S.Y.B.Sc Semester III Botany Paper II Unit II :Cytogenetics Chromosomal aberrations By Mrs. Mandakini R Ingle Department of Botany Satish Pradhan Dnyanasadhana College, Thane (w)

Basic definitions Chromosomes, DNA and genes Chromatides, and centromere Arms of a chromosome (p and q) Karyotype Autosomes and sex chromosomes Genotype and phenotype

Human Chromosomes The chromosome carries the genetic information. composed of deoxyribonucieic acid (DNA) on framework of protein . Segments of DNA molecules comprise the genes; the units of heredity.

Chromosomes During cell division, the chromosome can be seen to consist of 2 parallel strands; the chromatids, held together at one point, the centromere.

Human Chromosomes

Karyotype It is the set of chromosomes of an individual. It is the systematized arrangement of the chromosomes of a single cell. In the human cell, there are 46 chromosomes or 23 pairs (diploid number); of these 23 pairs, 22 are similar in both sexes and are called the autosomes. The remaining pair is called sex chromosomes : XX in the female cells and XY in the male cells . Chromosomes are arranged in groups A to G according to their shape & size.

Karyotype of a normal female

Karyotype of a normal male

Chromosomal Abnormalities

Chromosomal Abnormalities Chromosomal abnormalities are either numerical or structural. They are a very common cause of early spontaneous miscarriage. Usually, but not always, cause multiple congenital anomalies and learning difficulties.

Chromosomal Aberrations (abnormalities) Structural Aberrations Deletion Duplication Inversion Translocation Numerical Aberrations (abnormalities) Polyploidy: Multiple of the haploid (> Diploid) Aneuploidy: Abnormal number

Structural abnormalities Deletion : loss of a portion of a chromosome Duplication : extra piece of a chromosome. . Inversion : fragmentation of a chromosome followed by reconstitution with a section inverted. Translocation : the transfer of a chromosome or a segment of it to a non-homologous chromosome

Chromosomal Deletions a deletion results in a lost portion of a chromosome, Deletion Causative Agents: Heat, radiation, viruses, chemicals, errors in recombination. result in partial monosomy, the organism is monosomic for the portion of the chromosome that is deleted, as in monosomy, most segmental deletions are deleterious.

Deletion

Recognizing Deletions Terminal Intercalary

Homologous Pairs? Intercalary Hemizygous Terminal Hemizygous: gene is present in a single dose. Psuedodominance: hemizygous genes are expressed.

Cri-du-chat Syndrome Mental retardation Slow motor skill development Low birth weight and slow growth Small head (microcephaly) Partial webbing of fingers or toes Wide-set eyes (hypertelorism) High-pitched cry

Chromosomal Duplication ...an event that results in the increase in the number of copies of a particular chromosomal region,

Duplication Causes: Effects: duplications often result from unequal crossing over, can occur via errors in replication during S-Phase. Effects: results in gene redundancy, produces phenotypic variation, may provide an important source for genetic variability during evolution.

Unequal Crossing Over Produces both duplications and deletions!

Duplication in Evolution essential genes do not tolerate mutation, duplications of essential genes, then subsequent mutations, confers adaptive potential to the organism, new gene family members are ‘recruited’ to perform new functions.

Chromosomal Inversions inversion: aberration in which a portion of the chromosome is turned around 180o.

Paracentric Inversion ...an inversion in which the centomere is not included, A B C A B A B C ...a paracentric inversion does not change arm length ratio.

Pericentric Inversion ...an inversion in which the centromere is included, A B C A B C ...a pericentric inversion results in a change in chromosome arm length.

Inversion Loop no crossing over

Paracentric Produces haploid gamete.

Paracentric Produces gamete with inversion.

Produces a chromosome with two centromeres. Paracentric Produces a chromosome with two centromeres. Nonviable gametes.

Paracentric Outcomes 1 Normal Gamete, 1 Inversion Gamete, No Crossover Classes Recombination is not inhibited, but recombinant gametes are selected against.

Dicentric/Ascentric …results only when the crossing over occurs within the region of the paracentric inversion,

Dicentric ...a chromosome having two centromeres;

Non-Viable (gametes) Segregate

Acentric …a chromosome having no centromeres, …segregates to daughter cells randomly, or is lost during cell division, …deletions impart partial monosomy.

Pericentric

Recombination and Inversions Paracentric and Pericentric; 1 Normal Gamete, 1 Inverted Gamete, No Crossover Classes = No Recombination, Inversions select against recombinant gametes, thus preserves co-segregation of specific alleles.

Inversions and Evolution Inversions ‘lock’ specific alleles together, all offspring get the alleles from either a wild-type, or inverted chromosome, If the ‘set of alleles’ is advantageous, the set can be maintained in the population.

Terminal Translocation

Reciprocal Translocation

Robertsonian Translocations …the fusion of long arms of acrocentric chromosomes,

Down Syndrome 95% of Down Syndrome individuals are a result of Trisomy 21, the probability of having a second Down Syndrome child is usually similar to the population at large, However, there is second cause of Down Syndrome caused by a Robertsonian translocations that is heritable.

