제 6 장 염색체 이상

1. 염색체 수 이상

ㆍ정상적인 체세포는 46개의 염색체를 갖고 있다. 염색체 수가 정확하게 반수체의 배수로 되어 있고 2배체 이상일 때는 다배체(정배성)라고 하며, 그렇지 않은 경우, 즉 정확하게 배수가 아닌 경우는 비정배성이라고 한다.

1.1 Aneuploidy(비정배성)

ㆍ비정배성은 보통 분열 후기에 염색체 혹은 염색분체(chromatid)의 불분리에 의해 일어난다.

Table 6.1 Examples of numerical chromosomal abberations

ㆍ혹은 분열 후기에 염색체 이동의 지연(anaphase lag)에 의해 일어날 수도 있다.

ㆍ이상의 결과 세포분열 후에 한 딸세포는 여분의 염색체를 갖게되고

(trisomy), 다른 딸 세포는 한 염색체 모자라게 된다(monosomy).

ㆍ감수분열시 염색체 불분리의 원인은 모르지만 엄마의 나이 증가, 엄마의 hypothyroidism, 방사선치료, 바이러스 감염, 가족력 등에 의존한다.

Hypothyroidism

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Hypothyroidism /ˌhaɪpɵˈθaɪərɔɪdɪzəm/ is a state in which the thyroid gland does not make enough thyroid hormone.

Iodine deficiency is often cited as the most common cause of hypothyroidism worldwide but it can be caused by many other factors. It can result from the lack of a thyroid gland or from iodine-131 treatment, and can also be associated with increased stress. Severe hypothyroidism in infants can result in cretinism.

A 2011 study concluded that about 8% of women over 50 and men over 65 in the UK suffer from an under-active thyroid and that as many as 100,000 of these people could benefit from treatment they are currently not receiving.[1]

Classification

Hypothyroidism is often classified by association with the indicated organ dysfunction (see below):[2][3]

Type	Origin
Primary	Thyroid gland	The most common forms include Hashimoto's thyroiditis (an autoimmunedisease) and radioiodine therapy for hyperthyroidism.
Secondary	Pituitary gland	Occurs if the pituitary gland does not create enough thyroid-stimulating hormone(TSH) to induce the thyroid gland to produce enough thyroxine and triiodothyronine. Although not every case of secondary hypothyroidism has a clear-cut cause, it is usually caused by damage to the pituitary gland, as by a tumor, radiation, or surgery.[4] Secondary hypothyroidism accounts for less than 5%[5] or 10%[6] of hypothyroidism cases.
Tertiary	Hypothalamus	Results when the hypothalamus fails to produce sufficient thyrotropin-releasing hormone (TRH). TRH prompts the pituitary gland to produce thyroid-stimulating hormone (TSH). Hence may also be termed hypothalamic-pituitary-axis hypothyroidism. It accounts for less than 5% of hypothyroidism cases.[5]

Signs and symptoms

Early hypothyroidism is often asymptomatic and can have very mild symptoms. Subclinical hypothyroidism is a state of normal thyroid hormone levels, thyroxine (T4) and triiodothyronine(T3), with mild elevation of thyrotropin, thyroid-stimulating hormone (TSH). With higher TSH levels and low free T4 levels, symptoms become more readily apparent in clinical (or overt) hypothyroidism.

Hypothyroidism can be associated with the following symptoms:[7][8][9]

Early

�	Cold intolerance, increased sensitivity to cold

�	Constipation

�	Weight gain and water retention[10][11][12]

�	Bradycardia(low heart rate  fewer than sixty beats per minute)

�	Fatigue[13]

�	Decreased sweating

�	Muscle cramps and joint pain

�	Dry, itchy skin

�	Thin, brittle fingernails

�	Rapid thoughts

�	Depression

�	Poor muscle tone (muscle hypotonia)

�	Female infertility; any kind of problems with menstrual cycles

�	Hyperprolactinemia and galactorrhea

�	Elevated serum cholesterol

Late

�	Goiter

�	Slow speech and a hoarse, breaking voice  deepening of the voice can also be noticed, caused by Reinke's Edema.

