제 2 장 핵산 구조와 기능

1. 핵산 구조

ㆍ단위 : base pair, kilobase(1000 base pairs), megabase(1000 kb)

ㆍ인간게놈 : 3,095,677,412bp(haploid genome)

ㆍ인간유전자 수 : 60000-70000 예상 (게놈프로젝트 후 2만-2만5천)

ㆍ전체 DNA의 70 %가 유전자, 나머지 30%는 반복서열임

ㆍ반복서열은 tandem repeat(satelite DNA)와 interspersed repeat로 구분

Figure 2.1 Nucleic acid structure

Figure 2.2 Chemical structure of nucleic acid

ㆍTandem repeat는 길이에 따라 분류되어짐

- Microsatellite repeat : 1 kb 이하, 반복단위가 A AC AAAN, AAN, AG 등, 반복 횟수는 10-60회.(20-120bp), 약 30 kb 마다 한번씩 있음. 반복 횟수는 개인에 따라서 다를 수 있으므로 이러한 차이(다형성)를 이용해서 각 염색체의 유전 현상을 추적할 수 있다.

Figure 2.3 Double helix

- Minisatellite repeat는 1-30kb 임. 개인에 따라서 반복횟수가 다른 점을 이용하여 유전자 추적에 사용함. 여러 개의 minisatellite로부터 나오는 개인적 특이 band pattern을 이용하여 법의학에 사용함.

-Macrosatellite repeat는 Mb 이상으로서 염색체의 끝(telomere) 혹은 centromere에 존재함.  역시 길이차이가 있으며, centromere의 길이차이를 가시적으로 볼 수 있다.

Tandem repeat(출처: http://en.wikipedia.org/wiki/Tandem_repeat)

Tandem repeats occur in DNA when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to each other. [1]

Contents

1 Example

2 Terminology

3 Uses

4 See also

5 References

6 External links

Example

An example would be:

A-T-T-C-G-A-T-T-C-G-A-T-T-C-G

in which the sequence A-T-T-C-G is repeated three times.

Terminology

When between 10 and 60 nucleotides are repeated, it is called a minisatellite. Those with fewer are known as microsatellites or short tandem repeats.

When exactly two nucleotides are repeated, it is called a dinucleotide repeat (for example: ACACACAC…). The microsatellite instability in hereditary nonpolyposis colon cancer most commonly affects such regions.[2]

When three nucleotides are repeated, it is called a trinucleotide repeat (for example: CAGCAGCAGCAG…), and abnormalities in such regions can give rise to trinucleotide repeat disorders.

When the number is not known, variable, or irrelevant, it is sometimes called a variable number tandem repeat (VNTR). MeSH classifies variable number tandem repeats under minisatellites.[3]

Uses

Tandem repeat describes a pattern that helps determine an individual's inherited traits.

Tandem repeats can be very useful in determining parentage. Short tandem repeats are used for certain genealogical DNA tests.

DNA is examined from microsatellites within the chromosomal DNA. Minisatellite is another way of saying special regions of the loci. Polymerase chain reaction (or PCR) is performed on the minisatellite areas. The PCR must be performed on each organism being tested. The amplified material is then run through electrophoresis. By checking the percentage of bands that match, parentage is determined.

In the field of Computer Science, tandem repeats in strings (e.g., DNA sequences) can be efficiently detected using suffix trees or suffix arrays.

Studies in 2004 linked the unusual genetic plasticity of dogs to mutations in tandem repeats.[4]

See also

Variable number tandem repeats

Short tandem repeats

Satellite DNA

Minisatellite

Microsatellite

Tandem Repeats Database

Amino acid tandem repeat

References

^ Tandem+Repeat at the US National Library of Medicine Medical Subject Headings (MeSH)

^ Oki, E.; Oda, S.; Maehara, Y.; Sugimachi, K. (1999). "Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair". Oncogene 18 (12): 2143–2147. doi:10.1038/sj.onc.1202583. PMID 10321739. edit

^ Variable+Number+of+Tandem+Repeats at the US National Library of Medicine Medical Subject Headings (MeSH)

^ Pennisi, E. (Dec 2004). "Genetics. A ruff theory of evolution: gene stutters drive dog shape". Science 306 (5705): 2172–2120. doi:10.1126/science.306.5705.2172. ISSN 0036-8075. PMID 15618495. edit

ㆍInterspersed repeat는 일반적으로 single copy (단일 반복)으로 나타나며, 길이에 따라서 다시 분류됨

-SINES: 500bp 이하, 예를 들면 Alu repeat(300 bp)로서 게놈의 6%이며, 5-10kb에 한번씩 나타남.

-LINES: 1.5-5kb, 예를 들면, Kpn repeat로서 500bp-10kb

Interspersed repeats (출처: http://studentreader.com/interspersed-repeats/)

The most common type of repetitive DNA are interspersed repeats or moderately repeated sequences. These are present as a single copy at very many different loci and can move or jump to new locations.Interspersed repeats account for almost half of human DNA. These do not occur in tandem arrays. Individual copies of the same, or nearly the same sequence, ~100 bp to ~10 kb long, are found at tens of thousands to more than 1 million different positions dispersed all over the genome. This dispersion is the result of repeated insertions of transposons into new sites during the evolution. The interspersed elements are either transposons themselves or are derived from other genomic sequences acted on by transposon enzymes.

Notes on Interspersed Repeats(출처: http://globin.cse.psu.edu/courses/spring2000/repeats.html)

Major concepts. (See The origin of interspersed repeats in the human genome, by Smit AF.) Almost all mammalian interspersed repeats fall into three categories:

LINE and SINE repeats, also called non-LTR or poly-A retro(trans)posons

LTR retroposons, also called retrovirus-like elements

DNA transposons
In each category there are "autonomous" types (whose full-length elements encode one or more proteins) and "non-autonomous" types (which use proteins encoded by the autonomous types). There are many opinions about the potential role of interspersed repeats in evolution. For the latest thoughts, see Interspersed repeats and other mementos of transposable elements in mammalian genomes, by Smit AF, Curr Opin Genet Dev 1999 Dec;9(6):657-63.

