Chapter 5 Sex Determination and Sex Chromosomes

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1 Chapter 5 Sex Determination and Sex Chromosomes
Sexual differentiation play an important role in the life cycle of various plants and animals. While single pair of sex chromosome (e.g., the X and the Y ) often plays an important role in determining sexual maturation ,genes present on these chromosomes as well as on autosomes serve as the underlying basis of sex determination. In human, genes on the Y chromosome cause maleness,and in their absence, female development occurs.

2 Mechanisms have developed to compensate for the dosage of genetic expression in organisms where one sex contains two X,while other has but a single X. In mammals, random inactivation of one of the X chromosomes is the compensatory mechanism. Still other mode of sex determination have evolved. Reptile exemplify environmentally induced sex determination, where temperature during the incubation of eggs is the critical factor.

3 雌雄性别是生物的普遍现象之一。从酵母———人类一切生物的共同特征。
特别是高等动物，雌雄间的差别非常明显。这些差别不仅表现在个别性状上，而且还表现在许多其他性状上，除初级结构外在次级结构中也有明显差别。 两性生物中雌雄性别比1：1是一个定值。 从遗传学角度讲，性别是按孟德尔方式遗传。1：1是一种测交的结果，indicating one of the two sexes is homozygous and anther is heterozygous. 哺乳动物的性别形成有两个阶段：遗传学的性别决定（性染色体决定）和生殖腺的性别分化

4 性别决定（sex determination）
性别分化（sex differentiation ) 性染色体的组成首先决定早期未分化的生殖腺的分化

5 5.1 Sexual differentiation and life cycle
5.2 X and Y chromosomes: early studies 5.3 Chromosome composition and sex determination in human 5.4 Sexual differentiation in human 5.5 The sex ratio in humans 5.6 The X Chromosome and Dosage Compensation 5.7 Chromosome Composition and Sex Determination in Drosophlia 5.8 Temperature Variation and Sex Determination in Reptiles

6 5.1Sexual Differentiation and life cycle Sexual Differentiation Varies
Multicellular organisms, Primary vs secondary sexual differentiation For plants and animals, unisexual, dioecious, gonochoric, are equivalent bisexual, monoecious, hermaphroditic are equivalent intersex is intermediate (usu. Sterile) Primary vs secondary sexual differentiation

7 Chlamydomonas produces haploid isogametes 同形配子only under unfavorable conditions
Spend most of their life as haploids

8 Isogametes are designated mt+ or mt- (mt = mating types)

9 Seed plants alternate between haploid gametophyte and diploid sporophyte phases

10 C. elegans About 1000 cells There are two sexual phenotypes in these worms: Males, have only testes, Mostly hermaphroditic(两性), have testes and ovaries. During larval development of hermaphrodites, testes form that produce sperm, which is stored. Ovaries are also produced, but oogenesis does not occur until the adult stage is reached several days later. The eggs that are then produced are eggs are self-fertilized with stored sperm ~ 1% of offspring are male male x hermaphrodite yields 50/50 ratio

11 线虫的性别 0.2% male progeny 50% male progeny

12 C. elegans sex ratios from various crosses
Q: How is sex determined?

13 5. 2 X and Y chromosomes: early studies (E
5.2 X and Y chromosomes: early studies (E. Wilson, 1906) Types and Modes of Sex determination How sex is determined has long intrigued geneticist

14 直至1902年，美国的McLung第一次把X染色体和昆虫的性别决定联系起来。
1性染色体与常染色体 性染色体的发现 1891年德国细胞学家Henking在半翅目昆虫的精母细胞减数分裂中发现了一种特殊的染色质（实际上是一团异染色质），在一半的精子中带有这种异染色质，另一半没有。当时他对这种异染色质不大理解，并未把它与性别联系起来，因此就起名“X染色体”和“Y染色体” 直至1902年，美国的McLung第一次把X染色体和昆虫的性别决定联系起来。 后来许多细胞学家，特别是Wilson 1906年证明半翅目和直翅目等许多昆虫中

15 In 1906, Edmund B. Wilson clarified the findings of Henking and McClung when he demonstrated that
Female somatic cells in the insect Protenor contain 14 chromosomes, including 2 X chromosomes. During oogenesis, an even reduction occurs, producing gametes with 7 chromosomes, including 1 X.

16 Male somatic cells, on the other hand, contain only 13 chromosomes, including a single X chromosome. During spermatogenesis, gametes are produced containing either 6 chromosomes, without an X, or 7 chromosomes, one of which is an X. Fertilization by X-bearing sperm results in female offspring, and fertilization by X-deficient sperm results in male offspring

17 [Figure 5-4(a)]. The presence or absence of the X chromosome in male gametes provides an efficient mechanism for sex determination in this species and also produces a 1:1 sex ratio in the

18 absence of X determines male
Wilson also Protenor mode- XX/XO Female has 14 chromosomes, 2 are X female makes gametes with 7 chrom.(one X) Male makes gametes with 6 chrom (no X) absence of X determines male Lygaeus mode-XX/XY Both sexes have 14 chrom. Females have 2 X Males have X and smaller Y Male makes 6A+X or 6A+Y (50/50) sex ratio 1:1

19 Protenor mode- XX/XO Figure 5.4 (a) The Protenor mode of sex determination where the heterogametic sex is XO and produces gametes with or without the X chromosome.

