LINKAGE AND CROSSING-OVER
According to Mendel’s principle of independent assortment, a dihybrid cross with unlinked markers ought to produce a 1:1:1:1 ratio. If a significant deviation from this ratio occurs, it may be evidence that for linkage, that is, that the loci are located close to each other on the same chromosome pair.
During meiosis, a pair of synapsed chromosomes is made up of four chromatids, called a tetrad. The phenomenon of a cross - over occurs when homologous chromatids in the tetrad (one from each of the two parents) exchange segments of varying length during prophase. The point of crossover is known as a chiasma (pl. chiasmata). A tetrad typically has at least one chiasma along its length.
Generally, the longer the chromosome, the greater the number of chiasmata. There are two theories on the physical nature of the process. The classical theory proposes that cross-over and formation of the chiasma occur first, followed by breakage and reunion with the reciprocal homologues.
According to this theory, chiasma formation need not be accompanied by chromosome breakage.
Alternatively, according to the chiasmatype theory, breakage occurs first, and the broken strands then reunite. Chiasmata are thus evidence, but not the causes, of a cross-overs. Recent molecular evidence favours the latter theory, although neither is a completely satisfactory explanation of all of the evidence.
Chromosomal Aberrations: any change in the normal structure or number of chromosomes; often results in physical or mental abnormalities( Numerical disorders and Structural abnormalities)
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 nonhomologous 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 nonhomologous 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.
Chromosome abnormality
A chromosome anomaly, abnormality or aberration reflects on a typical number of chromosomes or a structural abnormality in one or more chromosomes. A karyotype refers to a full set of chromosomes from an individual which can be compared to a "normal" karyotype for the species via genetic testing. A chromosome anomaly may be detected or confirmed in this manner.
Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies.
Numerical disorders
This is called aneuploidy (an abnormal number of chromosomes), and occurs when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair
(trisomy, tetrasomy, etc.).
In humans an example of a condition caused by a numerical anomaly is Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Trisomy has been determined to be a function of maternal age.
An example of monosomy is Turner Syndrome, where the individual is born with only one sex chromosome, an X.
Structural abnormalities
When the chromosome's structure is altered, this can take several forms:
Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include
Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.
Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocations:
Reciprocal translocation: Segments from two different chromosomes have been exchanged.
Robertsonian translocation: An entire chromosome has attached to another at the centromere - in humans these only occur with chromosomes 13, 14, 15, 21 and 22.
Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted.
Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.
Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.
Inheritance
Most chromosome abnormalities occur as an accident in the egg or sperm, and therefore the anomaly is present in every cell of the body. Some anomalies, however, can happen after conception, resulting in Mosaicism (where some cells have the anomaly and some do not).
Chromosome anomalies can be inherited from a parent or be "de novo". This is why chromosome studies are often performed on parents when a child is found to have an anomaly. If the parents do not possess the abnormality it was not initially inherited; however it may be transmitted to subsequent generations.

Chromosomal Abnormalities:
I.
Abnormalities in chromosomal number
A.
How does it happen? nondisjunction
1.
nondisjunction - mistake in cell division where chromosomes do not separate properly in

 anaphase usually in meiosis, although in mitosis occasionally in meiosis, can occur in anaphase I or II
2.
polyploidy – complete extra sets (3n, etc.) – fatal in humans, most animals
3.
aneuploidy – missing one copy or have an extra copy of a single chromosome
 three copies of a chromosome in your somatic cells: trisomy
 one copy of a chromosome in your somatic cells: monosomy
 most trisomies and monosomies are lethal well before birth in humans; exceptions covered below
 generally, autosomal aneuploids tend to be spontaneously aborted
 over 1/5 of human pregnancies are lost spontaneously after implantation (probably closer to 1/3)
 chromosomal abnormalities are the leading known cause of pregnancy loss
 data indicate that minimum 10-15% of conceptions have a chromosomal abnormality
 at least 95% of these conceptions spontaneously abort (often without being noticed)
B.
aneuploidy in human sex chromosomes
1.
X_ female (Turner syndrome)
 short stature; sterile (immature sex organs); often reduced mental abilities
 about 1 in 2500 human female births
2.
XXY male (Klinefelter syndrome)
 often not detected until puberty, when female body characteristics develop
 sterile; sometimes reduced mental abilities; testosterone shots can be used as a partial treatment;
 about 1 in 500 human male births
3.
XYY male (XYY syndrome)
 usually tall, with heavy acne; some correlation with mild mental retardation and with aggressiveness; usually still fertile
 about 1 in 1000 human male births
4.
XXX female (triple X syndrome)
 usually just like XX females, except for having 2 Barr bodies in somatic cells

