Damage to the genetic apparatus more gross than that described above can sometimes be seen when the chromosomes of dividing cells are examined microscopically. An extra chromosome may be found, e.g. there instead of the normal pair of No. 21 chromosome are commonly present in cases of Down’s syndrome.. but it is not understood how the chromosome abnormality leads to the physical and mental defects found in this condition. Total absence of one chromosome from all body cells is almost invariably incompatible with survival, with the notable exception of the Y sex chromosome, present in males(XY) but not in normal females(XX). Individuals with one X and no Y chromosome are phenotypically females but have a group of physical abnormalities including dwarfism and failure of ovarian development known as Turner’s syndrome. Structural abnormality of chromosome in the form of deleted portions or added pieces derived from other chromosomes, or unusual shapes such as rings, are sometimes found and may be associated with characteristic clinical syndromes. In a family variety of Down’s syndrome the two No. 21 chromosomes are normal but there is an abnormal No. 13 chromosome with an attached extra piece derived from a No. 21. This arises from a reciprocal exchange of fragments between two chromosomes during meiosis.
染色体异常
有时遗传结构的损伤较严重，在镜下检查分裂的细胞核染色体时就可以发现，可见一个额外的染色体，例如先天愚型综合征时第21对正常染色体常变为三体性，但不知道在这种疾病时染色体异常如何导致机体和智力缺陷。全部体细胞的一条染色体完全缺如，这几乎是必然会导致死亡，但性染色体Y却是一个例外，只出现于男性（XY）而不见于女性（XX）。含有一个X而无Y染色体的患者表型为女性，但有一组机体异常表现，包括侏儒郑和卵巢不发育，称为Turner综合症。有时可见染色体缺失一部分或增加一部分（后者来自其他染色体片段）或形状异常（如环形）等染色体结构异常，并可拌有特殊的临床综合症。在先天性愚型综合症家族性亚型中2个21号染色体均正常，但有一个异常的13号染色体。后者有一个来自21号染色体片段的附加物。这是由于细胞核分裂时2个染色体之间片段互相交换而产生。
As would be expected, the gross chromosomal abnormalities described above, affecting all the cells of the body, lead to complex abnormalities since many genes must be involved. They arise during meiotic division of germ cells, the presence of an extra chromosome or absence of a chromosome being due to failure of separation of a pair of homologous chromosomes (non-disjunction); one of the resulting gametes will have an extra chromosome and the other will be correspondingly defective. Structural chromosomal abnormality is due to chromosome breakage with re-arrangement of fragments during repair. The reciprocal exchange of unequal fragments between nonhomologous chromosomes (translocation) accounts for the occurrence of abnormally large or small chromosomes.
如预计的那样，上述显著的染色体异常，可累及机体所有细胞，而引起复杂的异常，因为许多基因必然受累。这些异常是在生殖细胞减数分裂时产生的。出现一个额外的附加染色体或缺少一个染色体都是由于一对同源染色体不能分离（不分离）所致，所产生的配子之一就会有一个额外的染色体，而另一个配子就会出现相应的缺陷。结构染色体异常是由于断裂染色体在修复时重新排列所致。非同源染色体之间不相等片段的互相置换（转位）可说明异常大或小的染色体产生的原因。
Abnormal chromosome numbers (aneuploidy) and structural chromosomal aberrations are invariably found in the cells of malignant tumors. The best known example of a consistent structural chromosomal aberration is the ‘Philadelphia’ chromosome, present in white and red blood cell precursors in the marrow in chronic myeloid leukemia ( a neoplastic proliferation of leukocytes). Radiation damage is known to cause chromosomal abnormalities in somatic cells and the frequency of chromosomal breakage has been used assess exposure to radiation. Aneuploidy and structural abnormalities in individual chromosomes are also found in other circumstances, e.g.. in thyroid epithelial cells which have proliferated following stimulation by pituitary thyrotrophic hormone, and in cells damaged by viruses.