20 Lygaeus mode-XX/XY Figure 5.4 (b) The Lybaeus mode of sex determination, where the heterogametic sex is XY and produces gametes with either an X or a Y chromosome.

21 XO型性别决定：直翅目昆虫如蝗虫,蟋蟀,蟑螂属于这种类型。雌体的性染色体成对，为XX，雄体只有一条单一的X染色体，为XO。例如蝗虫雌体共有24条染色体，22条常染色体和XX，雄体则为 22＋ XO，只有 23条染色体。

22 Sex chromosome for sex determination
多数高等植物和低等动物：雌雄同株（体），无性别决定问题 高等动物和某些植物：雌雄分体（株）， （1）XY型性别决定：人类、哺乳类、两栖类、鱼类、昆虫、植物

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24 从进化角度讲，性染色体是由常染色体分化来的。随着分化的逐步加深，同源部分缩小或Y染色体缩短，有的最终消失。如雄蝗虫的染色体最初可能是XY型，进化过程中Y逐渐消失而成为XO型。

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26 男性Y染色体的短臂上有一个睾丸决定基因，从而具有男性决定的强烈作用, 可使中性状态的性原基分化发育为睾丸而成男性。由于X染色体几乎不起作用，所以只要含有Y，就将发育成男性
XY正常男性，XXY、XXXY异常男性 XX正常女性，XO异常女性

27 （2）ZW型性别决定：鸟类、爬行类、鳞翅目昆虫（家蚕） 这一类的性别决定与XY型相反 雄性：ZZ——同配性别 雌性：ZW——异配性别
The male is not always the heterogametic sex ZZ/ZW （2）ZW型性别决定：鸟类、爬行类、鳞翅目昆虫（家蚕） 这一类的性别决定与XY型相反 雄性：ZZ——同配性别 雌性：ZW——异配性别

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29 （3）植物的性别决定高等植物多为雌雄同株类型，无明显的性染色体决定性别的机制存在。但在少数雌雄异株的植物中，也有与动物相类似的性别决定机制。
大部分雌雄异株植物都属于雄性异配性别，雌株为XX，雄株为XY。如石竹科的女娄菜（Melandrium apricum），其性别主要取决于 Y染色体的存在与否。在无 Y染色体时，不论X染色体与常染色体（A）的比例如何均发育为雌株，相反，只要有Y染色体存在，无论X和A比例如何，统统发育为雄株。Y染色体有极强的雄性决定作用，带有雄性基因。女娄菜属植物的另一个种（Melandrium album）雄株的 Y染色体比 X染色体稍大一些，两个性染色体在细胞学上差别不大。在减数分裂时，X染色体与Y染色体配对，但分离较早，在常染色体还没有分开的时候，两个性染色体就分向两极了，这表明X染色体与Y染色体的同源部分很少

30 Genes for sex determination
由复等位基因决定性别 喷瓜（Ecballium elaterium） 基因 决定性别 基因型 aD ♂ aDaD，aDa+，aDad a 两性 a+a+，a+ad ad ♀ adad

31 由二对基因决定 玉米（Zea mays） 基因型 性别 表型 Ba _ Ts _ ♀♂ 顶端长雄花序，叶腋长雌花序 Ba_ tsts ♀ 顶端和叶腋都长雌花序 baba Ts_ ♂ 顶端长雄花序，叶腋不长花序 baba tsts ♀ 顶端长雌花序，叶腋不长花序

32 染色体组倍数与性别 蜂的性别决定——单倍体性决定 不仅与染色体数目有关，而且还与环境有关。 蜂王（皇）、雄峰、工蜂（职蜂）
雄峰 X 雌蜂 —— 卵： ↓ ↓ 死掉 得到足够4-5年的精子 不受精的卵 发育 雄峰——n=16 卵：受精卵 发育 雌蜂 食到高质量蜂王浆5天，16天后—— 蜂王 仅食到低质量蜂王浆2-3天的，21天后——职蜂

33 5.3 Chromosome Composition and Sex Determination in Humans
Normal female and male

34 Humans-Y chromosome determines maleness
Embryos are bipotential (Mullerian and Wolffian ducts +undifferentiated gonads) SRY region encodes TDF

35 Nondisjunction of Sex chromosomes can cause a number of developmental abnormalities
2 of 1,000Also XXXY, XXYY, XXXXY, XXXYY 1 of 1,200Also XXXX, XXXXX

36 染色体病 目前已发现的染色体异常核型达一万多种。 染色体病达100多种。
染色体病是由于染色体数目或结构异常而引起的具有一系列临床症状的综合征。 常染色体病的共同特征： 智力低下、发育迟缓、多发畸形。 性染色体病的共同特征： 性征发育不全或畸形、智力较低。

37 常见人类染色体数目异常 综合征 染色体核型 出生率

38 Sex chromosome polyploidy
HUMAN TRISOMY Except for the sex chromosomes, only three trisomies are compatible with life. Sex chromosome polyploidy 性染色体病 性染色体病占所有染色体病的1/3。总发病率为1/500。大多数到青春期因第二性征发育时才显现出症状。 47, XXY (Klinefelter’s syndrome) 45,XO (Turner’s Syndrome) 47,XYY (综合征XYYSyndrome)

39 abnormal female and male

40 47, XXY (Klinefelter’s syndrome) extra X Female phenotype development (micropenis, etc.), mental retardation, disproportionate growth of the legs, and other somatic anomalies, with estimated incidence of 1:500 in newborns. Klinefelter patients may occasionally demonstrate motile sperms in the ejaculate which is speculated to be due to a mosaic 46, XY cell line.