HOWEVER, more likely to be sterile, and if fertile, more likely to have XXY and XXX children
 about 1 in 1000 human female births
C.
aneuploidy in human autosomes
1.
autosomic monosomy appears to be invariably fatal, usually very early in pregnancy
2.
most autosomic trisomy is fatal, but sometimes individuals trisomic for autosomes 13, 15,
18, 21, or 22 survive to birth and even beyond
 chromosome number reflects size; bigger number = smaller size, and usually fewer genes

 extra 13, 15, or 18 leads to multiple defects and usually death well before 1 year of age extra 22 is much like extra 21 (Down syndrome, covered below), but usually more severe, with shorter life expectancy
3.
trisomy 21 (Down syndrome) : the only autosomal trisomy condition in humans that allows an appreciable number of individuals to survive to adulthood
 found in about 1 in 750 live births
 a phenotypically identical condition occurs that is not due to a true trisomy (it involves a chromosomal translocation, covered later)
 traits include abnormal facial appearance, high likelihood of mental retardation (degree varies considerably), and increased likelihood of developing leukemia and
Alzheimer’s disease
 likelihood of a child being born with Down syndrome increases with the age of the mother
 rate is as high as 1 in 16 live births for mothers age 45 and over at conception
 not completely clear why the odds go up so dramatically, likely a combination of factors
 is clear that nondisjunction is more common in eggs than sperm
 appears that spontaneous rejection of aneuploid pregnancies is more common in younger women
II.
Abnormalities in chromosomal structure: chromosomal rearrangements and fragile sites
A.
in addition to nondisjunction errors, there can be errors in homologous chromosome pairing and in crossing over; these produce chromosomal rearrangements

1.
reciprocal translocation – nonhomologous chromosomes pair and exchange parts (if only one gets new material, this is just called a translocation)
 can lead to deletions (loss of genetic material) and duplications (extra copies of genetic material)
 somewhat common in humans is a translocation of chromosome 21 to chromosome 14
 results in only 45 chromosomes in body cells of carrier (has one chr 14, one chr 21, one 14/21 = normal phenotype), but that individual has a high chance of producing offspring that are essentially trisomy 21 (with one chr 14, two chr 21, and one 14/21)
 this is called translocation Down syndrome , accounting for about 3% of all phenotypic Down syndrome individuals
2.
inversion – part of a chromosome is “flipped” relative to the normal gene sequence; can lead to deletions and duplications
3.
deletion
 causes include losses from translocations, crossovers within an inversion, and unequal crossing over
 can also be caused by breaking without rejoining, usually leading to large deletions
 small deletions are less likely to be fatal; large deletions are usually fatal – but always, there is variation based on what genes are lost
 some medium-sized deletions lead to recognizable human disorders
 several syndromes have been described that correspond to deletions of certain chromosomal regions; most commonly found in live births in humans is deletion of the short arm of chr 5
 called cri du chat (cat’s cry) syndrome
 found in about 1 in 50,000 live births
 surviving infants have a distinctive cry, severe mental retardation, and shortened lifespan
4.
duplication
 causes include extras from translocations, crossovers within an inversion, and unequal crossing over
 again, amount makes a difference, with larger duplications more likely to be fatal, but there is variation based on what genes are duplicated
 duplications also provide raw material for genetic evolution; for example, there are many
B.
fragile sites pseudogenes in humans that are “inactivated” duplicates
1.
some chromosomes have regions that are poorly connected to the rest of the chromosome;
 the “poor connection” is often a string rich in CGG or CGC repeats, and is inherited like a gene
 breaks from these fragile sites lead to loss of genetic material
2.
human X can have such a site ( fragile X syndrome )
 effects center on decreased mental capacity
 more prominent effects in males than females
 one of the trinucleotide repeat disorders :
 normally 5-55 CGG repeats
 diseased individuals have 200-1300 repeats
 like many trinucleotide repeat disorders, the repeat number may increase from one generation to the next
3.
other fragile sites may play a role in cancer