Detailed Description of Different type of chromosomal aberration,Pedigree,Chromosome classification,Cytogenetics,Genetic counselling,Prenatal Diagnosis and Modes of inheritance Inheritance of X and Y chromosome, Autosomal Dominant And autosomal recessive gene inheritance
Medical Genetics No two persons in this world, except the monozygotic twins, are exactly alike. All of us have some individuality in physical and biochemical characters. But some of our physical characters (traits) are common with the parents and ancestors. A trait appearing in the next generation is called a family character. But if the trait appears in at least three successive generations of a family it is called a hereditary character and transmission of several of characters from generation to generations is called heredity. Since hereditary characters are transmitted by the genes of located in the chromosomes, the branch of biological science dealing with the study of the principles of heredity is called genetics. Study of genetics in human subjects is human genetics. If the study is done with a clinical bias for detection, management and prevention of genetically inherited diseases it is called medical genetics. Since genes are located in a linear fashion along the length of the DNA molecules of the Chromosomes, knowledge about the Chromosomes is essential to understand the principles of genetics. A chromosome is made up of a DNA molecule and associated proteins. Individual chromosomes are visible under the light microscope only during cell division, i.e., only when each chromosome becomes sufficiently thick by being tightly coiled and folded along its entire length to shorten to a small fraction of its interphase length. During interphase individual chromosomes remain uncoiled at certain regions (to remain invisible as euchromatin), and remains coiled in certain other regions (to become visible as chromatin granules or heterochromatin). Each chromosome shows a constricted region, the centromere or primary constriction which gets attached to the chromosomal microtubules during cell division. If the centromere is located at the middle of the length of the chromosome, it is called a metacentric chromosome. If the centromere is located at a distance away from the end but not exactly at its middle, the chromosome is called a submetacentric one. In some chromosomes the centromere is nearer one end rather than its midpoint. Such chromosomes are called acrocentric ones. Human acrocentric chromosomes show small masses of chromatin which are attached to their shorter arms by a narrow stalk called secondary constriction. This small mass of chromatin is called satellite-body or sat- body. In subhuman species centromeres may be seen to be situated at one end of some chromosomes. Such chromosomes are called telocentric. The shorter arm of submetacentric and acrocentric chromosomes are called p arm (p = Petit = Small) and their longer arm is called q arm (q / g = Grand = Large). Each cell of any organism contains a fixed number of chromosomes, characteristic for that species. In human somatic cells this number is 46 and in the gametes it is 23 only. The chromosome number in a normal somatic cell is called the diploid number. That in a gamete cell is called haploid number since fusion of two haploid cells during fertilization restores the diploid number. The diploid numbers for some common species are: Dog-78, Horse-66, Guineapig- 64, Cow- 60, Sheep-54, Rabbit- 44, Cat- 38, and Mosquito- 6. Each chromosome in a haploid set is unique in size, position of centromere and location of genes. In a diploid set there are two pieces of such unique type of chromosomes. They are called homologous pair because one of the pair is derived from the paternal gamete and the other from the maternal gamete. Hence the chromosomes of a homologous pair are identical in length, position of the centromere, and loci of genes. Of the 23 homologous pairs of chromosomes in a normal human somatic cell, 22 homologous pairs regulate the body characters of a person and are called autosomes. The members of the other homologous pair are called sex chromosomes since they primarily regulate the sex characters of a person. In females the two sex chromosomes are identical and are called X chromosomes. However, in males the sex chromosomes are not identical; one is longer than the other. The longer one is called the X chromosome and the shorter one is the Y chromosome. Therefore, males are symbolized as 46 XY and females as 46 XX. The X chromosome being longer bears more number of genes all of which are not represented in the Y chromosome. The Y chromosome has a strong male sex determining influence. Its absence induces female Gonadal