41 Klinefelter综合征 1942年 Klinefelter首先发现。又称先天性睾丸发育不全、克氏征。1959年Jacob证实核型为47, XXY。发病率1/1000~1/500。在精神病患者中和收容所中达1/100，不育男性中1/10。 临床表现： 阴茎和睾丸小、身材高、第二性征差、四肢修长、有部分女性特征， 胡须少、无/小喉结、部分伴有尿道下裂和隐睾。1/4患者有乳房发育。纯合体中97%不育，因曲精小管玻璃样变性，无精子。少数有先天性心脏病，大部分患者智力正常或轻度低下。易患糖尿病、甲状腺疾病、哮喘和乳腺癌。 嵌合型中正常细胞比例大时，临床表现轻，可有生育力。 本病纯合体的产生原因1/2是因为父亲第一次减数分裂染色体不分离所致。

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44 Turner’s Syndrome 临床表现：
1938年Turner首先报道，又称先天性卵巢发育不全。1959年Ford证实核型为45, XO 。发病率在女婴中为1/5000，在自发流产中占18%~20%。 临床表现： 性发育幼稚，身材矮小(120m-140m)，肘外翻，上眼睑下垂，后发际低，50%有蹼颈，乳间距宽，皮肤色素增多。 55%的病例为纯合型，其他为各种嵌合型和结构异常（如46, X,i(Xq)）嵌合型表现轻者可生育。 研究表明，身材矮小和其他体征是由于Xp单体决定；卵巢发育不全和不育则与Xq单体有关。

45 Turner综合征照片

46 Y chromosome polyploidy:
XYY综合征supermale 1961年Sandburg首次报道，发病率为1/900，核型为47, XYY，发病原因为父亲减数分裂产生了Y染色体不分离。 Estimated incidence is 1:750 newborns, may be fertile with frequent miscarriage of their wives, perinatal death and chromosomal anomalies of their children. 临床表现： 表型一般正常，身材高大，偶见尿道下裂、睾丸发育不良、生育力下降，但大多数可以生育。具有攻击倾向和反社会行为。在监狱中调查发现本病患者较多。

47 多数为纯合体，少数为嵌合体，均为母方减数分裂染色体不分离。
多X综合征 临床表现：大多数正常，可生育，少数卵巢功能低下、原发或继发闭经、乳房发育不良，1/3患者患有先天性心脏病，部分有精神障碍。2/3患者智力稍低。 X染色体越多智力越低，畸形也越重。 多数为纯合体，少数为嵌合体，均为母方减数分裂染色体不分离。 1959年Jacob首先发现一例47, XXX女性，称为“超雌”。发病率在女婴中为1/1200。

48 染色体病的种类还有很多，但很多染色体变异所导致的疾病具有不确定性，既同一种染色体变化导致不同症状，或同一种症状可由不同染色体变异引起。
染色体的变化将导致众多基因的变化，在“平衡”变化中，有些没有异常症状，在“不平衡”变化中，大多将导致异常症状。

49 怀孕年龄与三体染色体发病率

50 5.4 sexual differentiation in human
Humans-Y chromosome determines maleness Embryos are bipotential (Mullerian and Wolffian ducts +undifferentiated gonads) SRY region encodes TDF X Mb, 1500 genes Y Mb, 50 genes (1/2 specialized for sex and spermatogenesis Share homology Pseudoautosomal region (PAR) that recombine at meiosis

51 There are men who appear to be normal men, but have an XX chromosomal combination (about 1 out of every 20,000 males), and women who appear to be normal women but have the XY combination.

52 In every Olympics since sex testing was initiated, several women have been disqualified because they were identified as XY.

53 SRY includes a single exon that acts as a transcription factor…
SRY includes a single exon that acts as a transcription factor…..a protein product recognizes and binds specifically to the DNA sequence: AACAAT

54 Four siblings with testicular feminization syndrome
Four siblings with testicular feminization syndrome. All four subjects in this photograph have 44 autosomes plus an X and a Y, (so they are genotypically MALES (!)) but they have inherited the recessive sex-linked allele conferring insensitivity to androgens (male hormones).

55 Evidence for the Y Mechanism
All other differences between males and females are secondary effects resulting: From hormone action or From action of other factors produced by the gonads. Therefore, sex determination = testis determination. Evidence for this gene came from studying sex reversal individuals.

56 Evidence for the Y Mechanism
Sex reversal individuals are either: Males who are XX instead of XY. They have a small piece of the tip of the Y chromosome attached via a translocation to one of the X chromosomes. Females who are XY instead of XX. They have a Y chromosome in which the tip of the short arm has been deleted. Suggests that the gene is on the small arm of the Y chromosome.

57 (sex-determining region of the Y chromosome)
睾丸决定基因为Y染色体上的SRY (sex-determining region of the Y chromosome) SRY是通过分析XX的men和XY的women的DNA而发现的(1990)。它是一种编码223 aa的转录因子，含有HMG DNA结合区。

58 Evidence for the Y Mechanism -5
Detailed molecular analysis of the DNA of XX males and XY females resulted in the id of a male-specific gene sequence near the end of the small arm of the Y chromosome. The DNA gene sequence is present in both normal XY males and the unusual XX males. The DNA gene sequence is absent in both normal XX females & unusual XY females. The gene is called SRY (sex-determining region Y) in humans, and Sry in mice.