�	Dry puffy skin, especially on the face

�	Thinning of the outer third of the eyebrows (sign of Hertoghe)

�	Abnormal menstrual cycles

�	Low basal body temperature

�	Thyroid-related depression

�	Infertility in women

�	Mood swings

�	Acute fatigue syndrome

�	Stress

�	Decreased libido in men

�	Hypotension;

�	Carpal tunnel syndrome and bilateral paresthesia

Uncommon

�	Impaired memory[14]

�	Impaired cognitive function (brain fog) and inattentiveness.[15]

�	A slow heart ratewith ECG changes including low voltage signals. Diminished cardiac output and decreased contractility

�	Reactive (or post-prandial) hypoglycemia[16]

�	Sluggish reflexes

�	Hair loss

�	Anemiacaused by impaired haemoglobin synthesis (decreased erythropoietin levels), impaired intestinal iron and folate absorption or B12 deficiency[17] from pernicious anemia

�	Difficulty swallowing

�	Shortness of breath with a shallow and slow respiratory pattern

�	Increased need for sleep

�	Irritabilityand mood instability

�	Yellowing of the skin due to impaired conversion of beta-carotene[18] to vitamin A (carotoderma)

�	Impaired renal function with decreased glomerular filtration rate

�	Acute psychosis (myxedema madness) (a rare presentation of hypothyroidism)

�	Decreased libido in men[19] due to impairment of testicular testosterone synthesis

�	Decreased sense of taste and smell (anosmia)

�	Puffy face, hands and feet (late, less common symptoms)

�	Gynecomastia

�	Deafness[20]

�	Enlarged tongue

Subclinical hypothyroidism

Subclinical hypothyroidism occurs when thyrotropin (TSH) levels are elevated but thyroxine (T4) and triiodothyronine (T3) levels are normal.[24] In primary hypothyroidism, TSH levels are high and T4 and T3 levels are low. TSH usually increases when T4 and T3 levels drop. TSH prompts the thyroid gland to make more hormone. In subclinical hypothyroidism, TSH is elevated but below the limit representing overt hypothyroidism. The levels of the active hormones will be within the laboratory reference ranges.

Pregnancy and fertility

Main article: Thyroid disease in pregnancy

During pregnancy there is a substantially increased need of thyroid hormones and substantial risk that a previously unnoticed, subclinical or latent hypothyroidism will turn into overt hypothyroidism.

Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, has been estimated to increase the risk of pre-eclampsia with an odds ratio (OR) of 1.7 and the risk of perinatal mortality with an OR of 2.7.[25]

Even mild or subclinical hypothyroidism is known to adversely affect fertility.

Epidemiology

0.3% of the general American population have overt hypothyroidism, and 4.3% have subclinical hypothyroidism.[26] A 1995 survey in the UK found the mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8–4.5) rising to 4.1/1000 survivors/year (3.3–5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3–1.2).[27] Data from the CDC spanning the years 1999 to 2010 yield similar numbers: hypothyroidism is four times as common among women as among men.[15]

Estimates of subclinical hypothyroidism range between 3–8%, increasing with age; the median age of someone with hypothyroidism is 58.[15][28]

Causes

Iodine deficiency is the most common cause of hypothyroidism worldwide.[4] In iodine-replete individuals hypothyroidism is frequently caused by Hashimoto's thyroiditis, or otherwise as a result of either an absent thyroid gland or a deficiency in stimulating hormones from the hypothalamus or pituitary.

Exposure to iodine-131 from nuclear fallout, which is chemically indistinguishable from non-radioactive isotopes and taken up by the thyroid gland with them, destroys thyroid cells and increases the risk of hypothyroidism.

Congenital hypothyroidism is very rare, accounting for approximately 0.2% of cases, and can have several causes such as thyroid aplasia or defects in the hormone metabolism. Thyroid hormone insensitivity (most often T3 receptor defect) also falls into this category, although in this condition levels of thyroid hormones may be normal or even markedly elevated.

Hypothyroidism can result from postpartum thyroiditis up to 9 months after giving birth, characterized by transient hyperthyroidism followed by transient hypothyroidism. The syndrome is seen in 5 to 9% of women. The first phase is typically hyperthyroidism; the thyroid then either returns to normal, or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, 25 to 30% will develop permanent hypothyroidism requiring lifelong thyroxin replacement therapy.[29]

Hypothyroidism can result from de Quervain's thyroiditis, which, in turn, is often caused by having bad case of flu that infects and destroys part, or all, of the thyroid.[30]

Hypothyroidism can also result from sporadic inheritance, sometimes autosomal recessive.[citation needed]

Temporary hypothyroidism can be due to the Wolff-Chaikoff effect. A very high intake of iodine can be used to temporarily treat hyperthyroidism, especially in an emergency situation. Although iodide is a substrate for thyroid hormones, high levels reduce iodide organification in the thyroid gland, decreasing hormone production. The antiarrhythmic agent amiodarone can cause hyper- or hypothyroidism due to its high iodine content.