Structural abnormalities Robertsonian Translocation Reciprocal Translocation

Reciprocal translocations An exchange of material between two different chromosomes is called a reciprocal translocation. When this exchange involves no loss or gain of chromosomal material, the translocation is 'balanced' and has no phenotypic effect. Balanced reciprocal translocations are relatively common, occurring in 1 in 500 of the general population.

Reciprocal translocations Finding a balanced translocation in one parent indicates a recurrence risk for future pregnancies and antenatal diagnosis by chorionic villus sampling or amniocentesis should be offered as well as testing of relatives.

Reciprocal Translocation

Reciprocal Translocation Robertsonian Translocation

Robertsonian Translocation

Figure 8. 4 Translocation Down's syndrome Figure 8.4 Translocation Down's syndrome. There is a translocation between chromosomes 21 and 14 inherited from a parent

Numerical Aberration Autosomal - Trisomies: 1 ch extra (e.g. trisomy 21-13-18) - Monosomies: 1 ch is missing Sex chromosome - Klinefelter syndrome (47, XXY male) - Turner syndrome (45, XO female)

Overview I. Chromosomal Variations A. Polyploidy B. Aneuploidy II. Syndromes resulting from Aneuploidy A. Trisomy 13 B. Trisomy 18 C. Down Syndrome D. Turner Syndrome E. Klinefelter Syndrome F. XYY Syndrome In particular, we will be investigating polyploidy and aneuploidy, two types of chromosomal variation. We will then look at five syndromes that result from aneuploidy, including occurrence and characteristics of each syndrome.

Numerical abnormalities Trisomy i.e. 47 chromosomes - Trisomy 21 (the extrachromosome is No 21) - Klinefelter syndrome ( 47, XXY male) Monosomy i.e. 45 chromosomes - Monosomy 21 - Turner syndrome (the missing chromosome is X in female : 45, X or 45 XO )

Variations in Chromosomal Number Euploidy – the usual number and sets of chromosomes Polyploidy – the presence of three or more complete sets of chromosomes Aneuploidy – the presence of additional chromosomes or missing individual chromosomes Euploidy is the presence of the usual number of chromosomes in a cell. In the case of humans, there are generally two sets of 23 chromosomes or 46 total chromosomes in cells. However, in variations of chromosomal number, there can be differences. For example, polyploidy is the presence of three or more complete sets of chromosomes in a cell. Another example of a chromosomal alteration is aneuploidy, the presence of additional chromosomes or missing individual chromosome. (1)

Types of Polyploidy Triploidy – three sets of chromosomes 23 x 3 = 69 Tetraploidy – four sets of chromosomes 23 x 4 = 92 There are two main types of polyploidy, triploidy and tetraploidy. Triploidy is the presence of three sets of chromosomes. This means that the total number of chromosomes in a triploidy cell would be 23 chromosomes per set multiplied by 3 sets or 69 total chromosomes. Tetraploidy is the presence of four sets of chromosomes or 92 chromosomes total. (1) In a cell, each chromosome can have 100 to 1000 genes. Cells with triploidy can have from 6900 to 69000 genes which is significantly more than the 4600 to 46000 genes in the usual cell. Cells with tetraploidy can have from 9200 to 92000 genes, double the genes found in typical cells. (1) Because of such an extreme difference in the amount of genetic material as compared to the usual amount, cases of triploidy and tetraploidy have severe effects. Babies with triploidy (referred to as triploidy syndrome) are usually lost through miscarriage. In rare cases, infants have survived up to five months with multiple birth defects present. Those that survive usually have some cells with a typical number of chromosomes (46 chromosomes) and some cells with the extra set (69 chromosomes). Babies with tetraploidy have an even rarer chance of surviving birth. (2)

Types of Aneuploidy Monosomy – one less chromosome (23 x 2) – 1 = 45 Trisomy – one additional chromosome (23 x 2) + 1 = 47 There are also two main types of aneuploidy, namely monosomy and trisomy. Monosomy is the absence of only one chromosome, leaving the affected individual with 45 chromosomes instead of 46. Trisomy is the presence of an additional chromosome, or 47 chromosomes instead of the typical 46. (1)

Aneuploidy When aneuploidy occurs in humans, syndromes can result. Examples include the following: 1. Trisomy 13 2. Trisomy 18 3. Down Syndrome 3. Turner Syndrome 4. Klinefelter Syndrome 5. XYY Syndrome It is possible for babies with monosomy or trisomy to survive. In many cases, there are certain characteristics associated with aneuploidy, depending on which chromosome(s) are affected and the severity of the affected chromosome(s). Characteristics also vary depending on the number of cells that have the chromosomal variation. If very few cells have the variation, severity will be minimal. If most have the variation, severity will be much greater. (3) When an individual has a particular karyotype as well as specified characteristics, their condition is defined as a syndrome. Some examples of aneuploidy associated syndromes include Trisomy 13, Trisomy 18, Down Syndrome, Turner syndrome, Klinefelter Syndrome, and XYY syndrome. The remainder of the presentation will discuss these syndromes and their features. (1)