59 In 1990, Sinclair and colleagues narrowed the region to a 35,000 base-pair domain of the small arm of the Y chromosome.

60 Evidence for the Y Mechanism -6
Characteristics of the SRY & Sry genes: Expressed only at the time (in embryo right before formation of testis) and place (undifferentiated genital ridges of embryo) expected for the testis-determining factor. In mice, when the Sry gene is microinjected into XX mouse embryos, they became all males. Proteins of the Sry gene are probably transcriptional factors that bind to the DNA and regulate gene expression.

61 Sry gene Sex-determining region (Sry)
When mouse sry was injected into the genome of a XX zygote, the transgenic female mice developed as males (sterile) 基因转移实验： 将Sry序列克隆到噬菌体L741中， f741为该片断 f741 注射到受精卵中 再转移到母体内发育

62 Sry对睾丸发育的影响的实验证据 小鼠Sry基因也存在于Y染色体上，在未分化的生殖腺和正在分化为睾丸的生殖腺中表达。转Sry基因的XX小鼠可长出睾丸和雄性特征，但不能产生正常的精子。 XY XX

63 These studies suggest that the SRY gene determines maleness
These studies suggest that the SRY gene determines maleness. Furthermore, it is present in all mammals examined so far, indicating that it has been conserved throughout the evolution of this diverse group of animals. How specifically the product of this gene triggers the embryonic gonadal tissue to develop into testes rather than ovaries is a question under extensive investigation. A number of other autosomal genes are believed to be part of a cascade of genetic expression initiated by SRY. Amh and P450 芳香酶 promoter One such autosomal gene is SOX9 in humans.

64 5.5 Human Sex Ratios Should be 1:1 if…… 第一性比 男胎儿  女胎儿＝120  100
= #s X and Y sperm Each sperm has same survival Egg is equally receptive 第一性比 男胎儿  女胎儿＝120  100 第二性比 男婴女婴＝ （103～105） 100 第三性比 男青年女青年＝ 1  1 老翁  老妪 ＝ 62  100 (85岁) ratio is >1.0 ratio is ! It is not clear why such a radical departure from the expected primary sex ratio of 1.0 occurs. To come up with a suitable explanation, we must examine the assumptions on which the theoretical ratio is based:

65 1. Because of segregation, males produce equal numbers of X- and Y-bearing sperm. 2. Each type of sperm has equivalent viability and motil- ity in the female reproductive tract. 3. The egg surface is equally receptive to both X- and Y-bearing sperm. While no direct experimental evidence contradicts any of these assumptions, the human Y chromosome is smaller than the X chromosome and therefore has less mass. Thus, it has been speculated that Y-bearing sperm are more motile than X-bearing sperm. If this is true, then the probability of a fertilization event leading to a male zygote is increased, providing one possible explanation for the observed primary ratio.

66 5.6 Dosage Compensation in Mammals
Two X chromosomes in normal human females and only one X in normal human males is unique compared with the equal numbers of autosomes present in the cells of both sexes. On theoretical grounds alone, it is possible to speculate that this disparity should create a "genetic dosage" problem between males and females for all X-linked genes. There is the potential for females to produce twice as much of each gene product for all X-linked genes.

67 The additional X chromosomes in both males and females exhibiting the various syndromes discussed earlier in this chapter should compound this dosage problem even more. In this section, we describe research findings on X-linked gene expression that demonstrate a genetic mechanism allowing for dosage compensation剂量补偿.

68 In 1961, Mary Lyon and Liane Russell independently proposed a hypothesis that answers these questions. They postulated that the inactivation of X chromosomes occurs randomly in somatic cells at a point early in embryonic development and that once inactivation has occurred, all progeny cells have the same X chromosome inactivated.

69 早在1949年Barr等人就发现 雌猫神经细胞间期核中有一个染色很深的染色质小体，而雄猫则没有。 后来在大部分正常女性口腔颊膜及羊水组织的间期核中也找到了这种浓缩的染色质小体，而男性中则没有。因此性染色质——异染色质——又名巴氏小体（Barr Body)，则是失活的X染色体。 M.F.Lyon提出的阐明哺乳动物剂量补偿效应和形成Barr Body的X染色体失活假说的主要内容是：

70 Lyon 莱昂Hypothesis X chromosome inactivation
Proposed that X chromosome inactivation occurs early in development All descendent cells have same one inactivated

71 Dosage Compensation in Mammals
In mammals, somatic interphase nuclei of normal XX females contain a highly condensed mass of chromatin called a Barr body, while normal males contain none. Lyon hypothesis expands the concept further: Barr body is a highly condensed and mostly genetically inactive X chromosome.

72 Dosage Compensation in Mammals
The Barr body undergoes a process called lyonization (extra X chromosomes are condensed and become transcriptionally inactive). It is purely random as to whether the maternal or paternal X is inactivated in each somatic cell. Inactivation of all descendant cells inherited the same inactivation pattern.

