. //www.ncbi.nlm.nih.gov/pmc/articles/PMC139905/.

^ Noma, K., et al. (August 2001). "transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries". Science 293 (5532): 1150–5. doi:10.1126/science.1064150. PMID 11498594.

^ Donze, D. &R.T. Kamakaka (2000). "RNA polymerase III and RNA polymerase II promoter complexes are heterochromatin barriers in Saccharomyces cerevisiae". Embo J. 20 (3): 520–31. doi:10.1093/emboj/20.3.520. PMC 133458. PMID 11157758. //www.ncbi.nlm.nih.gov/pmc/articles/PMC133458/.

^ Talbert PB, Henikoff S (October 2006). "Spreading of silent chromatin: inaction at a distance". Nat. Rev. Genet. 7 (10): 793–803. doi:10.1038/nrg1920. PMID 16983375.

^ Vavasseur, et al. (2008). "Heterochromatin Assembly and Transcriptional Gene Silencing under the Control of Nuclear RNAi: Lessons from Fission Yeast". RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. ISBN 978-1-904455-25-7. http://www.horizonpress.com/rnareg.

^ Djupedal I, Kos-Braun IC, Mosher RA, et al. (December 2009). "Analysis of small RNA in fission yeast; centromeric siRNAs are potentially generated through a structured RNA". EMBO J. 28 (24): 3832–44. doi:10.1038/emboj.2009.351. PMC 2797062. PMID 19942857. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2797062/.

Avramova Z (May 2002). "Heterochromatin in Animals and Plants. Similarities and Differences". Plant Physiology 129 (1): 40–9. doi:10.1104/pp.010981. PMC 1540225. PMID 12011336. http://www.plantphysiol.org/cgi/content/full/129/1/40.

Caron H, et al. (2001). "The Human Transcriptome Map: Clustering of Highly Expressed Genes in Chromosomal Domains". Science 291 (5507): 1289–92. doi:10.1126/science.1056794. PMID 11181992.

출처: http://en.wikipedia.org/wiki/Heterochromatin

ㆍheterochromatin은 telomere나 centromere에 보통 위치하며, 가끔 macrosatellite DNA 가 포함되어 있다.

1. 염색체 분석(핵형분석)

ㆍ림프구를 주로 염색체 분석에 이용, 5-10 ml 의 혈액으로부터 림프구를 분리하여 phytohaemagglutinin으로 처리하여 분열을 촉진시키고, 48-72시간 후에 colchicine을 처리하여  분열 중기에서 멈추게 한다. 저장액으로 세포를 팽창시키고 염색체를 고정한 다음 slideglass에 염색체를 펴어서 관찰한다

Figure 4.2 Male karyotype(G-banding)

ㆍ염색체는 사용한 염색액의 종류에 따라서 보이는 band의 pattern이 다르다. Giemsa stain으로 하면 G-banding pattern을 볼 수 있고, 염색체의 응축정도를 반영하는 진한 band와 연한 band를 300-400 개 볼 수 있다. 진한 band는 활성 유전자가 적으며, 주로 AT rich 하다. 반면, 연한 band는 활성유전자의 80%를 포함하며, GC-rich 한 편이다.

Figure 4.3 Female karyotype(G-banding)

ㆍQuinacrine 으로 염색하면 UV 하에서 Q-banding을 볼 수 있다.

ㆍ 일반적으로 4 Mb 이상의 차이를 band를 보고 판단할 수 있다.

ㆍprometaphase chromosome을 이용하거나, flow cytometry를 이용하면 분해능을 높일 수 있다.

ㆍ

Figure 4.4 C-banding

C-banding으로는 macrosatellite 반복서열이 있는 heteochromatin을 볼 수 있다(Giemsa staining의 변형-염색체 변성 후 Giemsa stain 처리) ).

ㆍsilver NOR(nucleolus organizer region을 silver nitrate로 염색) stain은 acrocentric chromosome의 nucleolus organizer 지역을 볼 수 있다.

Figure 4.5 Silver NOR stain

1.1 정상 인간 핵형

ㆍ사람의 염색체 수는 46개이며, 23개의 상동염색체 쌍으로 되어 있다.

ㆍ핵형은  22쌍의 상염색체를 크기순으로 배열하고 한 쌍의 성염색체를 배열 한다.

ㆍ각각의 상동염색체 쌍 중 하나는 엄마로부터, 다른 하나는 아빠로부터 받은 것이다.