Hypothyroidism can be caused by lithium-based mood stabilizers, usually used to treat bipolar disorder (previously known as manic depression).[4] In fact, lithium has occasionally been used to treat hyperthyroidism.[31] Other drugs that may produce hypothyroidism include interferon alpha, interleukin-2, and thalidomide.[4]

Stress and hypothyroidism

Stress is known to be a significant contributor to thyroid dysfunction; this can be environmental stress as well as lesser-considered homeostatic stress such as fluctuating blood sugar levels and immune problems.[citation needed] Stress's effect on thyroid function can be indirect, through its effects on blood sugar levels (dysglycemia),[32] but it can also have more direct effects. Stress may cause hypothyroidism or reduced thyroid functioning by disrupting the HPA axis which down-regulates thyroid function,[33] reducing the conversion of T4 to T3,[34] weakening the immune system thus promoting autoimmunity,[35] causing thyroid hormone resistance,[36] and resulting in hormonal imbalances. Indeed, excess estrogen in the blood caused by chronic cortisol elevations can result in hypothyroid symptoms by decreasing levels of active T3.[37] Stress also affects thyroid functioning through the sympathetic nervous system.[38] A 1994 study of refugees from East Germany who experienced chronic stress found them to have a very high rate of hypothyroidism or subclinical hypothyroidism, although not all refugees displayed clinical or behavioral symptoms associated with this reduced thyroid functioning.[39] TSH levels correlate positively with physiological stress.[40][41]

Adrenal insufficiency can also result in hypothyroid symptoms without affecting the thyroid itself.[42]

Diagnosis

Main article: Thyroid function tests

The only validated test to diagnose primary hypothyroidism, is to measure thyroid-stimulating hormone (TSH) and free thyroxine (T4).[43] However, these levels can be affected by non-thyroidal illnesses.

High levels of TSH indicate that the thyroid is not producing sufficient levels of thyroid hormone (mainly as thyroxine (T4) and smaller amounts of triiodothyronine (T3)). However, measuring just TSH fails to diagnose secondary and tertiary hypothyroidism, thus leading to the following suggested blood testing if the TSH is normal and hypothyroidism is still suspected:

Free triiodothyronine (fT3)

Free thyroxine (fT4)

Total T3

Total T4

Additionally, the following measurements may be needed:

Free T3 from 24-hour urine catch[44]

Antithyroid antibodies — for evidence of autoimmune diseases that may be damaging the thyroid gland

Serum cholesterol — which may be elevated in hypothyroidism

Prolactin — as a widely available test of pituitary function

Testing for anemia, including ferritin

Basal body temperature

Treatment

Main article: Medical use of thyroid hormones

Hypothyroidism is treated with the levorotatory forms of thyroxine (levothyroxine) (L-T4) and triiodothyronine (liothyronine) (L-T3). Synthroid, produced by Abbott Laboratories, is the brand name counterpart to the generic Levothyroxine. Synthroid is also the most common pill prescribed by doctors that has the synthetic thyroid hormone in it, and it is taken by over 40% of people with hypothyroidism.[15] This medicine can improve symptoms of thyroid deficiency such as slow speech, lack of energy, weight gain, hair loss, dry skin, and feeling cold. It also helps to treat goiter. It is also used to treat some kinds of thyroid cancer along with surgery and other medicines. Both synthetic and animal-derived thyroid tablets are available and can be prescribed for patients in need of additional thyroid hormone. Thyroid hormone is taken daily, and doctors can monitor blood levels to help assure proper dosing. Levothyroxine, the generic form of synthroid, is best taken 30–60 minutes before breakfast, as some food can diminish absorption. Calcium can inhibit the absorption of levothryoxine.[45] Compared to water, coffee reduces absorption of levothyroxine by about 30 percent.[46] Some patients might appear to be resistant to levothyroxine, when in fact they do not properly absorb the tablets — a problem which is solved by pulverizing the medication.[47] There are several different treatment protocols in thyroid-replacement therapy:

T4 only

This treatment involves supplementation of levothyroxine alone, in a synthetic form. It is currently the standard treatment in mainstream medicine.[48]