73 Dosage Compensation in Mammals
Inactivation occurs only in somatic cells not gametic cells. In humans, inactivation occurs about the 16th day after fertilization ( cell stage). Mammalian females heterozygous for X-linked traits are genetic mosaics when inactivation occurs. They have 2 types of cells, one showing one X and other cells showing the other X.

74 Dosage Compensation in Mammals
X inactivation process helps explain why there are so many more tolerated abnormalities of the X chromosome in contrast to the rareness of viable, autosomal abnormalities. All extra X chromosomes beyond one are inactivated, but no such mechanism occurs for autosomes.

75 X染色体的剂量补偿效应 关于LYON假说 X染色体上有许多重要的基因，女性有2条，男性1条。但X染色体基因产物并不比男性多一倍，这种男女X连锁的基因产物相等的现象，遗传学上称为剂量补偿。对与这种现象是解释有许多种。 （1）转录速率不同，例如果蝇雌性的细胞中2条XX，都是有活性的，但转录速率慢，低于雄性X染色体 （2）雌性2X染色体中一条失活，不进行转录（如人或哺乳动物） 这一假说是LYON提出的

76 （1）正常哺乳动物的体细胞中2条染色体遗传上一个有活性，一个失活，使X连锁基因得到剂量补偿，保证XX和XY具有相同有效的基因产物
（4）杂合体雌性在伴性基因的作用上是嵌合体 某些细胞来自父方的伴性基因表达 某些细胞来自母方…………………. 两类细胞镶嵌存在

77 EVIDENCES of Lyonization
（1）玳瑁猫的毛皮色 黄黑色斑，雌性杂合体XBXb A calico cat 三色猫（又叫做三玳瑁猫）是一个很好的例子。雌性的三色猫腹部的毛是白色的，背部和头部的皮毛由桔黄色和黑色斑组成，十分漂亮。这种雌猫是一个X-连锁基因杂合体，X-连锁的b基因控制橙色（orange）毛皮，其等位基因B是控制黑色的毛皮。带有b基因的X染体若失活，B基因表达产生黑色毛斑，若带有B基因的X染色体若失活，b基因表达则产生橙黄色毛斑。

78 （2）人的X连锁glucose-6-phosphate dehydrogenase G-6-PDH基因 GdA/GdB
The most direct evidence in support of the Lyon hypothesis comes from studies of gene expression in clones of human fibroblast cells. Individual cells are isolated following biopsy and cultured in vitro. If each culture is derived from a single cell, it is called a clone. The synthesis of the enzyme (G6PD) is controlled by an X-linked gene. Numerous mutant alleles of this gene have been detected, and their gene products can be differentiated from the wild-type enzyme by their migration pattern in an electrophoretic field.

79 Fibroblasts have been taken from
females heterozygous for different allelic forms of G6PD and studied. The Lyon hypothesis predicts that if inactivation of an X chromosome occurs randomly early in development and is permanent in all progeny cells, Such a female should show two types of clones, each showing only one electrophoretic form of G6PD, in approximately equal proportions. .

80 In 1963, Ronald Davidson and colleagues performed an experiment involving 14 clones from a single heterozygous female. Seven showed only one form of the enzyme, and 7 showed only the other form. What was most important was that none of the 14 showed both forms of the enzyme. Studies of G6PD mutants thus provide strong support for the random permanent inactivation of either the maternal or paternal X chromosome

81 （3）人的X染色体上次黄嘌呤磷酸核糖酰基转移酶HPRT。HPRT+/HPRT-个体皮肤细胞培养，每个细胞分裂形成细胞克隆：

82 The Lyon hypothesis is generally accepted as valid; in fact, the inactivation of an X chromosome into a Barr body is sometimes referred to as lyonization. One extension of the hypothesis is that mammalian females are mosaics for all heterozygous X-linked alleles—some areas of the body express only the maternally derived alleles, and others express only the paternally derived alleles.

83 Two especially interesting examples involve
(4) red-green color blindness and anhidrotic ectodermal dysplasia外胚层发育异常无汗症 , both X-linked recessive disorders.

84 In the former case, hemizygous（半合子） males are fully color-blind in all retinal cells. However, heterozygous females display mosaic retinas with patches of defective color perception and surrounding areas with normal color perception. Males hemizygous for anhidrotic ectodermal dysplasia show absence of teeth, sparse hair growth, and lack of sweat glands. The skin of females heterozygous for this disorder reveals random patterns of tissue with and without sweat glands. In both examples, random inactivation of one or the other X chromosome early in the development of heterozygous females leads to these occurrences.

85 （5） Barr body 数目正好为X染色体数目减lyonization （n-1）
Barr body formation prevents excessive expression of X-linked genes each cell gets one “dose” of an X-linked gene

86 若X染色体的个数为n 则巴氏小体的个数等于n-1

87 XY型性别决定的生物中，使性连锁基因在两种性别中有相等或相近的有效剂量的遗传效应。
转录速率不同 X染色体失活 Lyon 假说： 正常雌性哺乳动物的两条X染色体，只有一条有活性(activation X, Xa),另一条无活性(inactivation X, Xi) ; 失活是随机的。 失活发生在胚胎早期。 伴性基因的雌性杂合体是嵌合体（mosaic)。