LINE and SINE repeats. A LINE (long interspersed nuclear element) encodes a reverse transcriptase (RT) and perhaps other proteins. Mammalian genomes contain an old LINE family, called LINE2, which apparently stopped transposing before the mammalian radiation, and a younger family, called L1 or LINE1, many of which were inserted after the mammalian radiation (and are still being inserted). A SINE (short interspersed nuclear element) generally moves using RT from a LINE. Examples include the MIR elements, which co-evolved with the LINE2 elements. Since the mammalian radiation, each lineage has evolved its own SINE family. Primates have Alu elements and mice have B1, B2, etc. The process of insertion of a LINE or SINE into the genome causes a short sequence (7-21 bp for Alus) to be repeated, with one copy (in the same orientation) at each end of the inserted sequence. Alus have accumulated preferentially in GC-rich regions, L1s in GC-poor regions.

LTR retroposons These elements are characterized by a region of several hundred bp, called the long terminal repeat, that appears at each end. Some autonomous elements are cousins of retroviruses (e.g., HIV) but are unable to survive outside of the cell, and are called endogenous retroviruses. None are known to be currently active in humans, though some are still mobile in mice. The so-called MaLR (mammalian LTR) elements, which arose before the mammalian radiation, seem to be non-autonomous repeats that move via proteins from endogenous retroviruses.

DNA transposons. Full-length autonomous elements encode a protein, called transposase, by which an element can be removed from one position and inserted at another. Transposons typically have short inverted repeats at each end.

More on L1s. Full-length L1s are about 6-7 kb long. They have a 5' UTR, two ORFs (ORF2 encodes an RT), a 3' UTR and an A-rich tail. L1s, and perhaps the non-autonomous Alu and B1 elements and processed pseudogenes that use the L1's RT, preferentially insert at TT|AAAA (the vertical bar denotes the point of insertion.) Insertion of a transcribed element starts at the elements 3' end, and often results in only a portion being copied.

Many people believe that only a few "master" or "source" L1s are active at any time in evolution. The 3' UTRs of these master copies change extremely rapidly, far more quickly than the drift of neutral genomic sequence. (This may be driven by the competition with SINEs for the L1's RT. That is, changing the patterns used by RT to distinguish L1 transcripts keeps the SINEs from hogging the RT.) The 3' UTR varies in length from 500 bp to over 2000 bp, and the length of the 5' UTR is even more diverse. The 5' or 3' part of an ancient L1 is completely different from that of a recently inserted L1. On the other hand, the 3-kb ORF2 is extremely well conserved.

The rapid turn-over in 3' UTR sequence makes it easy to predict the insertion date of any particular L1 element. Another indicator of insertion age is the amount of nucleotide divergence from the consensus sequence. The following diagram indicates the age of major subclasses of L1 elements. It is adapted from Ancestral, mammalian-wide subfamilies of LINE-1 repetitive sequences, by Smit AF, Toth G, Riggs AD, Jurka J., J Mol Biol 1995 Feb 24;246(3):401-417. Approximate times of divergence of humans from (A) new-world monkeys, (B) prosimian primates (e.g., lemur) and (C) other mammals are indicated. For instance, the L1MA6 family was active around the time of the mammalian radiation.

Percent nucleotide substitutions:

A             B       C

0         5        10        15        20        25        30        35

|         |         |         |         |         |         |         |

----------------------------------------------------------------------------

PA2     PA6        PA12   PA16   MB1           ME1    ME2       ME3

PA4      PA9            PB3      MB8

MA6  MC1

MD1

The fact that L1s have a very well conserved ORF2 and highly variable UTRs has obvious repercussions for programs that attempt to identify repeat elements. RepeatMasker performs comparisons with three consensus sequences for ORF2 regions, 25 sequences for 5' UTRs and 50 sequences for 3' UTRs, then post-processes the results so as to predict entire L1s. Similarly, LINE2 elements are represented in RepeatMasker's database by one ORF2 consensus and a collection of 3' UTRs.

More on Alu elements. The Alu family descended from 7SL RNA (a component of the signal recognition particle), as did the mouse B1 repeats, and because of this, an Alu and a B1 will be recognizably similar in a sequence comparison. The Alu family arose from the tandem duplication of older 130-bp repeats, called FLAM and FRAM (free left/right Alu monomer), with an insertion of 31 bp of unrelated sequence in the "right half", making an Alu more than twice the length of a B1 (about 300 bp vs. 130 bp). Dimeric Alus divide neatly into the AluJ and AluS families, based on differences in at least 14 positions. AluJ, AluS and Alu-type monomers account for about 29%, 68% and 3% of Alu-type repeats in the human genome. The AluJ family includes the oldest Alu dimers, with the AluS family arising more recently. A subfamily of the AluS elements that were inserted very recently (e.g., after the human-chimp split) are now called AluY (Y = young).

Because all Alu elements are relatively young, they are very similar to the consensus sequences in RepeatMasker's database. When RepeatMasker finds one (or certain other young repeats), it deletes the copy and continues searching. In cases where the Alu inserted into an older repeat, the parts on either side can be recognized as belonging to the same element. Moreover, for short or highly diverged repeats, the joined portions may be detectable when the separated pieces are not.

MIRs (Mammalian-wide Interspersed Repeats). For some unknown region, MIR relics frequently mutate more slowly than neutral DNA, particularly in their middle 70 bp. (See: MIRs are classic, tRNA-derived SINEs that amplified before the mammalian radiation, Smit AF, Riggs AD. Nucleic Acids Res 1995 Jan 11;23(1):98-102.) In contrast, copies of other types of repeats accumulate mutations at the neutral rate.