T4 and T3 in combination

This treatment protocol involves administering both synthetic L-T4 and L-T3 simultaneously in combination.[49]

Desiccated thyroid extract

Desiccated thyroid extract is an animal-based thyroid extract, most commonly from a porcine source. It is also a combination therapy, containing natural forms of L-T4 and L-T3.[50]

Treatment controversy

The potential benefit from substituting some T3 for T4 has been investigated, but no conclusive benefit for combination therapy has been shown.[51][52]

The 2002 Laboratory Medicine Practice Guidelines of the National Academy of Clinical Biochemistry state that during pregnancy, "The L-T4 dose should be increased (usually by 50 mcg/day) to maintain a serum TSH between 0.5 and 2.0 mIU/L and a serum FT4 in the upper third of the normal reference interval." Doctors however often assume that if your TSH is in the "normal range", sometimes defined as high as 5.5 mIu/L, it has no effect on fertility. Healthy pregnant women however have a TSH level of around 1.0 mIU/L.

Subclinical hypothyroidism

There is a range of opinion on the biochemical and symptomatic point at which to treat with levothyroxine, the typical treatment for overt hypothyroidism. Reference ranges have been debated as well. As of 2003, the American Association of Clinical Endocrinologists (ACEE) considers 0.3–3.0 mIU/L within normal range.[53]

There is always the risk of overtreatment and hyperthyroidism. Some studies have suggested that subclinical hypothyroidism does not need to be treated. A 2007 meta-analysis by the Cochrane Collaboration found no benefit of thyroid-hormone replacement except "some parameters of lipid profiles and left-ventricular function."[54] A 2002 meta-analysis looking into whether subclinical hypothyroidism may increase the risk of cardiovascular disease, as has been previously suggested,[55] found a possible modest increase and suggested further studies be undertaken with coronary-heart disease as an end point "before current recommendations are updated."[56]

Alternative treatments

Compounded slow-release T3 has been suggested for use in combination with T4, which proponents argue will mitigate many of the symptoms of functional hypothyroidism and improve quality of life. This is still controversial and is rejected by the conventional medical establishment.[57]

Non-human presentation

Hypothyroidism is also a relatively common disease in domestic dogs, with some specific breeds having a definite predisposition.[58]

See also

Pituitary disease

Subacute lymphocytic thyroiditis

Thyroid hormone resistance

Hyperthyroidism

Adrenal insufficiency

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^ Villar, Heloisa Cerqueira Cesar Esteves; Saconato, Humberto; Valente, Orsine; Atallah, Álvaro N (2007). Thyroid hormone replacement for subclinical hypothyroidism. In Villar, Heloisa Cerqueira Cesar Esteves. "Cochrane Database of Systematic Reviews". Cochrane database of systematic reviews (Online) (3): CD003419. doi:10.1002/14651858.CD003419.pub2. PMID 17636722.

^ Biondi B, Palmieri EA, Lombardi G, Fazio S (December 2002). "Effects of subclinical thyroid dysfunction on the heart". Ann. Intern. Med. 137 (11): 904–14. PMID 12458990.

^ Ochs N, Auer R, Bauer DC et al. (June 2008). "Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality". Ann. Intern. Med. 148 (11): 832–45. PMID 18490668. http://www.annals.org/cgi/content/full/148/11/832.

^ Todd, C H (2010). "Management of thyroid disorders in primary care: challenges and controversies". Postgraduate Medical Journal 85 (1010): 655–9. doi:10.1136/pgmj.2008.077701. PMID 20075403.

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

Figure 6.1 Mitotic and meiotic non-disjunction of sex chromosomes

ㆍ유사분열시 염색분체의 불분리의 원인은 알려진 바 없다.

ㆍ비정배성은 감수분열과 유사분열에서 일어날 수 있으며, 감수분열의 경우 제 1 분열과 제 2 분열에서 일어날 수 있다. 제 1 감수분열에서 불분리가 발생하면, 여분의 염색체를 갖는 gamete는 동일한 양친의 상동염색체를 갖게 되고, 제 2 감수분열에서 불분리가 일어나면, 여분의 염색체는 모계 혹은 부계의 염색체가 될 수 있다(Fig. 6.1 참조).

ㆍ가끔, 어느 단계에서 불분리가 일어났는지 두 대립인자 혹은 DNA 다형성을 이용하여 알 수 있다.