88 Lyon 假说不能解释的一些涉及性染色体的临床现象
（1）一条X染色体就能保证完全发育为女性的话，那么为什么XO（Turner综合症）会有异常 （2）另一方面，一条XX染色体完全失活的话，为什么X多体患有各种异常症状，而且越多越重。 由此可见，正常发育或者说胚胎发育的某一时期需要双份X染色体上的基因 Recently,人们对X染色体的 失活机制和Lyon 假说实质的认识有了新的补充和发展

89 The Mechanism of Inactivation
XIC region sets this XIST encodes X-inactive specific transcript non-translated RNA may coat X chromosome in nucleus

90 The least understood aspect of the Lyon hypothesis is the mechanism of chromosome inactivation in mammals. How are almost all genes of an entire chromosome inactivated? Recent investigations are beginning to clarify this issue. A single region of the human X chromosome, called the X-inactivation center (XIC), is the major control unit. Genetic expression of this region, located on the proximal end of the p arm, occurs only on the X chromosome that is inactivated. The constant association of expression of XIC and X chromosome inactivation supports the conclusion that this region is an important genetic component in the inactivation process.

91 X inactivation center (XIC in humans; Xic in mice) is a region on each X chromosome involved in chromosome counting. There must be 2 or more X chromosomes for inactivation to occur. X-controlling element (Xce) located in the XIC or Xic region determines which X chromosome is inactivated.

92 Dosage Compensation in Mammals
There are different Xce alleles that affect the probability that the X chromosome with the allele will be inactivated: Females homozygous for the same Xce allele result in equal probability that each X could be inactivated. Females heterozygous for 2 Xce alleles show a biased X inactivation pattern.

93 The X inactive specific transcript (XIST in humans; Xist in mice) also located in the XIC or Xic region, is expressed only in the inactive X. It has no initiator or terminator codons. XIST is a gene that is expressed on the inactivated X. XIST transcribes a 17,000 bp non-translated poly A-RNA, which stabilizes and coats the X from which it was transcribed.

94 Dosage Compensation in Mammals
The coating by the RNA silences most other genes on that X. The XIST gene functions downstream from the Xce gene as evidence from deletion studies. There is still much to learn about the X inactivation step, although it is known that it is initiated from the XIC region and proceeds in both direction to heterochromatinize the X.

95 Barr bodies are inactive X chromosomes "painted" with XIST RNA.
XIST encodes a large molecule of RNA Barr bodies are inactive X chromosomes "painted" with XIST RNA.

96 Some genes on X are not inactivated.
Genes in pseudo-autosomal regions PAR1 and PAR2. XIST, active only on the Inactive X.

97 In 1996, a research group led by Graeme Penny provided convincing evidence that transcription of Xist is the critical event in chromosome inactivation. These researchers were able to introduce a targeted deletion (7 kb) into this gene. As a result, the chromosome bearing this mutation lost its ability to become inactivated.

98 Several intriguing questions remain.
First, in cells with more than two chromosomes, what sort of "counting" mechanism designates all but one X chromosome to be inactivated? Second, what "blocks" the Xic of the active chromosome, preventing transcription of Xistl Third, how is inactivation of the same X chromosome or chromosomes subsequently maintained in progeny cells, as the Lyon hypothesis calls for? The inactivation signal must somehow remain stable as cells proceed through mitosis. Whatever the answers to these questions, we have taken an exciting step toward understanding how dosage compensation is accomplished in mammals.

99 X染色体随机 失活的分子机制 1、大多数的X连锁基因在胚胎早期发育过程中表现为稳定的转录失活，但并非正条X染色体上的所有基因均失活。在X染色体的短臂远端编码细胞表面蛋白的基因MIC2（由单克隆抗体2F7、F21鉴定出的抗原）、XG（Xg血型）、淄固醇硫酸酯酶基因STS是逃避失活的，还有与Y染色体配对的区域内或处于附近的基因，也有短臂近端或长臂上的基因。这些基因可由Xa也可由Xi表达；其中有定位于Xp21.3-Xp22.1d ZFX基因（与Y染色体上的锌指蛋白基因ZFY同源的序列），位于Xp11的AIS9T（与小鼠DNA合成突变互补序列同源）。此外失活染色体上还发现了一个可转录的基因XIST，该基因可能与X染色体失活机制有关。

100 2、在失活染色体上，表达的基因（逃避失活的基因）与失活的基因穿插排列。这意味着失活基因转录的关闭不是由它们所在的区域决定的，而是与某些特定的位点有关。
46,XX,t(1;2)(p21;q23) 染色体总数，性染色体组成， 染色体变化 染色体号；臂号；区号；带号；(.亚带）

101 3、X染色体上存在一个特异失活位点，即所谓X失活中心（X inacrivation center, XIC)。
最初的线索是X染色体异常突变的小鼠，它们的X染色体不出现失活，同时观察到这些X染色体缺失了一个特定的区段 kb，于是把这个区段称为X染色体失活中心。小鼠以Xic，人类以XIC表示。该失活中心产生一个失活信号，关闭X染色体上几乎所有的基因转录。 Brown等1991年以Xq11-q12区域的DNA为探针，对一组有结构突变的X染色体的杂交细胞系的DNA进行分子杂交，将XIC较精确定位在Xq13，后来他们又在XIC的同一区域内鉴定出一个新的基因，既X染色体失活特异转录子（XIST）。研究表明XIST转录产物是一个顺式作用的核RNA，而不编码生成蛋白质。

