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Chromosomal Aberrations: Numerical disorders and Structural abnormalities
#1
The chromosomes represent genetic material of an organism and are the most stable organic compound that maintains constancy both in number and structure. However chromosomes undergo unusual changes called as aberrations which can be numerical or structural. In numerical aberrations, increase or decrease in number of chromosomes are seen. Types of numerical aberrations are:

Euploidy- complete set of chromosomes present in multiples
Aneuploidy- partial change in chromosomes

When there is an increase in number of chromosomes compared to the chromosomal number of an organ, then the condition is called as hyperaneuploidy. It is represented as 2n+1, 2n+2 etc. Aneuploidy is also classified as Monosomy, Trisomy and Nullisomy.

Monosomy is hypoaneuploidy where one of alleles of the homologous pair is lost. Monosomy is found rarely in diploids and is commonly found in polyploidy. Depending on the chromosome number, that many types of monosomies can develop. When two different chromosomes are lost, it's denoted as 2n-1-1, when 3 different chromosomes of a different homologous pair are lost, it is represented as 2n-1-1-1. It is called as tri Monosomy. Trisomy is a type of hyperaneuploidy where the number of individual chromosomes is more than the number of chromosomes in an organism. Edward syndrome is caused because of a trisomy. Nullisomy is the condition where both the alleles of a gene of the same pair of homologous chromosomes are lost. It is represented as 2n-2. Usually nullisomies hardly survive.

Euploidy exists in three conditions; monoploidy, haploidy and polyploidy. Monoploidy refers to the normal condition where one set of chromosome is present. Haploidy is the presence of half the number of chromosomes in a somatic cell. Haploidy can be induced by X rays, temperature shock, colchisin and delayed pollination. Experimental methods of developing haploidy involve distant hybridization, production of androgenic plants. Haploids usually produce sterile plants. Polyploidy is the condition where the number of chromosomes present in multiple copies. Types of polyploidy include autopolyploidy, allopolyploidy and segmental alloploidy.

Structural chromosomal aberrations can be intra chromosomal or inter chromosomal. Intra chromosomal structural aberrations include deletion, duplication and inversion. Inter chromosomal aberrations include translocations. Deletions can be terminal or inter special and can be caused naturally and also by chemical mutagens and radiation. These can be identified by size of the chain, change in the position of centromere and formation of loops in pachytene stage. Deletion of a portion of a dominant allele may result in expression of a recessive character. This is called as pseudodominance.

Duplication results in structural chromosomal aberrations. Duplications occur in a lower frequency than deletions. Bar eye mutation in Drosophila results in duplication in X chromosome. Inversion is an intra-chromosomal aberration where segment of chromosomes are inverted on reversed by 180 degrees. Inversions can be paracentric, where centromere is not involved or pericentric where the centromere is involved in the inverted segments of chromosome. Translocations involve two non-homologous chromosomes and position of part of the chromosome is changed leading to change in arrangement of chromosomes. Types of arrangements in translocation include alternate, adjacent I and adjacent 2. In simple translocation, a single nick occurs and the terminal position of the chromosome gets translocated on another non-homologous chromosome. In shifted translocations, two nicks are created and interstitial chromosome segment gets translocated onto another non-homologous chromosome. In reciprocal translocation, two nicks occur on both non-homologous chromosomes and separated segments get interchanged. The translocated chromosomes show change in the size of the chromosome and in position of the centromere. During pairing of homologous chromosomes, the translocate part forms a loop. Translocation brings about new linkage groups or new variation can be linked with normal genes. Translocation in human beings can lead to leukemia.
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#2
Prenatal testing

Main reasons for the changes in number and structure of the chromosomes are radiation, UV lighting and toxic chemical exposure. Negative environmental effects could alter genetic material in the gametes (before fertilization) or in the fertilized egg (called de novo). Substantial errors in genetic material would prevent fetus from normal development and miscarriage will happen (usually at the beginning of the pregnancy). Some alterations in the structure and number of chromosomes are carried to the next generation; lifespan of those individuals will depend on the importance of altered chromosome(s) or gene(s).

Fetal health could be detected non-invasively (using ultrasound and maternal blood testing techniques) or by screening fetal genetic material. All methods that are dealing with fetal DNA material are considered aggressive and potentially harmful for the baby. Amniocentesis is one of those methods. Needle inserted in the uterus during amniotic fluid sampling could result in fetal damage or trigger series of events that will lead to spontaneous miscarriage. Chorionic villus sampling can be performed earlier than amniocentesis and it is another aggressive method focused on placental tissue sampling. Although those methods are risky, both amniotic fluid and placental tissue contain more than enough fetal genetic material and testing will provide precise evidence of fetal genetic health.

Less invasive methods that could provide more details about fetal health can be conducted on maternally derived samples. Fetal DNA could be obtained from the mother's blood because it contains fetal cells and free fetal DNA (2-10% of total DNA in the blood). During in vitro fertilization, embryos could be tested prior implantation (to prevent implanting genetically altered embryos).