1.2 정배성

ㆍtriploidy는 두 개의 정자에 의한 수정이 일어나면 발생하거나, 혹은 정자나 난자의 형성과정 중 두 번의 감수분열중 한번이 분열되지 않아서 diploid gamete가 형성되면 발생한다. 이러한 경우 69,XXY 혹은 69,XXX가 될 것이다.

Figure 6.2 Six families with a child of trisomy 21

Figure 6.3 triploidy detected at amniocetesis

ㆍtetraploidy는 수정 후의 첫 유사분열을 완전하게 진행하지 못하면 발생한다.

ㆍ정상적인 세포일 지라도 부분적으로 polyploidy가 관찰 되어 진다. 예를들면, 골수의 megakaryocyte는 8-16 ploidy를 갖고 있고, 재생 중인 간세포 등에서 tetraploidy는 보통 발견된다.

megakaryocyte /mega·karyo·cyte/ (-sīt″) the giant cell of bone marrow containing a greatly lobulated nucleus, from which mature blood platelets originate.

2. 구조이상

ㆍ구조이상은 염색체의 절단이 원인이다. 염색체가 절단되면 두 개의 접착성 말단이 형성되는데 그 것을 회복하는 기작에 의해 다시 붙게 된다. 그러나 하나 이상의 장소가 절단되면, 절단을 회복하는 기작의 실수로 서로 다른 말단끼리 접착시킴으로서 구조적 변화를 초래하게 된다.

ㆍ염색체의 절단은 전자파에 노출 되거나,  어떤 경우에는 유전적으로 잘 일어날 수 도 있다.

ㆍX선은 언제든지 염색체를 절단할 수 있으며, sister chromatid 사이의 교환에는 영향을 주지 못하지만,, 화학물질들은 S 기에 주로 절단을 유도하며, sister chromatid 사이의 교환을 증가시킨다.

ㆍ구조 이상은 다음 몇 가지로 구분 되어진다.

2.1 Translocations

ㆍtranslocation은 염색체간 염색체부분의 전달을 말한다. 이과정은 두 염색체의 절단과 비정상적인 상태로의 수정이라고 할 수 있다.

ㆍ이 과정은 보통 염색체의 손실이 없으며, 그 개체도 유전적으로 정상일 경우가 많다. 이러한 경우를 균형전좌라고 한다.

ㆍ3가지 type의 translocation 이 있다

2.1.1 Reciprocal translocation

ㆍ두 염색체의 절단된 부위로부터 먼 쪽(바깥 쪽) 부분이 서로 교환되는 것이다.

ㆍ긴팔 혹은 짧은 팔이 관여할 수 도 있고, 상동 혹은 비 상동 염색체가 관여할 수 있다.

ㆍFig. 6.4, Fig. 6.5 설명: 균형 전좌를 갖고 있는 경우 불균형 gamete를 만들 수 있다. 그 이유는 균형전좌의 염색체가 짝 짓기 할 때 십자형으로 짝을 짓고 분열 후기에 염색체가 분리되면, 분리되는 형태에 따라서, 12가지의 서로 다른 gamete가 형성될 수 있는데, 2:2로 분리될 경우에는 6가지 가능성이 있다. 그 6가지 중 한 gamete 만이 정상이다.

ㆍ염색체가 만약 3:1로 분리된다면, 또다른 6가지 형태의 gamete가 생성된다. 그러나 이 경우 염색체의 불균형이 심각하여 유산이 불가피 할 것이다.

ㆍ따라서 출생자들은 정상 1, 균형1, 불균형 4로 예상 되겠지만, 실제는 불균형인 개체에 대한 자연도태가 어느 정도 있으므로, 불균형으로 태어나는 비율이 기대치보다 작다.

Denotation

The International System for Human Cytogenetic Nomenclature (ISCN) is used to denote a translocation between chromosomes.[6] The designation t(A;B)(p1;q2) is used to denote a translocation between chromosome A and chromosome B. The information in the second set of parentheses, when given, gives the precise location within the chromosome for chromosomes A and B respectively—with p indicating the short arm of the chromosome, q indicating the long arm, and the numbers after p or q refers to regions, bands and subbands seen when staining the chromosome with a staining dye. See also the definition of a genetic locus.

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

2.1.2 Centric fusion(Robertsonian) translocation.

ㆍ두개의 acrocentric chromosome의 동원체 부위에 절단이 일어나서 두 염색체가 부착하는 것이다.