ㆍ각 염색체는 centromere라고 하는 허리 부분을 갖고 있다. centromere의 위치는  각 염색체에 따라서 다르며, 그 위치에 따라서 subgroup으로 나눈다.

-metacentric chromosome

-submetacentric chromosome

-acrocentric chromosome

ㆍcentromere를 중심으로 긴팔과 짧은 팔로 나누며, 짧은 팔은 p arm 긴팔은 q arm이라고 함

ㆍ정상 인간 핵형은 46,XX 혹은 46, XY 로 표시할 수 있다

※핵형표시에 사용되는 기호를 알아봅시다. (Table 4.1)

Table 4.1 Symbols for karyotype description

ㆍG-banding 의 각 band의 numbering은 p, q arm으로 구분하고 각 arm은 다시 두개 이상의 지역으로 구분하며, 각 지역은 다시 subregion으로 세분하여 표시한다. 예를 들면, band Xp21.2는 X염색체 짧은 팔의 2 구역(subdivision) 1번 지역(subregion) 2번 band를 말하며, X 염색체 단완의 21.2 밴드라고 읽음(Fig. 4. 6)

Chromosome Mapping: Idiograms

출처: http://www.nature.com/scitable/nated/article?action=showContentInPopup&contentPK=302

By: Clare O'Connor, Ph.D. (Biology Department, Boston College) © 2008 Nature Education

Citation: O'Connor, C. (2008) Chromosome mapping: Idiograms. Nature Education 1(1)

Most cytogeneticists are skilled at identifying individual chromosomes based on their sizes, their shapes, and the banding patterns of their arms. Still, the ability to pinpoint particular chromosomes or regions thereof is of little use unless researchers also have a uniform system for referring to these structures in their communications with one another. This is precisely where the practice of chromosome mapping comes into play.

Today, researchers all over the world rely on a regularly updated mapping system that allows them to refer to specific portions of particular chromosomes with extreme accuracy. This system follows international standards, and it revolves around use of the schematic diagram known as an idiogram, or ideogram. (Both spellings of the word are commonly found in scientific literature.) Idiograms provide a pictorial reference point that is useful for locating the positions of individual genes on chromosomes, as well as for identifying various abnormalities associated with a range of chromosomal disorders. Moreover, idiograms enable members of the scientific community to reference important sources, like the Human Genome Project, through a universal vocabulary that allows for quick, clear interpretation.

Understanding the ISCN Mapping System

Figure 1

A consistent numbering system for mapping genes on chromosomes is essential for producing relevant idiograms. Researchers rely on a mapping system known as the International System for Cytogenetic Nomenclature (ISCN) for this purpose. In the ISCN scheme, the numbering system for a chromosome begins at its centromere. Chromosomes are assigned a long arm and a short arm, based on the position of their centromeres. The shorter arm of the chromosome is known as the p, or petite arm, from the French word for "small." The longer arm is known as the q, or queue arm, from the word meaning a line of people. Thus, chromosomal regions that are present on the short arm will begin with the designation p, whereas regions on the long arm will begin with q. By convention, the p arm of the chromosome is always shown at the top in a karyotype.

Each arm of the chromosome is then divided into regions, and the numbers assigned to each region get larger as the distance from the centromere to the telomere increases. Regions are identified by the specific morphological features that are consistently found in a chromosome, such as the presence of prominent Giemsa-staining bands. The regions are named p1, p2, etc., on the short arm and q1, q2, etc., on the long arm. Depending on the resolution of the staining procedure, it may be possible to detect additional bands within each region, which are designated by adding another digit to the number of the region, once again increasing in value as the distance from the centromere increases.

The Mapping System in Practice

Figure 2

A specific example helps illustrate how the chromosome numbering system works. Figure 1 shows an idiogram for chromosome 12, a medium-sized chromosome with one long and one short arm. The position of the centromere, which separates the p and q arms, is shown by the hatched area. This particular idiogram depicts the pattern of Giemsa staining at a fairly low resolution (i.e., it produces about 400 total bands in a karyotype, which is just above the threshold that is clinically useful). At this resolution, the long q arm of chromosome 12 can be subdivided into two main regions, which are designated 12q1 and 12q2. Region 12q1 can be further subdivided into five subregions, designated 12q11 through 12q15, each of which corresponds to a band detected by Giemsa staining. Orally, these subdivisions are referred to as "12q one-one" through "12q one-five" (not as "12q eleven" through "12q fifteen"). The more distal 12q2 region can be subdivided into subregions 12q21 through 12q24. In addition, subregion 12q24 can be further subdivided into regions 12q24.1 through 12q24.3, even at this relatively low resolution.