development in the embryo; but its presence induces development of male gonads. X chromosomes probably do not contain any potent sex determining gene. For normal development of the ovary genes should be present in both the p and q arms of the X chromosome. Presence of genes in the short arms of both the X chromosomes is essential for normal female somatic characters. Classification of chromosomes Groups Chromos Length Position Appearance in Karyograms ome Nos. of centromer e Gr. A 1 2 3 Longest Meta centric Gr. B 4 5 Long Sub Meta centric Gr. C 6 7 8 9 Medium Sub 10 sized Meta 11 12 centric 13 & X Gr. D 13 14 Medium Acro 15 sized centric with sat- body Gr. E 16 17 short Sub 18 meta centric but no 16 is meta centric Gr. F 19 20 shortest Meta centric Group G 21 22 & shortest Acro Y centric with sat body but Y has no sat-body Thus Groups A and F and also Chromosome no 16 are metacentric; Groups D & G are acrocentric and all the rest are submetacentric. Except Y chromosome all members of D & G groups bear Sat-bodies. Chromomosomal aberrations Many birth defects, mental deficiencies and pregnancy wastes are frequently related to chromosomal disorders. 50% of all spontaneous abortions during the first trimester and 10% of all congenital defects are associated with chromosomal disorders. It is estimated that 3% of pregnancies result in a child with a genetic disease or defects at birth. About 10% of all pediatric and adult hospitalizations involves some kind of genetic problems. The causes of chromosomal abnormalities are: i) aberrations in mitosis, ii) aberrations in meiosis, iii) ionising radiations, iv) exposure of gonads to high temperatures, v) high maternal age, vi) viral infections, exposure to chemicals like formaldehyde, nitrogen mustard, ethyl urethane etc. In certain diseases called genetic diseases the genetic component of the individual is so overwhelming that it expresses itself in a predictable manner without any extraordinary environmental challenges. The genetic diseases fall into one of the following three categories: a.Chromosomal disorders ( microscopic defects)- due to excessive or deficient genetic material ( numerical or morphological alterations of chromosomes. b.Mendelian disordres or single gene defects (submicroscopic defects)- due to an abnormal single mutant gene involving one or both chromosomes of a homologous pair at a partticular locus. c.Multifactorial disorders- due to interaction of multiple genes and multiple exogenous environmemtal factors. Numerical alterations in chromosomes Numerical alterations may involve all cells of the body if the error occurs prior to fertilization or only certain cells of the individual if the error occurs subsequent to fertilization. The former variety includes monoploidy, aneuploidy and polyploidy. The latter variety includes mosaicism and chimera. Monoploidy Somatic cells having haploid number of chromosomes is monoplidy. It is unknown in man but common in lower plants. Except in male honey bees it is rare in adult animals. Polyploidy It is a condition where somatic cells possess chromosomes in numbers which is in multiples of the haploid number (but excepting the diploid number) e.g., triplody, tetraploidy etc. It occurs in certain cells under normal conditions in old age e.g., some liver cells, mucosal cells of the urinary bladder. Polyploid cells seen in interphase state show large nuclei. The condition may arise due to: i) During mitosis after each of the chromosomes has separated into chromatids the two sets of chromosomes do not pull apart but remain in the equatorial region until a nuclear membrane envelopes both the sets in the same nucleus of a cell. ii) Fertilization of an ovum by more than one spermatozoa ( but survival rate of such zygotes is very poor). iii) During telophase of mitosis after the formation of two nuclear envelops around the chromosomes at each pole of the dividing cell there may be failure in cytokinesis. The two nuclear envelops may subsequently fuse and thus enclose double the chromosomal complement of the normal kinds of cells. Failure of such cytokinesis during meiosis I leads to formation of gamets with diploid number of chromosomes. Their subsequent fertilization with a normal gamet leads to triploidy. Aneuploidy In this condition the number of chromosomes in a somatic cell is either greater or lesser than the diploid number; but not in multiples of the haploid number. Most such hazards take place during anaphase due to abnormal spindle apparatus functioning in either mitosis or meiosis. Aneuploidy may be trisomy or monosomy. In trisomy a particular chromosome is present in triplicate instead of the normal homologous pair. Thus there is one extra chromosome in the cell. In monosomy a particular chromosome is present as a lone member instead of the normal homologous pair. Thus the cell is deficient in one of the chromosomes. In tetrasomy the cell contains 4 members of the same chromosome i.e., two extra chromosomes are present. Aneuploidy results from any of the following two mechanisms: 1.Anaphase lag- here after splitting of the centromere one member of the pair undergoes normal migration to one pole of the dividing cell but the other member of the pair fails to migrate to the other pole. Thus one of the daughter cells is normal but the other one is monosomic. 