Table 6.2 Examples of structural chromosomal abberations

Figure 6.4 (a) Reciprocal translocation between chromosome 10 and 11. Normal chromosome on the left for each pair. (b)Meiotic quadrivalent. (c) Meiotic quadrivalent at pachytene. (d)EM photomicrograph

Figure 6.5 (a)Reciprocal translocation between chromosome 5 and 10. Normal chromosome placed on the left for each pair. (b)Meiotic quadrivalent for a balanced 5;10 reciprocal translocation at first meiosis. (c)Meiotic chain quadrivalent at diakinesis(arrowed). (d)Three types of segregation

Figure 6.6 Maternal reciprocal translocation between chromosome 11 and 22 with 3:1 segregation to produce partial duplication of chromosome 22 in a mentally handicapped daughter.

Figure 6.7 Accidental recombination between homologous regions of non-homologous chromosomes during meiosis as a cause of dicentric fusion chromosome

Figure 6.8 Centric fusion translocation

ㆍ일반적으로 동원체의 바로 윗 부분이 절단되어 융합하므로, 동원체가 두개인 염색체가 만들어짐(dicentric).

ㆍ때로는 제 1감수분열시 비상동염색체간에 유사한 부분사이에서 교차가 일어남으로서, 발생할 수도 있다.

ㆍ가장 흔한 type은 13번과 14번 사이 그리고 14번과 21번 염색체사이의 동

원체 융합이다.

ㆍ이러한 동원체 융합의 경우 그 개인은 45개의 염색체를 갖게 되고, 정상처럼 보이나, 역시 gamete 생산시에 문제가 발생하게 된다.

ㆍ제 1 감수분열시 trivalent 가 형성되고, 분열 후기에 염색체가 분리될 때 6가지의 gamete가 형성되며, 그 중, 하나만 정상, 하나는 균형, 나머지4개는 불균형이 된다.

Figure 6.9Meiotic trivalent for a t(13;14)

Figure 6.10 Segregation of a centric fusion translocation at 1st meiosis

Figure 6.11 Insertional translocation showing interstitial deletion and insertion

2.1.3 Deletion 과 Ring chromosome

ㆍ염색체의 두 부분이 절단되고 그 사이가 결손 되거나, 부등교차, 부모의 전좌, 염색체 말단의 손실 등에 의해 발생함

ㆍ염색체 말단이 손실되면, telomere와 유사한 부분이 나올때까지 결손이 진행됨.

ㆍring chromosome은 한 염색체의 양쪽 팔의 한 부분이 모두 절단되어 융합하여 발생하고, ring chromosome의 sister chromatid 사이의 교차는 dicentric ring chromosome을 생성함.

Figure 6.12 (a)Ring chromosomes. (b)Double-ring chromosome

ㆍ눈으로 확인 가능한 4MB 이상의 결손은 정신지체, 기형 등이 나타난다.

2.1.4 Duplication

ㆍ염색체의 일부분이 부가적으로 존재함.

ㆍ감수분열시 부등교차의 결과 중복과 결손이 동시에 발생하며, translocation, inversion, isochromosome이 있는 부모의 감수분열에 의해 발생할 수 있다.

ㆍduplication은 deletion 보다 흔하며, 해가 적으며, 소규모의 deletion은 진화에 도움이 됨.

Figure 6.13 Results of unequal crossing-over

2.1.5 Inversion

ㆍinversion은 염색체의 두 부분이 절단되고 절단된 조각이 180˚ 위치를 바꾼 것임.

ㆍinversion된 부위가 동원체를 포함하면 pericetric inversion이고 그렇지 않으면, paracentric inversion 이다.

ㆍinversion 된 경우 상동염색체가 짝지기 위해서는 한 염색체가 loop를 형성해야한다.

ㆍparacentric의 경우 loop 내에서 교차가 일어나면, dicentric 하나와 acentric 하나가 발생하고, 이 두개의 염색체 모두 불안정하므로 비정상적인 자손이 거의 나오지 않으며(개체의 발생이 되지 않아 유산), pericentric 의 경우 loop 내에서 홀수의 교차가 일어나면, 각 염색체는 결손과 중복 모두 갖게 되어 비정상적 자손이 출생한다. 이러한 불균형 염색체는 항상 절단된 한 부위로부터 먼 쪽의 염색체 부분이 결손 되고, 다른 절단부위로부터 먼쪽은 중복된다.