Higher resolution views of the chromosome can be obtained if staining is done while the chromosomes are in prometaphase and are less condensed. At this higher level of resolution, approximately 850 bands can be distinguished in a karyotype. As Figure 2 illustrates, additional subdivisions can be detected in all of the regions on chromosome 12 under these conditions.

The Human Genome Project Provides the Ultimate Chromosome Map

Once a defect has been associated with a particular chromosomal position by traditional cytogenetics, investigators are often interested in identifying candidate genes within that region that may be responsible for the symptoms displayed by a patient. With the completion of the Human Genome Project (HGP), this process has been greatly accelerated. The HGP data provide a map of all human chromosomes at single-nucleotide resolution, and the positions of individual genes have been correlated with specific bands detected on high-resolution idiograms of individual chromosomes. Indeed, the Graphic Chromosome Map Viewer available from the National Center for Biotechnology Information provides a simple link between the cytogenetic and sequence data.

Summary

As scientists work to correlate specific genes with specific chromosomal bands, idiograms are becoming increasingly important. Idiograms ensure consistent identification of regions within chromosomes, thereby enabling consistent dialogue and easy cross-referencing between individual samples and reference sources. They also provide links between structural abnormalities and the individual genes correlated with various diseases or syndromes. Thus, idiograms are essential to our ability to organize genomic information as we move into an increasingly molecular era of cytogenetics.

References and Recommended Reading

Braude, P., et al. Preimplantation genetic diagnosis. Nature Reviews Genetics 3, 941–953 (2002) doi:10.1038/nrg953 (link to article)

Scherer, S. E., et al. The finished DNA sequence of human chromosome 12. Nature 440, 346–351 (2006) doi:10.1038/nature04569 (link to article)

Strachan, T., &Read, A. P. Human Molecular Genetics, 2nd ed. (New York, Wiley, 1999)

Figure 4.6 Human idiogram

id·i·o·gram (d--grm)

n.

A diagrammatic representation of chromosome morphology characteristic of a species or a population

1.2 Flow karyotyping

ㆍ각 염색체의 DNA 양이 서로 다른 점을 이용하여 각 염색체를 flow cytometry로 구분할 수 있음.

ㆍ염색체를 EtBr로 염색하고 각 염색체가 laser beam에 의해 발산하는 형광의 양을 측정하여 구분함.

ㆍ1-2 Mb의 차이를 구분할 수 있으므로, 염색체 구조 이상을 보통의 광학적인 방법보다 정확하게 진단할 수 있음.

Figure 4.7 Flow karyotype

Figure 4.8 (a)Bivariate flow karyotype from normal male. (b)Female patient with 9:14 translocation. (c) Microdensitometry vs flow cytometry

2. 염색체 이형성

ㆍ정상적인 염색체의 개인적인 차이점을 말함.

ㆍY 염색체가 변이가 가장 심하며, X 염색체는 변이가 적음.

ㆍsize polymorphism의 경우는 보통 반복서열이 관여되어 있으며, 그 변이 정도는 정상분포를 하고 있다.

2.1 Size of Yq

ㆍ가징 흔한 것은 Yq arm의 길이 다형성이다.

ㆍ정상 남성의 10%는 보통 보다 길거나 짧은 Yq arm을 갖고 있다. long arm은 비전사부위인 반복서열을 포함하고 있으며, Q-banding에 의해 진하게 염색됨

Figure 4.9 Yq polymorphism

Figure 4.10 Fluorescent Y chromatin

2.2 Size of centromeric heterochromatin

ㆍ1,9, 16번 염색체에서  자주 보임(Fig. 4.12)

Figure 4.11 Chromosome 16 centromeric heterochromatin polymorphism(16qh+)

2.3 Satellite polymorphism

satellite 의 크기 변이는 Q-banding 에 의해 acrocentric chromosome인 13, 14, 15, 21, 22에서 관찰 됨.

Figure 4.12 Flow karyotype of 16qh+

ㆍ주로 반복서열에 의한 것이며, rRNA gene의 반복 횟수의 변이로 인한 것도 있음.

ㆍ감수분열시 mispairing에 의해 발생할 수도 있다(Fig. 4.13).