ㆍRNA

-rRNA : 13-15, 21, 22 번 염색체의 nucleolus organizer에 있는 multiple copy rRNA gene에서 전사되어짐

-tRNA: 40 가지가 발견됨. multiple copy로 존재하는 경향이 있음

Table 2.1 Proportions of different types of nuclear DNA

Table 2.2 Types of RNA

2. 핵산의 기능

ㆍ핵산의 기능은 두 가지: 단백질 합성과 유전정보의 세대간 전달

ㆍ유전자의 크기는 작은 것(수백 염기쌍, bp) 부터 수 백 kb 까지 되는 것 까지 다양하다.

ㆍ3개의 염기가 하나의 codon으로서 하나의 아미노산에 해당한다.

ㆍmethionine과 tryptophan을 제외한 모든 아미노산에 대한 codon은 둘 이상이다.

ㆍ단백질의 평균 크기는 300 aa, DNA로는 900 bp에 해당하나 실제로 유전자는 훨씬 크다. 그 이유는 intron이 있기 때문.

Table 2.3 Genetic code with codons

ㆍ일반적으로 단백질은 합성된 후에 변형을 거치게 된다. 그 변형은 disufide bond 형성, hydroxylation, glycosylation, phosphorylation등이다.

Disufide(출처: http://what-when-how.com/molecular-biology/disulfide-bonds-molecular-biology/)

Hydroxylation(collagen alpha chain, 출처: http://chempolymerproject.wikispaces.com/Collagen+-+B-+rgam)

Glycoprotein

2.1 Gene regulation

ㆍ세포마다 전체유전자 중 일부만 발현하며, 세포 종류에 따라서 발현되는 유전자가 다름.

ㆍ그 이유는 각 유전자의 주위에 있는 DNA 부분이 전사를 조절하기 때문이다.

Table 2.4 Genes and their proteins

RNA polymerase II의 promoter는 수백 bp의 길이로 되어 있으며,TATA box가 있다.

RNA polymerase in eukaryotes(출처: http://en.wikipedia.org/wiki/RNA_polymerase)

Structure of eukaryotic RNA polymerase II (light blue) in complex with α-amanitin (red), a strong poison found in death cap mushrooms that targets this vital enzyme

Eukaryotes have multiple types of nuclear RNAP, each responsible for synthesis of a distinct subset of RNA. All are structurally and mechanistically related to each other and to bacterial RNAP:

RNA polymerase I synthesizes a pre-rRNA 45S (35S in yeast), which matures into 28S, 18S and 5.8S rRNAs which will form the major RNA sections of the ribosome.

RNA polymerase II synthesizes precursors of mRNAs and most snRNA and microRNAs. This is the most studied type, and, due to the high level of control required over transcription, a range of transcription factors are required for its binding to promoters.

RNA polymerase III synthesizes tRNAs, rRNA 5S and other small RNAs found in the nucleus and cytosol.

RNA polymerase IV synthesizes siRNA in plants.

RNA polymerase V synthesizes RNAs involved in siRNA-directed heterochromatin formation in plants.

Eukaryotic chloroplasts contain an RNAP very highly structurally and mechanistically similar to bacterial RNAP ("plastid-encoded polymerase").

Eukaryotic chloroplasts also contain a second, structurally and mechanistically unrelated, RNAP ("nucleus-encoded polymerase"; member of the "single-subunit RNAP" protein family).

Eukaryotic mitochondria contain a structurally and mechanistically unrelated RNAP (member of the "single-subunit RNAP" protein family).

Given that DNA and RNA polymerases both carry out template-dependent nucleotide polymerization, it might be expected that the two types of enzymes would be structurally related. However, x-ray crystallographic studies of both types of enzymes reveal that, other than containing a critical Mg2+ ion at the catalytic site, they are virtually unrelated to each other; indeed template-dependent nucleotide polymerizing enzymes seem to have arisen independently twice during the early evolution of cells. One lineage led to the modern DNA Polymerases and reverse transcriptases, as well as to a few single-subunit RNA polymerases from viruses. The other lineage formed all of the modern cellular RNA polymerases

ㆍ이러한 RNA Pol II promoter에는 general transcription factor가 부착한다.

※general transcription factor의 종류와 그들의 기능에 대해서 조사해 봅시다.

ㆍpromoter의 활성은 enhancer 들에 의해 조절되어진다. 이러한 enhancer는 specific transcription factor들이 부착하는 20-30 bp의 짧은 sequence이다.

ㆍ대부분의 enhancer들은 특별한 세포에서만 기능을 발휘한다. 그러므로, 세포특이적 유전자 발현을 조절하게 된다.

ㆍ유전자의 약 80%는 특별한 시기 혹은 장소에서 발현된다. 나머지 20%는 house-keeping gene 으로서 모든 세포에서 발현되며, 기본적인 대사에 관여한다.

Figure 2.5 Beta-globin gene structure

ㆍ대부분의 house-keeping gene과 tissue-specific gene의 40% 정도는 유전자의 5‘부위에 CpG island를 갖고 있다. CpG island는 약 1kb 정도이며, CpG 의 빈도가 높은 지역이다.

ㆍ일반적으로 CpG 의 C는 methylation 되어 있으나, 활발히 발현되는 유전자의 CpG island의 C는 methylation이 없다.

출처: http://www.web-books.com/MoBio/Free/Ch7F2.htm

DNA Methylation and CpG Island

ℼ

Origin of CpG (CG) islands

The CG island is a short stretch of DNA in which the frequency of the CG sequence is higher than other regions.  It is also called the CpG island, where "p" simply indicates that "C" and "G" are connected by a phosphodiester bond.

CpG islands are often located around the promoters of housekeeping genes (which are essential for general cell functions) or other genes frequently expressed in a cell.  At these locations, the CG sequence is not methylated.  By contrast, the CG sequences in inactive genes are usually methylated to suppress their expression.  The methylated cytosine may be converted to thymine by accidental deamination.  Unlike the cytosine to uracil mutation which is efficiently repaired, the cytosine to thymine mutation can be corrected only by the mismatch repair which is very inefficient.  Hence, over evolutionary time scales, the methylated CG sequence will be converted to the TG sequence.  This explains the deficiency of the CG sequence in inactive genes.