ㆍ절단 부위가 telomere에 가까우면 가까울 수록 태아의 출생가능성이 증가 한다.

2.1.6 Isochromosome

ㆍ한 팔은 결손 되고 다른 팔은 중복된 형태의 염색체임

Figure 6.14 (a)Two examples of paracentric inversion. (b)Pericentric inversion of chromosome 9 which is present in 1% of normal population.

Figure 6.15 EM photomicrograph of the synaptonemal complex inv(2)(p13;q25) carrier.

Figure 6.16 Pericentric inversion. (a)Parent with balanced inversion. (b)Abnormal child with duplication and deficiency resulting from a cross-over within the parental inversion. Normal chromosome in each case to the left.

Figure 6.17 The results of crossing-over at meiosis(a,b)within and (c)outside the pericentric inversion. A is normal. D is pericentric inversion. B and C are each with a duplication deficiency. In (c), crossing-over outside the inversion produces no abnormal recombinant

ㆍ세포분열동안 동원체의 횡분열, isochromatid의 절단과 융합(dicentric)에 의해 발생함.

ㆍ가장 흔한 것은 X의 긴 팔 isochromosome이다(Turner syndrome)(short arm monosomy, long arm trisomy).

ㆍY isochromosome 도 발생할 수 있음

ㆍ다른 종류의 isochromosome들은 자연 유산되나, 9번 12번 의 short arm isochromosome의 경우 출산 가능.

ㆍ많은 경우 isochromosome은 dicentric 이나, 그 중 하나는 불활성이므로 정상적인 염색체처럼 분열함.

2.1.7 Centric fragments.

ㆍ작은 metacentric fragment 가 관찰되는 경우가 있다. 어떤 경우는 가족성이며, 부모나 조상의 감수분열에서 satellite chromosome 사이의 centric fusion 에 의해 발생할 수 있다.

ㆍ이 부분은 반복서열 혹은 rRNA gene 만 가지고 있으므로, 임상학적 이상은 없을 수 있다.

3. Other Aberration

3.1 Mosaic

ㆍ하나의 수정란으로부터 유래된 두 가지 이상의 세포로 구성된 개체를 말함.

ㆍ예를 들면, trisomy 21 환자의 1%는 정상세포와 trisomy 세포가 섞여 있는 mosaic 이다. 보통 수정란은 trisomy 이었으나 그 후 세포분열 하는 동안 정상세포가 anaphase lag 등에 의해 발생함. 혹은 정상 수정란으로부터 non-disjunction 에 의해 trisomy가 발생할 수 도 있음.

ㆍ만약 생식선에 비정상적인 세포가 국한되어져 있으면(gonadal mosaic), 비정상적 자손이 나올 확률은 증가함.

3.2 Chimera

ㆍchimera는 두개의 서로 다른 수정란으로부터 나온 두 가지의 세포로 이루어진 개체를 말함.

ㆍ쌍둥이 수정란의 융합, 쌍둥이(이란성) 조혈 줄기세포의 혼합 등에 의해 발생함.

Figure 6.18 (a)Dicentric isochromosome for the long arm of X. (b)Dicentric chromosome for the short arm of chromosome 9

3.3 Uniparental disomy and isodisomy

ㆍ정상적으로 양친 중 한 사람은 각 염색체쌍 중 하나씩만을 자손에게 전달한다. 그러나 가끔, 상동염색체가 둘 다 한 부모에게서 오며, 다른 부모에게서는 그 상동염색체를 받지 못하는 경우가 있다.

ㆍtrisomy 상태로 임신한 후 초기 세포 분열 시에 anaphase lag에 의해 부모중 한 사람에게서 받은 염색체쌍을 제외한 나머지 한 상동염색체를 잃어버리면 발생.

ㆍtrisomy가 제 1감수분열의 non-disjunction에 의해 발생했다면, 그 gamete는 두 양친의 상동 염색체를 다 갖게 되고, 수정 후 trisomy를 거쳐서 disomy로 되면, uniparental disomy가 된다.

ㆍ반면에 trisomy가 제 2감수분열의 non-disjunction 에 의해 발생했다면, 생성된 gamete는 부모중 한 쪽의 상동염색체가 추가되어 있는 상태이며 수정후에는 uniparental isodisomy의 원인이 될 수 있다.

Figure 6.19 Diagram of mechanism of origin of uniparental disomy and isodisomy.