102 而且发现只有在失活的X染色体存在的情况下，才有XIST转录，有活性X染色体上不表达。
XIST转录产物大小：人17kb，小鼠 15kb，两者间同源性很低。关于XIST的功能尚不清楚。但推测可能在XIC位点内与其他相关基因共同作用，十X染色体上的大部分基因失活： XIST产物可能作用于XIC，而XIC则产生某中物质诱导失活分子相互作用。

103 Sex Determination in Drosophila (Calvin Bridges)
XXY Female and XO male Studied nondisjunction and triploid crosses Y chromosome needed for fertility, but not for sex determination X to autosomal ratio determines sex 4 chromosomes total 2X/2A is normal female XY/2A is normal male

104 * * * * * indicates sterile fly

105 Table 11.3 summarizes the sex balance theory of sex determination in D. melanogaster.
If the X: A ratio is equal or greater than 1.00, the fly is a female. If the X: A ratio is equal or less than 0.50, the fly is a male. If the X: A ratio is between 0.50 and 1.00, the fly is an intersex (neither male or female).

106 Dosage Compensation in Drosophila
Different mechanism than mammals Male X-linked genes transcribed at twice the rate as in female Several autosomal genes control this Sxl is master switch

107 5.8 Temperature Variation and Sex Determination in Reptiles
Many snakes have sex chromosmomes (ZZ/ZW determination) can’t tell in boas and pythons lizards, find both XX/XY and ZZ/ZW TSD in turtles, all crocs, some lizards Three patterns temp range is narrow (1° - 5°C) thought to involve enzymes of steroid synthesis (aromatase, converts androgens to estrogens))

108 蠕虫后嗌：据说雌虫的吻上有一种激素似的化学物质，有力地影响幼虫的性别分化。环境上起着较重要作用。幼虫是落在海底，还是附在雌虫口吻上，有其遗传基础。
幼虫中性——落入海底——雌 ——落入雌虫口吻中——雄 ——落入口中再出来——中 这取决于时间的长短

109 Sex Determination andTemperature
Case I - Most crocs and lizards Case II- Most Turtles Case III- Some crocs, turtles, lizards

110 扬子鳄卵 < 30ºC 雌体 > 34ºC 雄体 乌龟卵 23ºC ～ 27ºC 雄性 32ºC ～ 33ºC 雌性

111 激素的影响 性反转的现象 性反转（sex reversal） 酵母 交配型的转变 果蝇 的性别转换基因（transformer，tra）
黄鳝（Monopterus albus） 欧洲鳗鲡 （Anguilla anguilla), 红鲈鱼（Sacura margafacd）, 石斑鱼, 鯛鱼等自然性反转 雄 雌 蠕虫（Ophrgtrocha Puerilis）

112 激素的影响 人类中激素的作用

113 4.10 Genes on the X Chromosome伴性遗传
In many animal and some plant species, one of the sexes contains a pair of unlike chromosomes that are involved in sex determination. In many cases, these are designated as the X and Y chromosomes. For example, in both Drosophila and in human

114 Morgan's work established that the inheritance pattern of the white-eye trait is clearly related to the sex of the parent carrying the mutatant allele. Unlike the outcome of the typical monohybrid cross, reciprocal crosses between white and red-eyed flies did not yield identical results. In contrast, in all of Mendel's monohybrid crosses, Fl and F2 data were very similar regardless of which P1 parent exhibited the recessive mutant trait. Morgan's analysis lead to the conclusion that the white locus is present on the X chromosome rather than on one of the autosomes. As such, both the gene and the trait are said to be X-linked

115 X-Linkage in Drosophila
One of the first cases of X linkage was documented by Thomas H. Morgan around l920 during his studies of the white mutation in the eyes of Drosophila (Figure 4-10). We use this case to illustrate X-linkage

116 Morgan was able to correlate these observations with the difference found in the sex chromosome composition between male and female Drosophila. He hypothesized that the recessive allele for white eye is found on the X chromosome. but its corresponding locus is absent from the Y chromosome. Females XX Males X Morgan's interpretation of X-linked inheritance, shown in Figure 4-11, provides a suitable theoretical explanation for his result. Since the Y chromosome lacks homology with most genes on the X chromosome, whatever alleles are present on the X chromosome of the males will be expressed directly in their phenotype.

117

118 Results of reciprocal crosses between white-eyed and red-eyed flies are shown in Figure 4-l0 The obvious differences in phenotypic ratios in both the F1 and F2 generations are dependent on whether or not the P1 white-eyed parent was male or female.

119 Because males cannot be either homozygous or heterozygous for X-linked genes, this condition is referred to as being homizygous. One result of X-1inkage is the crisscross pattern of inheritance, whereby phenotypic traits controlled by recessive X linked genes are passed from homozygous mothers to all sons. This pattern occurs because females exhibiting a recessive trait carry the mutant allele on both X chromosomes. Because male offspring receive one of their mother's two X chromosomes and are hemozygous for all alleles present on that X, all sons will express the same recessive X linked traits as their mother

120 Morgan's work has taken on great historical significance
Morgan's work has taken on great historical significance. By l910, the correlation between Mendel's work and the behavior of chromosomes during meiosis had provided the basis for the chromosome theory of inheritance, as postulated by Sutton and Boveri (see Chapter 3). The work involving the X chromosome is considered to be the first solid experimental evidence in support of this theory. In the ensuing two decades, these findings inspired further research, the outcomes of which provided indisputable evidence in support of this theory.