Inheritance of DNA methylation pattern

Any type of cells have their own methylation pattern so that a unique set of proteins may be expressed to perform functions specific for this cell type.  Thus, during cell division, the methylation pattern should also pass over to the daughter cell.  This is achieved by the enzyme, DNA methyltransferase, which can methylate only the CG sequence paired with methylated CG.

Figure 7-F-2.  Inheritance of the DNA methylation pattern.  The DNA methyltransferase can methylate only the CG sequence paired with methylated CG.  The CG sequence not paired with methylated CG will not be methylated.  Hence,  the original pattern can be maintained after DNA replication.

Figure 2.6 Transcription, processing and translation

ㆍ대부분의 유전자 발현 조절은 은 transcription 수준에서 일어나지만, 전사 후에도 조절될 수 있다. 예를 들면, splicing에 의해 다른 종류의 단백질을 만들 수 있으며, 번역의 속도를 조절하는 등을 들 수 있다.

Figure 2.7 Post-translational modification of insulin

Figure 2.8 Regulatory region of insulin gene

ㆍ유전자의 조절부위의 돌연변이는 gene product를 만들지 못하거나, 유전자가 비정상적으로 계속 발현되거나, 비정상적인 형태로 발현되는 등의 현상이 일어날 수 있다.

3. 돌연변이

ㆍ길이돌연변이와 점돌연변이로 나눌 수 있다.

3.1 길이돌연변이

ㆍ결손, 중복, 삽입, trinucleotide repeat 등이 있음.

ㆍ결손 : 단일 염기 결손부터 수 Mb까지 결손(눈으로 식별 가능). 대량 결손은 부모 염색체의 재배열로 인한 염색체 파열 혹은 부등교차 등으로 인해 일어날 수 있다.

ㆍ1-5 염기 정도의 결손은 약간 비뚤어진 짝짓기로 인하여 생길 수 있으며, 2 개 염기 이상으로 된 반복서열 혹은 동일 염기의 반복 서열이 있을 때 일어날 수 있다.

ㆍ염색체 파열은 전자파나, 화학물질에 의해 증가될 수 있고, 부등교차는 중복 유전자가 있을 때 생길 수 있다.

ㆍ색상인식 유전자의 예(Fig. 2.12)

ㆍ대량 결손은 인접한 유전자들이 제거되며, 아이가 여러 가지의 X-linked 유전질환을 갖고 있거나, 단일 유전자 이상을 갖고 있는 환자가 정신지체를 갖고 있다든지, 선천성 기형이 있다면 대량결손일 가능성이 있다.

ㆍ소규모 결손이라 할지라도 해독틀이 바뀔 수 있으며, 삽입도 같은 결과를 초래 할 수 있다.

Frameshift mutation(출처: http://www.narragansett.k12.ri.us/NHS/scienceweb/mrreis/AP%20Biology_files/AP%20Biology%20Midterm%20Review%20Sheet%20Diagrams.htm)

ㆍ또 다른 형태의 길이돌연변이는 trinucleotide repeat amplification 이다. 게놈의 약 10%는 tandem repeat 로서 대부분 변하지 않고 유전된다. 그러나 이들 중 trinucleotide repeat 중 일부는 어느 정도 이상 길어지면 불안정해지며, 관련된 유전자의	발현에 영향을 미친다. 이 경우 같은 가족구성원이라 할지라도 반복서열 길이가 다를 수 있으며, 질병의 정도도 다를 수 있다.

ㆍmyotonic dystrophy(근이영양성근긴장증)은 CTG repeat가 환자의 경우 정상인 반복횟수가 5-35 보다 많은 50-1000이상으로 증가해 있다.

Myotonic dystrophy(출처:

http://ghr.nlm.nih.gov/condition/myotonic-dystrophy

What is myotonic dystrophy?

Myotonic dystrophy is part of a group of inherited disorders called muscular dystrophies. It is the most common form of muscular dystrophy that begins in adulthood.

Myotonic dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. For example, a person may have difficulty releasing their grip on a doorknob or handle. Also, affected people may have slurred speech or temporary locking of their jaw.

Other signs and symptoms of myotonic dystrophy include clouding of the lens of the eye (cataracts) and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). In affected men, hormonal changes may lead to early balding and an inability to father a child (infertility). The features of this disorder often develop during a person's twenties or thirties, although they can occur at any age. The severity of the condition varies widely among affected people, even among members of the same family.

There are two major types of myotonic dystrophy: type 1 and type 2. Their signs and symptoms overlap, although type 2 tends to be milder than type 1. The muscle weakness associated with type 1 particularly affects the lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves the muscles of the neck, shoulders, elbows, and hips. The two types of myotonic dystrophy are caused by mutations in different genes.

A variation of type 1 myotonic dystrophy, called congenital myotonic dystrophy, is apparent at birth. Characteristic features include weak muscle tone (hypotonia), an inward- and upward-turning foot (clubfoot), breathing problems, delayed development, and intellectual disability. Some of these health problems can be life-threatening.

How common is myotonic dystrophy?

Myotonic dystrophy affects at least 1 in 8,000 people worldwide. The prevalence of the two types of myotonic dystrophy varies among different geographic and ethnic populations. In most populations, type 1 appears to be more common than type 2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.

What genes are related to myotonic dystrophy?

Myotonic dystrophy type 1 is caused by mutations in the DMPK gene, while type 2 results from mutations in the CNBP gene. The specific functions of these genes are unclear. The protein produced from the DMPK gene may play a role in communication within cells. It appears to be important for the correct functioning of cells in the heart, brain, and skeletal muscles (which are used for movement). The protein produced from the CNBP gene is found primarily in the heart and in skeletal muscles, where it probably helps regulate the function of other genes.