Figure 4.13 Tandem duplication of nucleolar orgarnization region on chromosome 15

2.4 Fragile site

ㆍcentromere 외의 다른 지역에 잘록한 부위가 있는 경우가 발견되며, 이 부위는 쉽게 끊어 질 수 있다.

ㆍaphidicolin을 처리하면 약 80개의 fragile site가 유도되며, 상동염색체 모두에 존재함.

ㆍ또 다른 26개 정도는 5% 인구에서 드물게 발견되며, antifolate에의해 유도된다. 일반적으로 상동염색체 중  한 염색체에서 발견됨.

ㆍ대부분 임상적으로 정상이나, Xq27.3에 있는 것은 정신지체자에서 나타나며, trinucleotide repeat amplification에 의한 것이다.

Figure 4.14 Fragile sites on chromosome 2(2q13). A, B and C, site shown as gap. D-F, Triradial produced by chromatid breaks and non-disjunction. G, H, Acentric fragments generated bychromatid breaks

Table 4.2 Chromosomes in different species

Figure 4.15 Gorilla karyotype

3. 미토콘드리아 염색체

ㆍ사람의 미토콘드리아는 세포질에 존재하며, 원형 게놈을 10개 정도 갖고 있으며, 그 크기는 16569bp로서 22개의 mitochondria tRNA 유전자, 두 개의 rRNA 유전자, 13개의 단백질 유전자를 갖고 있다.

ㆍ모계유전을 함

4. 유사분열

ㆍ각 염색체는 DNA 복제시 각기 특징적인 pattern을 보인다. house-keeping type gene이나 발현되는 조직특이 유전자들은 일찍 복제하는 반면, centromeric heterochromatin 과 발현되지 않는 조직특이 유전자들은 늦게 복제함.

Figure 4.16 Cell cycle

Figure 4.17 Mitosis

ㆍ불활성화된 X 염색체는 맨 나중에 복제함

ㆍsister chromatid 사이에도 교차가 일어남(Fig. 4.18)

Figure 4.18 Sister chromatid exchanges

ㆍ가끔 유사분열시에도 상동염색체 사이의 교차가 일어날 수 있는데, 이러한 것은 암의 발생단계에서 일어나는 중요한 단계가 될 수 있다.

Figure 4.19 Chiasma formation in a somatic cell

Mitotic crossover

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Mitotic recombination is a type of genetic recombination that may occur in somatic cells during mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual.[1] Additionally, mitotic recombination can result in the expression of recessive genes in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive genes.[1][2]

Contents

1 Discovery

2 Occurrence

3 Mechanisms

4 Method

5 Advantages and Disadvantages

6 References

Discovery

The discovery of mitotic recombination came from the observation of twin spotting in Drosophila melanogaster. This twin spotting, or mosaic spotting, was observed in D. melanogaster as early as 1925, but it was only in 1936 that Curt Stern explained it as a result of mitotic recombination. Prior to Stern's work, it was hypothesized that twin spotting happened because certain genes had the ability to eliminate the chromosome on which they were located.[3] Later experiments uncovered when mitotic recombination occurs in the cell cycle and the mechanisms behind recombination.

Mitotic recombination can result in homozygous expression in a heterozygous individual

Occurrence

Mitotic recombination can happen at any locus but is observable in individuals that are heterozygous at a given locus. If a crossover event affects that locus, then both homologous chromosomes will have one chromatid containing each genotype. The resulting phenotype of the daughter cells depends on how the chromosomes line up on the metaphase plate. If the chromatids containing different alleles line up on the same side of the plate, than the resulting daughter cells will appear heterozygous and be undetectable, despite the crossover event. However, if chromatids containing the same alleles line up on the same side, the daughter cells will be homozygous at that locus. This results in twin spotting, where one cell presents the homozygous recessive phenotype and the other cell has the homozygous wild type phenotype. If those daughter cells go on to replicate and divide, the twin spots will continue to grow and reflect the differential phenotype.