Proteins in the blood could be good indicators of potential genetic defects. Human chorionic gonadotropin (hCG) level is typical marker of pregnancy (home tests are designed to register pregnancy by detecting beta hCG in the urine sample). It’s produced by placenta from the moment women become pregnant and its level keep on rising during pregnancy. hCG influence yellow body (corpus luteum) by promoting its progesterone secretion. Triple test (known as Kettering test or the Bart's test) is screening beta hCG, AFP and estriol levels to detect any chromosomal aberration during second trimester of pregnancy. Impaired hormone level could indicate neural tube defect and couple other genetic conditions. For example, if all three hormones are present in lower than expected level, there is high chance that baby has Edward’s syndrome (trisomy 18). If AFP and estriol levels are low, and beta hCG level is high – there is high chance that baby with Down syndrome (trisomy 21) will be born. Down syndrome could be detected with ~80% sensitivity and 5% false positive rate.

Pregnancy-associated plasma protein A (pappalysin 1 or PAPPA) is another protein used in prenatal screening. Low PAPPA plasma level suggests that women is probably carrying aneuploid fetus.
Alpha-fetal protein (alpha-1-fetoprotein) is produced by the yolk sac and liver during pregnancy. It’s fetal form of serum albumin and this is the most abundant fetal protein. It’s used as clinical marker for couple of genetic disorders. When alpha-1-fetoprotein level is increased, open neural tube defects and omphalocele are suspected. Decreased hormone levels points to the Down syndrome.

When serious genetic disorder is suspected after maternal testing or ultrasound check – extraction and screening of fetal genetic material is needed to confirm or discard initially obtained results.

Karyotype (set of chromosomes) is prepared when cells are in the metaphase stage of division. That’s when chromosomes are condensed, duplicated and easily recognized after staining. Photomicrographs of stained chromosomes (karyogram) allow further examinations of their number and structure. Karyogram could show if some chromosomes are missing or are present abundantly. Staining of the chromosomes will show if deviation such as deletions, duplications or translocations are present. PCR analysis of the fetal DNA sample is used to provide more information on the altered genes.

Prenatal testing is especially important if there are suspected genetic disorders in the family or if parents already have a child with genetic abnormalities. Women that are older than 35 years are at increased risk of giving birth to babies with Down syndrome (1 out of 400 babies) and genetic testing is strongly advised. Information on the disorder could prevent parents from having a baby with impaired genetic material or prepare them (economically and physically) to nurture a child that needs special heath care and unique social environment.
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#3
Genetic engineering is a tool which is helping medical and biotechnology field to continuously grow. DNA is the basic unit of genetics and a molecule in which all information related to life are coded. The complete knowledge of DNA and its scanning is employed in detection of mutated sequences. This genetic testing is direct examination of the DNA itself. These testing are of two types.
In first test, the researchers collects all samples and design a probe that is a short pieces of DNA whose sequences are complementary to the sequence of mutated sites. The probe will bind to the mutated sequence if it is present. This way the probe will find their complement within the base pairs of any individual genome. If the probe binds to the base pairs, it will flag mutation. This way it can be identified using first type of Genetic testing.
In second type of testing, the researcher actually conduct the test by comparing the sequence of DNA bases of patients genes to diseases in healthy. This helps in diagnostic of mutation by this alternative method.
There are many applications of genetic testing: (This includes but not limited to):
1) Identification of unaffected individuals carrying a copy of gene
for disease.
2) Forensic testing/ Identification testing.
3) Screening of newborn.
4) Symptomatic individual’s conformational diagnosis
5) Prenatal diagnosis screening.
6) Pre-symptomatic testing for evaluation of risk of developing
onset cancers.
This way genetic testing is greatly applied in various fields, including biological science, medical science etc.
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#4
Karyotyping is a technique used for screening for genetic disorders. A karyotype refers to the number and size of chromosomes in the nucleus of an organism’s cell. The arrangement of chromosomes according to a pattern (usually number) is known as a karyogram or an ideogram.
Since it is very difficult to spot chromosomes under a light microscope, the chromosomes have to be stained in order to allow proper visualization of the condensation and also the banding patterns. Traditional stains cannot be used for staining chromosomes; instead stains like Giemsa and quinacrine are used.

Once the chromosomes have been visualized under the light microscope, the chromosomes are arranged according to their number. The arrangement formed is then compared to a standard to determine the presence or absence of any abnormality.

It is possible to perform karytoping of chromosomes collected from any nucleated cell; however for cytogenetic purposes lymphocytes, skin or tumour cells are preferably used in adults and amniotic cells or chorionic villi cells in foetuses. Knowledge of a genetic disorder at an early age makes treatment and management much easier.

Amniocentesis is a form of prenatal testing involving karyotyping. This test, also known as amniotic fluid testing is done to screen for any chromosomal aberrations in a fetus. Between 15th and 20th week of gestation, the physician after giving a local anaesthetic to the mother extracts 20 ml of amniotic fluid using a syringe. This fluid is then cultured for foetal cells which are analysed and a karyotype is performed.

Amniocentesis can indicate any chromosome disorder and also other developmental disorders like lung immaturity, Rh incompatibility etc. However, since this technique can be misused to detect the sex of the fetus and is therefore banned in some countries. Chorionic villi sampling or CVS is a technique similar to amniocentesis where cells from the chorionic villi are taken and analysed for chromosomal aberrations.

Most developed countries advice expecting parents to undergo amniocentesis and karyotyping for screening for a variety of diseases. Some of these are Down’s syndrome, Turner’s syndrome, Fragile X syndrome, Edward’s syndrome, HIV etc.
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Chromosomal Aberrations: Numerical disorders and Structural abnormalities00