Similar changes in the structure of the DMPK and CNBP genes cause the two forms of myotonic dystrophy. In each case, a segment of DNA is abnormally repeated many times, forming an unstable region in the gene. The mutated gene produces an expanded version of messenger RNA, which is a molecular blueprint of the gene that is normally used to guide the production of proteins. The abnormally long messenger RNA forms clumps inside the cell that interfere with the production of many other proteins. These changes prevent muscle cells and cells in other tissues from functioning normally, which leads to the signs and symptoms of myotonic dystrophy.

Read more about the CNBP and DMPK genes.

How do people inherit myotonic dystrophy?

Both types of myotonic dystrophy are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

As myotonic dystrophy is passed from one generation to the next, the disorder generally begins earlier in life and signs and symptoms become more severe. This phenomenon, called anticipation, has been reported with both types of myotonic dystrophy. However, the evidence for anticipation appears to be strongest in myotonic dystrophy type 1. In this form of the disorder, anticipation is caused by an increase in the length of the unstable region in the DMPK gene. It is less clear whether anticipation occurs in myotonic dystrophy type 2, and the mechanism is unknown. A longer unstable region in the CNBP gene does not appear to influence the age of onset of the disorder.

Where can I find information about diagnosis or management of myotonic dystrophy?

These resources address the diagnosis or management of myotonic dystrophy and may include treatment providers.

Gene Review: Myotonic Dystrophy Type 1

Gene Review: Myotonic Dystrophy Type 2

Gene Tests: Myotonic Dystrophy Type 1

Gene Tests: Myotonic Dystrophy Type 2

MedlinePlus Encyclopedia: Muscular Dystrophy

University of Washington: Myotonic Dystrophy: Making an Informed Choice About Genetic Testing

You might also find information on the diagnosis or management of myotonic dystrophy in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about myotonic dystrophy?

You may find the following resources about myotonic dystrophy helpful. These materials are written for the general public.

MedlinePlus - Health information (2 links)

Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases (3 links)

Additional NIH Resources - National Institutes of Health

National Institute of Neurological Disorders and Stroke: Muscular Dystrophy Information Page

Educational resources - Information pages (4 links)

Patient support - For patients and families (5 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary (2 links)

Gene Tests - Genetic tests ordered by healthcare professionals (2 links)

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

OMIM - Genetic disorder catalog (2 links)

What other names do people use for myotonic dystrophy?

dystrophia myotonica

myotonia atrophica

myotonia dystrophica

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about myotonic dystrophy?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What are the different ways in which a genetic condition can be inherited?

If a genetic disorder runs in my family, what are the chances that my children will have the condition?

Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding myotonic dystrophy?

anticipation ; atrophy ; autosomal ; autosomal dominant ; cardiac ; cataract ; cell ; clubfoot ; congenital ; contraction ; DNA ; gene ; hypotonia ; infertility ; messenger RNA ; muscle tone ; muscular dystrophy ; mutation ; myotonia ; population ; prevalence ; protein ; proximal ; RNA ; sign ; skeletal muscle ; symptom ; syndrome ; tissue ; wasting

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (13 links)

Figure 2.9 Initiation of replication

Figure 2.10 Semiconservative replication

Figure 2.11 Harlequin chromosome(BrdU staining). Semiconservative

정의:

har·le·quin (härl-kwn, -kn)

n.

1. Harlequin A conventional buffoon of the commedia dell'arte, traditionally presented in a mask and parti-colored tights.

2. A clown; a buffoon.

adj.

Having a pattern of brightly colored diamond shapes.

Harlequin chromosomes

With the use of a more modern staining technique, it is now possible to visualize the semiconservative replication of chromosomes at mitosis without the aid of autoradiography. In this procedure, the chromosomes are allowed to go through two rounds of replication in bromodeoxyuridine (BUdR). The BUdR labeling pattern, shown in Figure 8-16a, is the reciprocal of that of Figure 8-15, because the BUdR is used in both replications, rather than being replaced by normal thymidine for the second replication as in the autoradiographic process. The chromosomes are then stained with fluorescent dye and Giemsa stain; this process distinguishes hybrid chromatids with one BUdR-containing strand and one original strand (dark stain) from those in which both strands contain BUdR (light stain), and generates so-called harlequin chromosomes (Figure 8-16b). (Note, in passing, that harlequin chromosomes are particularly favorable for the detection of sister-chromatid exchange at mitosis; two examples are seen in Figure 8-16b). Using similar techniques. Taylor showed that chromosome replication at meiosis also is semiconservative.

Figure 8-16

(a) A diagrammatic representation of the production of harlequin chromosomes. In this procedure, the chromosomes go through two rounds of replication in the presence of bromodeoxyuridine (BUdR), which replaces thymidine in the newly synthesized DNA. The chromosomes (more...)(출처: http://www.ncbi.nlm.nih.gov/books/NBK21790/)

Figure 2.12 Gene loss or fused gene created by unequal recombination

Table 2.5 Examples of DNA mutation

Figure 2.13 Normal recombination and gene conversion

Gene Conversion

Gene conversion is a nonreciprocal transfer of genetic information.  The following figure illustrates the difference between gene conversion and DNA crossover.  An origin of gene conversion is explanined in Figure 8-D-5.

Figure 8-D-4.  Comparison between gene conversion and DNA crossover. (a) Two DNA molecules. (b) Gene conversion - the red DNA donates part of its genetic information (e-e' region) to the blue DNA.  (c) DNA crossover - the two DNAs exchange part of their genetic information (f-f' and F-F').

