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Medical Genetics 09 人类染色体 human chromosome Medical Genetics A chromosome is the visible state of genetic material during a phase of the division of the cell (metaphase). Medical Genetics Humans have 23 pairs of chromosomes, which makes the diploid number 46. The diploid number is the number of chromosomes of a normal cell. Medical Genetics The haploid number is the number of chromosomes in a gamete. Usually, the diploid number is twice the haploid number. Medical Genetics The number of chromosomes varies depending on the species. Medical Genetics 1. chromatin Chromatin is that portion of the cell nucleus which contains all of the DNA of the nucleus in animal cells. (A small amount of special DNA is also found in the mitochondria of the cell cytoplasm outside of the cell nucleus.) Medical Genetics Medical Genetics A. heterchromatin and euchromatin The degree of condensation of the nuclear DNA is variable. Strongly condensed DNA is called heterochromatin, Less condensed one euchromatin. Heterochromatin is stained more intense than euchromatin by certain nuclear dyes. Medical Genetics Heterochromatin is the condensed form of chromatin organization. It is seen as dense patches of chromatin. Medical Genetics Abundant heterochromatin is seen in resting, or reserve cells such as small lymphocytes (memory cells) waiting for exposure to a foreign antigen. Heterochromatin is considered transcriptionally inactive. Medical Genetics There are two types of heterochromatin: Facultative heterochromatin and Constitutive heterochromatin. Medical Genetics Facultative heterochromatin is condensed chromatin that unfolds and becomes transcriptionally active during some portion of the cell cycle (Barr body). Medical Genetics Constitutive heterochromatin refers to the chromatin that remains transcriptionally inert during the entire cell cycle. Medical Genetics The bulk of constitutive heterochromatin is composed of noncoding DNA sequences that are repeated hundreds of thousands or even millions of times. Medical Genetics Medical Genetics Euchromatin is threadlike, delicate. It is most abundant in active, transcribing cells. Thus, the presence of euchromatin is significant because the regions of DNA to be transcribed or duplicated must uncoil before the genetic code can be read. Medical Genetics Condensation and decondensation of the DNA are at least partially reversible processes. Each DNA segment that has to be replicated or transcribed has to be decondensed during this time. Medical Genetics The highest degree of condensation can be found in the chromosomes (mitosis, meiosis) during cell division. Medical Genetics Medical Genetics Medical Genetics B. the nucleosome The fundamental structural unit of chromatin is an assemblage, called the nucleosome, composed of five types of histones (designated H1, H2A, H2B, H3, and H4) and DNA. Medical Genetics A nucleosome consists of approximately 1.8 turns of DNA wound around a core particle of histone proteins. The core particle is a roughly heart-shaped octamer of 4 types of histones: two each of the H2A, H2B, H3, and H4 proteins. Medical Genetics The DNA between two nucleosomes is called the linker segment. This linker segment gives unfolded chromatin a beads-on-astring appearance (the nucleosomes are the beads). Medical Genetics Medical Genetics Medical Genetics Medical Genetics DNA is bound to the histones through electrostatic forces between the negatively charged phosphate groups in the DNA backbone and positively charged amino acids (e.g., lysine and arginine) in the histone proteins. Medical Genetics At times, histone proteins are modified by the addition of acetyl, methyl, or phosphate groups, and this alters the strength of the bonding between the histones and DNA. Medical Genetics Modifications such as these are usually associated with the regulation of biological processes such as DNA replication, gene expression, chromatin assembly and condensation, and cell division. Medical Genetics C. Scaffold-radial loop structure model Chromatin refers to proteins that help organize the long DNA molecule. The protein supports and organizes small loops of DNA. Medical Genetics Medical Genetics 2.Chomosome At some point during the cell division process, the chromatin will be packaged tightly enough that we are able to visualize distinct chromosomes under the light microscope. Medical Genetics A. chromosome biology The chromosomes do not actually become visible in the eukaryotic cell until after the DNA is replicated. So, a newly-visible chromosome is a duplicated chromosome, and contains two copies of the DNA double helix. Medical Genetics These chromosomes are composed of two threads of chomatin, called chromatids, which are attached to one another at the centromere of the chromosome. The 2 chromatids that make up a duplicated chromosome are the products of DNA replication, and are known as sister chromatids. Medical Genetics Organisms that reproduce through sexual reproduction have two copies of each type of chromosome in their somatic (body) cells, one inherited from each of their parents. Such organisms are said to be diploid, whereas cells with only one copy of each type of chromosome (such as germ cells or gametes) are said to be haploid. Medical Genetics Cytogenetic analyses are almost always based on examination of chromosomes fixed during mitotic metaphase. Medical Genetics Metaphase chromosomes differ from one another in size and shape, and the absolute length of any one chromosome varies depending on the stage of mitosis in which it was fixed. Medical Genetics A model of a chromosome during metaphase Medical Genetics However, the relative position of the centromere is constant, which means that that the ratio of the lengths of the two arms is constant for each chromosome. This ratio is an important parameter for chromosome identification, and also, the ratio of lengths of the two arms allows classification of chromosomes into several basic morphologic types. Medical Genetics Medical Genetics Similar chromosomes inherited from different parents are