121 X-Linked Inheritance in Humans 携带者（Carrier） 半合子（hemizygote)
In humans, many genes and the respective traits controlled by then are recognized as being linked to the X chromosome. as shown in Tab1e 4.2. These X-1inked traits can be easily identified in a pedigree because of the crisscross pattern of inheritance. A pedigree for one form of human color blindness is shown in Figure 4-l2. The mother in generation I passes the trait to all her sons but to none of her daughters.

122 Table 4.2 Condition Characteristics Color blindness Insensitivity to green light Color blindness Insensitivity to red light 红绿色盲(congenital dyschromatopsia of the protan and deutan type Fabry’s disease) Deficiency of galactosidase A; heart and kidney defects, early death G-6-PD deficiency Hemophilia A X-连锁显性遗传 Hemophilia B Hunter Syndrome Ichthyosis Lesch-Nyhan自毁容貌综合征 SyndromeDeficiency of hypoxanthine-guanine phosphoribosyl transferase enzyme (HGPRT) leading to motor and mental retardation, self-mutilation, and early death. Musccular Dystrophy (Duchenne type)

123 If the offspring in generation II carry normal individuals, the color-blind sons will produce all normal male and female offspring (III-1, 2, and 3); the normal-visioned daughters will produce normal-visioned female offspring (III-4. e. and 7), as well as color-blind (III-8) and normal-visioned (III-l and 5) male offspring. Note: Males are much more likely than females to exhibit X-linked recessive traits.

124 2．X-连锁显性遗传 （X-linked dominant inhertance）
（Vitamin D resistant rickets） (1)患者女性多于男性； (2)每代都有患者； (3)男性患者的女儿都为患者； (4)女性患者的子女患病的机会为1/2。

125 卢花鸡的毛色遗传也是性连锁 卢花基因B对非卢花基因b为显性，Bb这对基因位于z染色体上而W染色体上不含有它的等位基因。 以雌芦花鸡(ZBW)与非芦花鸡雄鸡(ZbZb)杂交，F1公鸡的羽毛全是芦花，而母鸡全是非芦花。 如果进行反交, 以非芦花雌鸡(ZbW)作母本与芦花雄鸡(ZBZB)杂交，F1公鸡和母鸡的羽毛全是芦花。(如图)

126 4.11 Sex-limited限性 and Sex-influenced inheritance从性遗传
In still other instances, inheritance is affected by the sex of an individual, though not necessarily by genes on the X chromosome. There are numerous examples in different organisms where the sex of the individual plays a determining role in the expression of certain phenotypes. In some cases, the expression of a specific phenotype is absolutely limited to one sex; in others, the sex of an individual influences the expression of a phenotype that is not limited to one sex or the other This distinction differentiates sex-limited inheritance from sex-influenced inheritance.

127 限性遗传(sex-limited inheritance)：人类的Y连锁毛耳（hairy ears）　

128 In domestic fowl, tail and neck plumage is often distinctly different in males and females (Figure 4-l3), demonstrating sex-limited inheritance. Cock feathering is longer, more curved, and pointed, while hen feathering is shorter and mere rounded. Inheritance of these feather phenotypes is controlled by a single pair of autosomal alleles whose expression is modified by the individual's sex hormones. As shown in the following chart, hen feathering is due to a dominant allele, H; but regardless of the homozygous presence of the recessive h allele, all females remain hen-feathered.Only in males does the hh genotype result in cock feathering.

129 In certain breeds of fowl, the hen-feathering or cock-feathering allele has become fixed in the population. In the Leghorn breed, all individuals are of the hh genotype; as a result, males always differ from females in their plumage, Sebright bantams are all HH, resulting in no sexual distinction in feathering phenotypes.

130 Still another example of sex limited inheritance involves the autosomal genes responsible for milk yield in dairy cattle. Regardless of the overall genotype that influences the quantity of milk production, those genes are obviously expressed only in females.

131 Sex-influenced inheritance从性遗传
Cases of sex-influenced inheritance include pattern baldness in humans, horn formation in certain breeds of sheep (eg. Dorsett Horn sheep), and certain coat patterns in cattle. In such cases, autosomal genes are responsible for the contrasting phenotypes displayed by both males and females, but the expression of these genes is dependent on the hormone constitution of the individual. Thus, the heterozygous genotype exhibits one phenotype in one sex and the contrasting one in the other. For example, pattern baldness in humans, where the hair is very thin on the top of the head (Figure 4-14), is inherited m the following way

132

133

134 Even though females can display pattern baldness, this phenotype is much more prevalent in males. When females do inherit the BB genotype, the phenotype is much less pronounced than in males and is expressed later in life.

135 表3-5 从性遗传 类型 范例 基因型 表型 ♀ ♂ 从性显性 人类早秃 b+b+ 正常 正常 b+b 正常 早秃 b b 早秃 早秃
表3-5 从性遗传 类型 范例 基因型 表型 ♀ ♂ 从性显性 人类早秃 b+b+ 正常 正常 b+b 正常 早秃 b b 早秃 早秃 从性显性 绵羊长角 h+h+ 有角 有角 h+h 无角 有角 h h 无角 无角 从性隐性 鸡羽形态 h+h+ 雌羽 雌羽 h+h 雌羽 雌羽 h h 雌羽 雄羽