Figure 8-D-5.  An origin of gene conversion.  (a) Heteroduplexes formed by the resolution of Holliday structure or by other mechanisms.  (b) The blue DNA uses the invaded segment (e') as template to "correct" the mismatch, resulting in gene conversion.  (c) Both DNA molecules use their original sequences as template to correct the mismatch.  Gene conversion does not occur

출처: http://www.web-books.com/MoBio/Free/Ch8D4.htm

Figure 2.14 DNA analysis od a family with myotonic dystrophy

3.2 점돌연변이

ㆍ단일 염기가 다른 염기로 치환됨

- transition : pyrimidine-pyrimidine, purine-purine 치환

- transversion : pyrimidine-purine 치환

Structure and Properties of Purines and Pryimidines

Purines and pyrimidines are two of the building blocks of nucleic acids. Only two purines and three pyrimidines occur widely in nucleic acids. Here are their structures in organic chemists' line notation:

The Purines
Adenine		Guanine
The Pyrimidines
Cytosine	Thymine	Uracil

Crucial property: formation of hydrogen-bonded pairs composed of one purine and one pyrimidine, such as guanine-cytosine (left, below) and adenine-thymine (right).

Guanine-Cytosine	Adenine-Thymine

Red dashes = the strong hydrogen bonds holding the dimers together

"Squiggly lines = position of attachment to the nucleic acid chains of DNA or RNA.

The dimers have exactly the same long dimension, enabling them to fit equally well into the three dimensional structures derived from them.

This steric "fit" is crucial to maintaining the helical structure of DNA

Tubular structures = ab initio MO calculated structures for the dimers.

Hydrogen bonding only possible in correct tautomers.

Remember: tautomers are isomers related by changing the positions of attachment of a single hydrogen and a single double bond, in a three-atom system, such as the keto- and enol tautomers of a ketone.

For example, the tautomers of adenine:

Tautomers A and C both have an aromatic 6-ring

Structures like C, which must be considered for adenine itself, are ruled out in the nucleic acids by the attachment to the sugar.

Thus A is the favored tautomer for reasons of both stability and incorporation into nucleic acids

The tautomers of guanine include the structure that hydrogen bonds well to a pyrimidine (A), and an aromatic one (B)

Several that must be considered for guanine itself, but not for guanine incorporated into a nucleic acid, also can be drawn

Here are the tautomers of cytosine, thymine, and uracil:

Cytosine Tautomers

Thymine Tautomers

Uracil Tautomers

Again, these equilibria involving the "abnormal" tautomers have relevance only for the individual pyrimidine in aqueous solution. The inter-base hydrogen bonds in the dimers strongly stabilize the structure indicated in the base pairs.

출처: http://chemistry.umeche.maine.edu/CHY431/Basics/PurPyrm.html

ㆍ점돌연변이는 아미노산을 변화시키지 않을 수도 있거나(25%), 혹은 다른 아미노산으로 바뀌게 하거나(70%), 혹은 nonsense codon으로 바뀌게 할 수 있다(5%)

ㆍDNA 복제실수와 실수의 회복에 문제가 발생하면 점돌연변이 발생

ㆍ자연돌연변이률은 109-1010 bp에 한 염기씩 일어남

ㆍ돌연변이물질(hydroxylamine, nitrogen mustard)등의 농도에 비례해서 증가함

※돌연변이물질의 작용 기작을 조사해 봅시다.

ㆍ자외선은 pyrimidine dimer를 형성하게 하며 돌연변이를 유발하며, 자외선에 대한 방어에 필요한 효소가 없는 환자는 조기에 암이 발생.

Figure 2.15 Examples of DNA repair

Mutation by UV light

UV light may cause two adjacent pyrimidine residues (cytosine or thymine)  to form a dimer.  In a normal cell, the dimer can be detected by p53, which then triggers the repairing process.  However, if p53 itself is mutated and become non-functional, the pyrimidine dimer may lead to mutation

Figure 7-F-4.  Pyrimidine dimer induced by UV light.  This figure uses thymine as an example.  Cytosine may form a similar dimer.

Figure 7-F-5.  A possible mechanism for the mutation induced by UV light.

In the above figure, the UV light first causes two adjacent cytosine residues to form a dimer.  During DNA replication, both strands are used as templates to synthesize new strands.  The cytosine dimer could cause adenine (instead of the normal guanine) to be incorporated into the new strand.  Subsequent DNA replication will produce CC to TT mutation.  Although the cytosine dimer may eventually be corrected, the mutation cannot be detected by the DNA repair system.

출처: http://www.web-books.com/MoBio/Free/Ch7F5.htm

Xeroderma pigmentosum

On this page:

Description

Genetic changes

Inheritance

Diagnosis

Additional information

Other names

Glossary definitions

Reviewed May 2010

What is xeroderma pigmentosum?

Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also have problems involving the nervous system.

The signs of xeroderma pigmentosum usually appear in infancy or early childhood. Many affected children develop a severe sunburn after spending just a few minutes in the sun. The sunburn causes redness and blistering that can last for weeks. Other affected children do not get sunburned with minimal sun exposure, but instead tan normally. By age 2, almost all children with xeroderma pigmentosum develop freckling of the skin in sun-exposed areas (such as the face, arms, and lips); this type of freckling rarely occurs in young children without the disorder. In affected individuals, exposure to sunlight often causes dry skin (xeroderma) and changes in skin coloring (pigmentation). This combination of features gives the condition its name, xeroderma pigmentosum.

People with xeroderma pigmentosum have a greatly increased risk of developing skin cancer. Without sun protection, about half of children with this condition develop their first skin cancer by age 10. Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on the face, lips, and eyelids. Cancer can also develop on the scalp, in the eyes, and on the tip of the tongue. Studies suggest that people with xeroderma pigmentosum may also have an increased risk of other types of cancer, including brain tumors. Additionally, affected individuals who smoke cigarettes have a significantly increased risk of lung cancer.

The eyes of people with xeroderma pigmentosum may be painfully sensitive to UV rays from the sun. If the eyes are not protected from the sun, they may become bloodshot and irritated, and the clear front covering of the eyes (the cornea) may become cloudy. In some people, the eyelashes fall out and the eyelids may be thin and turn abnormally inward or outward. In addition to an increased risk of eye cancer, xeroderma pigmentosum is associated with noncancerous growths on the eye. Many of these eye abnormalities can impair vision.