known as homologous chromosomes, with corresponding homologous chromatids. These chromosomes are similar in that they have the same genes at the same locations on the chromosome, but may have different forms (or alleles) of those genes. Medical Genetics Medical Genetics B. chromosome staining Medical Genetics Medical Genetics 人类染色体非显带核型图 Medical Genetics Chromosome banding • Q banding • G banding • R banding • T banding • C banding • N banding • High resolution banding Medical Genetics Medical Genetics G banding (model) Medical Genetics Model banding Medical Genetics Model banding Medical Genetics Chromosome 1 Medical Genetics • X chromosome • Contains over 1400 genes • Contains over 150 million base pairs, of which approximately 95% have been determined Medical Genetics C显带核型图 Medical Genetics 3. Sex chromosome and sex-determination Humans usually have 46 chromosomes per diploid cell consisting of 22 sets of autosomes and a set of sex chromosomes either XX or XY. In the usual course of events, individuals with the karyotype 46, XX are female and individuals with 46, XY, are male. Medical Genetics The question arises as to how the sex of an individual is determined. Is sex determined by the number of X chromosomes - with one X you are male or with 2 X's you are female? Medical Genetics Or is sex determined by the presence or absence of the Y chromosome - the presence of a Y makes for a male or the absence of a Y produces a female? Medical Genetics The answer was provided by individuals resulting from nondisjunction of the sex chromosomes. Medical Genetics Some individuals have 45 chromosomes and have only one X chromosome; other individuals have 47 chromosomes and have two X chromosomes and a Y. Medical Genetics Chromosome Constitution Name of Syndrome Sex of Individual Frequency in Population 46, XX Normal Female 0.511* 46, XY Normal Male 0.489* 45, XO Turner's Syndrome Female 1/5,000 47, XXY Klinefelter's Syndrome Male 1/700 emale (46,XX) and Male (46,XY) frequencies taken from the US Census projection Medical Genetics Usually, a woman has two X chromosomes (XX) and a man one X and one Y (XY). Medical Genetics However, both male and female characteristics can sometimes be found in one individual, and it is possible to have XY women and XX men. Medical Genetics Analysis of such individuals has revealed some of the molecules involved in sex determination, including one called SRY, which is important for testis formation. Medical Genetics SRY (which stands for sexdetermining region Y gene) is found on the Y chromosome. In the cell, it binds to other DNA and in doing so distorts it dramatically out of shape. Medical Genetics This alters the properties of the DNA and likely alters the expression of a number of genes, leading to testis formation. Medical Genetics Most XX men who lack a Y chromosome do still have a copy of the SRY region on one of their X chromosomes. This copy accounts for their maleness. However, because the remainder of the Y chromosome is missing they frequently do not develop secondary sexual characteristics in the usual way. Medical Genetics • Contains over 200 genes • Contains over 50 million base pairs, of which approximately 50% have been determined Medical Genetics Medical Genetics 4. chromosomal polymorphism Polymorphism is a general concept in biology, referring to a more than one version of a trait being actively present in a population. Medical Genetics Chomosomal polymorphism refers to the condition where one species contains members with varying chromosome counts or shapes. In most cases, the difference in chromosome counts is the result of a single gene undergoing fission, where it splits into two smaller chromosomes, or two undergoing fusion, where two chromosomes join to form one. Medical Genetics 5. An International System for Human Cytogenetic Nomenclature Symbols and abbreviated terms used in the description of chromosomes and chromosomal abnormalities are listed below. For a detailed discussion of these terms, consult ISCN (1995): An International System for Human Cytogenetic Nomenclature, Mitelman, F (ed); S. Karger, Basel, 1995. Medical Genetics • add additional material of unknown origin • arrow (->) from - to, in detailed system • brackets, square ([]) surround the number of cells • cen centromere • colon, single (:)break, in detailed system • colon, double (::)break and reunion, in detailed system • comma (,)separates chromosome numbers, sex chromosomes, and chromosome abnormalities • decimal point (.) denotes sub-bands Medical Genetics • del deletion • de novo designates a chromosome abnormality which has not been inherited • der derivative chromosome • dic dicentric • dup duplication • fra fragile site • h heterochromatin, constitutive • hsr homogeneously staining region • i isochromosome Medical Genetics • • • • • • • ins insertion inv inversion mar marker chromosome mat maternal origin minus sign (-)loss p short arm of chromosome Parenthese ssurround structurally altered chromosome and breakpoints • pat paternal origin Medical Genetics • plus sign (+) gain • q long arm of chromosome • question mark (?) questionable identification of a chromosome or chromosome structure • r ring chromosome • rec recombinant chromosome • s satellite • sce sister chromatid exchange Medical Genetics • semicolon (;) separates altered chromosomes and breakpoints in structural rearrangements involving more than one chromosome • slant line (/) separates clones • t translocation • ter terminal (end of chromsome) • upd uniparental disomy Medical Genetics In Situ Hybridization: Symbols and Abbreviations • minus sign (-) absent from a specific chromosome • plus sign (+) present on a specific chromosome • multiplication sign (x) precedes the number of signals seen • period (.) separates cytogenetic observations from results of in situ hybridization • semicolon (;) separates probes on different derivative chromosomes • fish fluorescence in situ hybridization • ish in situ hybridization; when used without a prefix applies to chromsomes (usually metaphase or prometaphase) of dividing cells • wcpwhole chromosome paint