染色体数目异常（非整倍体）和染色体结构畸变经常可见于恶性瘤细胞。大家最熟悉的经常出现的染色体结构畸变的例子是费城染色体，它出现于慢性髓细胞白血病（一种白细胞瘤性增生）病人的骨髓内未成熟的白细胞和红细胞中。据了解放射损伤可引起未成熟的体细胞染色体异常，因此人们用染色体破损率来估价接触放射情况。在个别染色体中非整倍体和结构异常也可见于其他情况，如在用垂体促甲状腺激素刺激后增生的甲状腺上皮细胞中和在病毒损伤的细胞内。
Staining techniques which demonstrate structural transverse banding patterns are revealing less gross abnormalities and variations in chromosomes and proving valuable in relating normal and abnormal genes to particular sites on individual chromosomes (gene mapping ).
显示染色体结构横带构型的染色体技术可显示较不明显的染色体异常和变异，并证明在说明正常和异常基因与各个染色体特殊位置之间的关系（绘制基因图方面）是有价值的。
Nutritional nuclear damage
An interesting and clinically important form, of nuclear damage is encountered in patients deficient in vitamin B12 or folic acid. The nuclei are larger than normal but contain less than optimal amounts of DNA for cell division. The chromatin of the large nuclei is arranged in a fine threadlike fashion compared with the condensed masses seen normally. And when mitosis occurs the chromosomes in affected individuals are longer and less tightly coiled than normal. These changes occur in many tissues but are best known in the precursors of red cells in the bone marrow which is said to exhibit megaloblastic erythroblastosis. In addition to nuclear enlargement in megaloblasts there is increased amount of cytoplasm, cytoplasmic basophilia due to excessive RNA and premature haemoglobinisation as judged by the immature state of the nucleus.
营养性核损伤
一种有趣味而具有临床重要性的刻损伤常见于维生素B12和叶酸缺乏症的病人。其核比正常增大，但其DNA含量少于适合于细胞分裂的最佳量，大核的染色质排列为细丝状，而正常所见则为致密块状。因而当核分裂时，受累个体的染色体比正常较长，但不象正常的盘绕得那么紧密。这些变化出现于许多组织，但在巨成红细胞生成的骨髓红细胞前身中最好识别，巨成红细胞除核增大外，胞浆量增加，由于RNA过多致胞浆呈嗜碱性和早熟的血红蛋白形成，这是根据其核的不成熟状态而作出的判断。
The mechanism of these changes is incompletely understood. Folate plays an essential role in the synthesis of purine bases and thymine, and deficiency of these substances presumably impairs nucleic acid synthesis, especially DNA which, unlike RNA, contains thymine. This could explain the delay of DNA synthesis prior to cell division together with excessive cytoplasmic growth and premature haemoglobinisation. Vitamin B12 is thought to influence nuclear structure by affecting folate metabolism. Methyl folate is inactive in purine and thymine biosynthesis and one of the main functions of vitamin B12 is the transfer of methyl groups from methyl folate for the synthesis of choline. Accordingly, when there is severe vitamin B12 deficiency as in pernicious anaemia megaloblastic change occurs due to accumulation of methyl folate, and is reversed temporarily by the administration of folic acid, and permanently by life-long administration of vitamin B12.
对这些变化的机制尚不清楚。叶酸盐在嘌呤碱和胸腺嘧啶合成中起着必不可少的作用，而且这些物质的缺乏可能削弱核酸合成，特别是DNA的合成，因为它和RNA不同，有胸腺嘧啶。这可说明为什么在细胞分裂前DNA合成延时、过多的胞浆生成和不成熟的血红蛋白的形成。据认为维生素B12是通过干扰叶酸盐代谢来影响核的结构。甲基叶酸盐在嘌呤和胸腺嘧啶生物合成中是无活性的，而B12的主要功能之一是从甲基叶酸盐传递甲基组提供胆碱合成。因此，当有严重维生素B12缺乏（如在恶性贫血）时，巨成红细胞的变化是由于甲基叶酸盐的堆积所致，因而病人可通过用叶酸暂时逆转，而且可终身用维生素B12而得到永久恢复。