About 30 percent of people with xeroderma pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time.

Researchers have identified at least eight inherited forms of xeroderma pigmentosum: complementation group A (XP-A) through complementation group G (XP-G) plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase skin cancer risk, although some are more likely than others to be associated with neurological abnormalities.

How common is xeroderma pigmentosum?

Xeroderma pigmentosum is a rare disorder; it is estimated to affect about 1 in 1 million people in the United States and Europe. The condition is more common in Japan, North Africa, and the Middle East.

What genes are related to xeroderma pigmentosum?

Xeroderma pigmentosum is caused by mutations in genes that are involved in repairing damaged DNA. DNA can be damaged by UV rays from the sun and by toxic chemicals such as those found in cigarette smoke. Normal cells are usually able to fix DNA damage before it causes problems. However, in people with xeroderma pigmentosum, DNA damage is not repaired normally. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die.

Many of the genes related to xeroderma pigmentosum are part of a DNA-repair process known as nucleotide excision repair (NER). The proteins produced from these genes play a variety of roles in this process. They recognize DNA damage, unwind regions of DNA where the damage has occurred, snip out (excise) the abnormal sections, and replace the damaged areas with the correct DNA. Inherited abnormalities in the NER-related genes prevent cells from carrying out one or more of these steps. The POLH gene also plays a role in protecting cells from UV-induced DNA damage, although it is not involved in NER; mutations in this gene cause the variant type of xeroderma pigmentosum.

The major features of xeroderma pigmentosum result from a buildup of unrepaired DNA damage. When UV rays damage genes that control cell growth and division, cells can either die or grow too fast and in an uncontrolled way. Unregulated cell growth can lead to the development of cancerous tumors. Neurological abnormalities are also thought to result from an accumulation of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Inherited mutations in at least eight genes have been found to cause xeroderma pigmentosum. More than half of all cases in the United States result from mutations in the XPC, ERCC2, or POLH genes. Mutations in the other genes generally account for a smaller percentage of cases.

Read more about the ERCC2, ERCC3, POLH, XPA, and XPC genes.

See a list of genes associated with xeroderma pigmentosum.

How do people inherit xeroderma pigmentosum?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of xeroderma pigmentosum?

These resources address the diagnosis or management of xeroderma pigmentosum and may include treatment providers.

American Cancer Society: How are Squamous and Basal Cell Skin Cancer Diagnosed?

American Cancer Society: How is Melanoma Diagnosed?

Gene Review: Xeroderma Pigmentosum

Gene Tests: DDB2-Related Xeroderma Pigmentosum

Gene Tests: ERCC1-Related Xeroderma Pigmentosum

Gene Tests: ERCC2-Related Xeroderma Pigmentosum

Gene Tests: ERCC3-Related Xeroderma Pigmentosum

Gene Tests: ERCC4-Related Xeroderma Pigmentosum

Gene Tests: ERCC5-Related Xeroderma Pigmentosum

Gene Tests: POLH-Related Xeroderma Pigmentosum

Gene Tests: Xeroderma Pigmentosum Multi-Gene Panels

Gene Tests: XPA-Related Xeroderma Pigmentosum

Gene Tests: XPC-Related Xeroderma Pigmentosum

MedlinePlus Encyclopedia: Xeroderma Pigmentosum

National Cancer Institute: Melanoma Treatment

National Cancer Institute: Skin Cancer Treatment

Xeroderma Pigmentosum Society, Inc.: Beta Carotene

Xeroderma Pigmentosum Society, Inc.: Ultraviolet Radiation and Protection

You might also find information on the diagnosis or management of xeroderma pigmentosum in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about xeroderma pigmentosum?

You may find the following resources about xeroderma pigmentosum helpful. These materials are written for the general public.

MedlinePlus - Health information (3 links)

Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases

Additional NIH Resources - National Institutes of Health (3 links)

Educational resources - Information pages (3 links)

Patient support - For patients and families (6 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary

Gene Tests - Genetic tests ordered by healthcare professionals (10 links)

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

OMIM - Genetic disorder catalog (8 links)

What other names do people use for xeroderma pigmentosum?

DeSanctis-Cacchione syndrome

XP

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about xeroderma pigmentosum?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What are the different ways in which a genetic condition can be inherited?

If a genetic disorder runs in my family, what are the chances that my children will have the condition?

Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding xeroderma pigmentosum?

autosomal ; autosomal recessive ; cancer ; carcinoma ; cell ; cornea ; difficulty swallowing ; DNA ; DNA damage ; gene ; melanoma ; mutation ; NER ; nerve cell ; nervous system ; neurological ; nucleotide ; nucleotide excision repair ; pigmentation ; protein ; recessive ; seizure ; sensitivity ; sign ; symptom ; syndrome ; toxic ; tumor ; UV rays

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (8 links)

출처: http://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum

ㆍDNA 복제시 발생하는 실수를 고치는데 필요한 mismatch repair의 한 경로가 고장난 사람은 조기에 대장암 발생.

Mismatch-repair(E, coli)

Mismatch repair of newly replicated DNA by the MutSLH proteins.