2.Non dysjunction (dysjunction = seperation)- During anaphase when the centriole has splitted one or more chromosomes may fail to migrate properly due to faulty spindle apparatus functioning. Thus both members of a particular homologous pair move towards the same pole and the other pole receives none. This results in one cell having an extra member of the homologous pair (trisomy) and the other sister cell having a deficiency in that chromosome (monosomy). Non dysjunction in gonads during meiosis I results in abnormality in all the four resultant gamets but if it occurs during meiosis II two gamets will be normal and two gamets will be abnormal. Non dysjunction during 1st cleavage division of the zygote will result in aneuploidy in all cells of the foetus and the foetus will be a mosaic of trisomic and monosomic cells. When non dysjunction occurs during later parts of the embryonic differentiation only those cells which are derived from such abnormal mitosis will show aneuploidy. Hence the person will be having a milder form of mosaicism of euploid tissues with aneuplody in some organs and tissues. Fertilization of a normal gamete with an aneuploid gamete will result in formation of a aneuploid zygote. Very prolonged prophase of meiosis I in elderly women possibly favour non dysjunction. Autosomal nondysjunction is less viable particularly when it affects a large chromosome. Nature is more tolerant to trisomic cells than monosomic ones. Due to absence of all the genes in a whole chromosome the cell degenerates early. 99% cases of monosomy of the sex chromosome (Turner’s syndrome cases with 45 XO status) result in abortion. Chimera A chimeric individual has two or more cell types which differ in their cromosomal number because they have a different genetic origin. This is done usually in experimental studies in a laboratory. It differs from mosaicism since in the latter condition all the cells with different chromosomal numbers are of the same genetic origin. Morphological alterations in chromosomes 1.Deletion- Loss of a segment ( whole or part of an arm) of a chromosome. May be terminal or interstitial. It is comparable to partial monosomy. Denoted by ‘-’ sign after the appropriate arm. 2. Duplication- Addition of the deleted portion of a chromosome to another homologous chromosome due to unequal crossing over. There is duplication of genes. Not seen in human beings. It is comparable to partial trisomy. Less harmful than deletion. 3. Inversion- Detachment of a segment of a chromosome and its later union with the same homologous member during crossing over in an inverted position. No loss of genes; but they are in altered loci. Usually inversion does not lead to abnormal phenotypes. Denoted by ‘inv’ sign. 4. Ring chromosome- A chromosome after deletion at both ends form a ring due to adherence of the two deleted ends to each other. Usually it is not transmitted to the next generation. Denoted by ‘r’ sign. 5.Isochromosome- The centromere in stead of normal longitudinal splitting if splits transversely will form two metacentric chomosomes of equal length and each arm of it having identical genes. Denoted by ‘i’ sign. Turner’s syndrome (usually 45XO) can result with 46 chromosomes if the long arm of one X chromosome forms isochromosome. 6. Translocation- Exchange of chromosomal segments between nonhomologous chromosomes. It may be heterozygous (when only one member of the chromosome pairs is involved in exchanging segments) or homologous (when both members of the chromosome pairs are involved in exchanging segments). If breaks occur at the centromeres of the two chromosomes and the whole arms of the chromosomes are exchanged it is called Robertsonian translocation. Usually it is seen between D and G groups and is often heterozygous. The long arm of a G group chromosome may be fused with the long arm of a D group chromosome. The fragment formed by fusion of their short arms is lost because they are without a centromere. Mothers of translocated Down’s syndrome babies are usually a carrier of the trait.
Pages to are hidden for
"Genetics"Please download to view full document