Mitotic recombination takes place during interphase. It has been suggested that recombination takes place during G1, when the DNA is in its 2-strand phase, and replicated during DNA synthesis.[4] More recently it was argued that the DNA break leading to mitotic recombination happened during G1, but repair happens after replication.[5]

Mechanisms

The mechanisms behind mitotic recombination are similar to those behind meiotic recombination. These include sister chromatid exchange and mechanisms related to double-stranded break repair such as single-strand annealing, synthesis-dependent strand annealing (SDSA), and gene conversion through a double-Holliday Junction intermediate or SDSA. In addition, non-homologous mitotic recombination is a possibility and can often be attributed to non-homologous end joining.[5][6][7]

Method

There are several theories on how mitotic crossover occurs. In the simple crossover model, the two homologous chromosomes overlap on or near a common Chromosomal fragile site (CFS). This leads to a double-strand break,[8] which is then repaired using one of the two strands. This can lead to the two chromatids switching places. In another model, two overlapping sister chromosomes form a double holiday junction at a common repeat site and are later sheared in such a way that they switch places. In either model, the chromosomes are not guaranteed to trade evenly, or even to rejoin on opposite sides thus most patterns of cleavage do not result in any crossover event. Uneven trading introduces many of the deleterious effects of mitotic crossover.

Alternatively, a crossover can occur during DNA repair[9] if, due to extensive damage, the homologous chromosome is chosen to be the template over the sister chromatid. This leads to gene synthesis since one copy of the allele is copied across from the homologous chromosome and then synthesized into the breach on the damaged chromosome. The net effect of this would be one heterozygous chromosome and one homozygous chromosome.

Advantages and Disadvantages

Mitotic crossover is known to occur in D. melanogaster, some asexually reproducing fungi and in normal human cells, where the event may allow normally recessive cancer-causing genes to be expressed and thus predispose the cell in which it occurs to the development of cancer. Alternately, a cell may become a homozygous mutant for a tumor-suppressing gene, leading to the same result.[2] For example, Bloom's syndrome is caused by a mutation in RecQ helicase, which plays a role in DNA replication and repair. This mutation leads to high rates of mitotic recombination in mice, and this recombination rate is in turn responsible for causing tumor susceptibility in those mice.[10] At the same time, mitotic recombination be beneficial: it may play an important role in repairing double stranded breaks, and it may be beneficial to the organism if having homozygous dominant alleles is more functional than the heterozygous state.[2] For use in experimentation with genomes in model organisms such as Drosophila melanogaster, mitotic recombination can be induced via X-ray and the FLP-FRT recombination system.[11]

References

^ a b Hartel, Daniel L. and Maryellen Ruvolo (2012). Genetics: Analysis of Genetics and Genomes. Burlington: Jones &Bartlett.

^ a b c Tischfield, Jay A. (November 1997). "Loss of Heterozygosity, or: How I learned to Stop Worrying and Love Mitotic Recombination". American Journal of Human Genetics 61 (5): 995–999.

^ Stern, Curt (1936). "Somatic Crossing Over and Segregation in Drosophila Melanogaster". Genetics 21 (6): 625–730.

^ Esposito, Michael S (September 1978). "Evidence that Spontaneous Mitotic Recombination Occurs at the Two-Strand Stage". Proceedings of the National Academy of Sciences of the USA 75 (9): 4436–4440.

^ a b LaFave, MC; J Sekelsky (2009). "Mitotic Recombination: Why? When? How? Where?". PLoS Genet 5 (3). doi:10.1371/journal.pgen.1000411.

^ Helleday, Thomas (2003). "Pathways for Mitotic Homologous Recombination in Mammalian Cells". Mutation Research 532 (1-2): 103–115.

^ Pâques, Frédéric; James E. Haber (1999). "Multiple Pathways of Recombination Induced by Double-Strand Breaks in Saccharomyces cerevisiae". Microbiology and Molecular Biology Reviews 63 (2): 349–404.

^ Helleday, T.. "Double-Strand Break Repair via Double Holliday Junctions (Szostak Model)". Animation. MIT. http://web.mit.edu/engelward-lab/animations/DSBR.html.

^ Helleday, Thomas (27). "Pathways for mitotic homologous recombination in mammalian cells". Mutation research 532 (1-2): 103–115. http://ww2.biol.sc.edu/~awaldman/mammalianrecombinationreview.pdf. Retrieved 2012-12-26.

^ Luo, Guangbin; et al. (2000). "Cancer predisposition caused by elevated mitotic recombination in Bloom mice". Nature Genetics 26: 424–429.

^ Xu, T; GM Rubin (April 1993). "Analysis of genetic mosaics in developing and adult Drosophila tissues". Development 117 (4): 1223-12237

출처: http://en.wikipedia.org/wiki/Mitotic_crossover.