Box 1 | Mismatch repair (eucaryotes)

From the following article:

AID and mismatch repair in antibody diversification

Alberto Martin &Matthew D. Scharff

Nature Reviews Immunology 2, 605-614 (August 2002)

doi:10.1038/nri858

Back to article

The mismatch-repair (MMR) system is important for promoting the genetic stability of eukaryotes and prokaryotes. MMR proteins, which are mutated frequently in colon cancer48, recognize DNA mismatches that are produced during DNA replication, homologous recombination, cytidine deamination or other forms of DNA damage103, 104. The repair process is then mobilized to correct these mutations. In addition, the MMR system also inhibits homologous recombination between non-identical sequences104. In prokaryotes, MMR is carried out by MutS, MutL and MutH105. MutS and MutL bind DNA mismatches in an ATP-dependent manner and direct MutH to cleave the unmethylated DNA strand and initiate the repair process. In eukaryotes, many homologues of bacterial MutS and MutL have been identified, but homologues of MutH have yet to be discovered. MutS homologues (MSHs) form heterodimers with each other to carry out specific functions. For example, MSH4–MSH5 heterodimers promote crossing-over during meiosis, whereas MSH2–MSH3 heterodimers bind mismatches that are caused by insertions or deletions103, 104. MSH2–MSH6 heterodimers bind to single base-pair mismatches, as shown in the figure. Heterodimers of MutL homologues, such as MLH1–MLH3, and post-meiotic segregation 2 (PMS2), as well as the EXO1 exonuclease, are then recruited to this complex. Proliferating cell nuclear antigen (PCNA), which links the DNA polymerase to the DNA template during replication, interacts with this complex, which indicates that MMR might occur during DNA replication104. Single-stranded DNA breaks occur during MMR, although it is unclear whether they are generated by an unknown homologue of bacterial MutH, or whether they are already present at the replication fork. The lesion is digested by exonucleases, such as EXO1, and then filled-in by translesional and/or replicative DNA polymerases.

출처: http://www.nature.com/nri/journal/v2/n8/box/nri858_BX1.html

ㆍmismatch repair system이 잘 인식하지 못하는 점돌연변이가 있으며, 이 점돌연변이가 자주 나타나게 되며, 단일유전자 이상을 일으키게 된다. cytosine은 deamination에 의해 uracil이 되며, depurination/deamination repair 에 의해 제거된다. 그러나 CpG island의 C가 methylation 되어 있는 경우는 deamination 에의해 T로 전환되게 된다. 이 경우 methylation 된 CpG의 C가 줄어들게 되고, C to T transition이 점돌연변이의 35-50%를 차지하게 된다.

ㆍC to T transition은 정자에서 많이 일어난다.

3.3 단일 유전자 이상의 분자 병리학

ㆍ돌연변이 형태에 따라서 전사, 전사 후 RNA 가공, 단백질합성, 합성된 단백질의 특징 등이 결정됨.

Figure 2.16 Possible faults in protein synthesis

※돌연변이 형태와 그 것이 유전자 발현에 어떻게 영향을 미치는지 알아봅시다.

ㆍ대부분의 단일유전자 이상은 길이돌연변이 혹은 점돌연변이에 의해 초래되나, 특정한 질병에 대해서 특정한 형태의 돌연변이가 주로 일어난다. 예를 들면, trinucleotide repeat amplification은 myotonic dystrophy, fragile X syndrome, Hungtinton disease의 주요 원인이 되고 있다.

HUNTINGTON'S DISEASE

What is Huntington's Disease?

Huntington's Disease (HD) is a brain disorder that affects a person's ability to think, talk, and move.

The disease destroys cells in the basal ganglia, the part of the brain that controls movement, emotion, and cognitive ability. HD is caused by a mutation in a gene on chromosome 4. The job of its protein product, huntingtin, is to direct the delivery of small packages (vesicles containing important molecules) to the outside of the cell. Normally, the coding region of this gene contains the DNA sequence "CAG" repeated again and again. The number of times this triplet is repeated varies from person to person, ranging from 10 to 26 times. People with HD have an abnormally high number of these CAG triplets, approximately 40 or more. This likely disrupts the function of the gene's protein product, but how the expansion of the CAG repeat causes disease is unknown. Somehow the brain cells of HD patients accumulate clumps of protein that become toxic, resulting in cell death. Some patients lose more than 25% of their brain cells before they die.

How do people get Huntington's Disease?

Huntington's disease is inherited in an autosomal dominant pattern. This means that everyone who inherits the faulty gene will eventually get the disease. A parent with a mutation in the HD gene has a 50 percent chance of passing on the disease to their children.

What are the symptoms of Huntington's Disease?

Huntington's disease affects the part of the brain that controls thinking, emotion, and movement. Most people who have the disease start to see symptoms between the ages of 30 and 50 (but symptoms can appear earlier or later in life). The disease gets worse over time.

Some of the symptoms include: poor memory, depression and/or mood swings, lack of coordination, twitching or other uncontrolled movements, and difficulty walking, speaking, and/or swallowing. In the late stages of the disease, a person will need help doing even simple tasks, such as getting dressed.

How do doctors diagnose Huntington's Disease?

During pregnancy a woman can find out if her baby will have the disease with two tests: taking a sample of fluid from around the fetus (amniocentesis), or by taking a sample of fetal cells from the placenta (chorionic villus sampling (CVS)).

After the child is born, doctors can identify the disease by first doing a series of neurological and psychological tests. A genetic test can then confirm the diagnosis by determining if the person indeed has inherited the HD gene mutation (an expansion of the CAG triplet). However, the test cannot tell at what age a person will begin to get sick.

How is Huntington's Disease treated?

Treatments do not slow the progression of the disease, but they can help make the patient more comfortable.

Medications ease feelings of depression and anxiety; others control involuntary movements.

Physical or speech therapy helps HD patients lead more normal lives.

Interesting facts about Huntington's Disease

The disease was named for Dr. George Huntington, who first described it in 1872.

In the United States, about 1 in every 30,000 people has Huntington's disease.

출처: http://learn.genetics.utah.edu/content/disorders/whataregd/hunt/

ㆍ더물게, 어떤 질병의 경우는 오직 한 가지 type의 돌연변이만이 발견된다.

ㆍ질병에 대한 돌연변이 형태는 지리적 차이가 있다. 영국과 미국에 있는 낭포성 섬유증을 앓는 북구인의 3분의 2 는 508번째 아미노산의 three-base deletion을 갖고 있지만, Turky와 Arab의 경우는 3분의 1이하가 이러한 돌연변이를 갖고 있다.

※돌연변이 형태를 표시하는 방법을 숙지합시다.

Table 2.6 Examples of mutations causing cystic fibrosis

Figure 2.17 Point mutation in beta-globin gene