Trisomy of Autosomes Trisomy 13 or D-trisomy (Patau syndrome) Trisomy 18 or E-trisomy (Edward syndrome) Trisomy 21 or G-trisomy (Down syndrome)

Trisomy 13 (Patau Syndrome) 1st described by Bartholin (1657) & redefined by Patau (1960). Chromosomal complement: 47,XX,+13 (female) or 47,XY,+13 (male) Phenotype: Male or female Incidence: 1:12,000 (increases with the age of mother)

Patau syndrome

Features of Patau Syndrome Mental deficiency Low birth weight Abnormal development of frontal lobe Absence of corpus callosum Hypoplasia of cerebellum Sloping forehead Scalp defects Malformed ears Congenital heart defects Renal tract anomalies Microphthalmia Bilateral cleft lip/palate Polydactyly with rudimentary digits Rocker-bottom heel

Patau syndrome

Trisomy 18 (Edward Syndrome) Chromosomal complement: 47,XX,+18 (female) or 47,XY,+18 (male) Phenotype: Male or female Incidence: 1:8000

Features of Edward Syndrome Mental deficiency Growth retardation Prominent occiput with elongated head Webbing of the neck Short sternum Micrognathia Low-set malformed ears Ventricular septal defects Renal anomalies Clenched fists with overlapping of fingers Hypoplastic nails

Trisomy 18, Edward Syndrome Overlapping of the fingers inEdwards' syndrome Short broad hand

Edward syndrome

Pathogenic mechanisms Disruption Involves destruction of a fetal part which initially formed normally; e.g. amniotic membrane rupture may lead to amniotic bands which may cause limb reduction defects. Dysplasia Refers to abnormal cellular organization or function of specific tissue types, e.g. skeletal dysplasias and dysplastic kidney disease.

Down Syndrome Chromosomal Variation – Trisomy 21 (three copies of chromosome 21) Occurrence – 1 in 800-1000 Cardiofaciocutaneous Syndrome Antimongoloid slant

Down Syndrome (Mongolism) Trisomy 21 Incidence : The most common chromosomal aberration Incidence 1/700 live birth & 10 % of M.R. Definition : It is trisomy 21 i.e. the cell contain an extra chromosome, number 21 i.e. the cell contains three 21 chromosomes instead of two .

Genetic types (Cytogenetics) (1) Non-disjunction : “ 95 % of cases” It is due to failure of disjunction of the 2 chromosomes of the pair No 21 during division, the extra 21 chromosome is separate and so total no. in cell is 47. Incidence is higher with increasing maternal age & so it is age-dependent

Non-disjunction

Genetic types (Cytogenetics) Translocation : “ 4 % of cases” The extra 21 chromosome is translocated (attached) to another chromosome e.g. (15/21) so total no. of chromosomes is 46 but the genetic material is that of 47 chromosomes . Incidence is usually in young mothers & risk of recurrence is high & mother is called translocation carrier

Down syndrome Translocation carrier One parent contains a 14/21 translocation and has only 45 chromosomes, and is a phenotypically normal carrier. 1/4 of the individual's gametes will have almost 2 copies of chromosome 21. The resulting zygote has 46 chromosomes, but almost 3 copies of chromosome 21, and exhibits Down syndrome.

Translocation carrier Recurrence Risk ??

Genetic types (Cytogenetics) Mosaicism : “ 1 % of cases” Some cells are normal (46 chromosomes) & others are trisomic (47 chromosomes) Clinical feature are less evident & M.R. is mild . Characteristic physical features (in the absence of mental retardation, they should NEVER be considered diagnostic)

Clinical Features Hands Simian crease (transverse palmar crease) Clinodactly (incurved little finger) Short broad hand Feet Big space between the first and second toes

Simian Crease, Trisomy 21 Down syndrome Brushfield spots Gap between first and second toes Simian Crease, Trisomy 21

Micrognathia Low set Ears Clinodactyly

Features of Down Syndrome Short height Severe mental deficiency with decline in the IQ with age Brachycephaly with flat face and occiput Flat and low nasal bridge Upward slant to palpebral fissures Malformed large ears Epicanthal folds of the eyes Brushfield spots in iris Renal anomalies Prominent and protruding tongue (scrotal tongue) Simian crease Clinodactyly of 5th digit

Down Syndrome

Klinefelter Syndrome Trisomy of sex chromosome - XXY (An additional X chromosome in males) Occurrence – 1 in 500-1000 males Kilinefelter syndrome can occur as the result of an individual having one Y and two X chromosomes instead of one of each. The occurrence of Klinefelter’s is estimated to be one in 500 to 1000 males, making it one of the most common sex chromosome disorders. (10,11)

Features of Klinefelter Syndrome Tall , Comparatively low weight relative to stature Infertility , Sexually underdeveloped Sparse facial and body hair Developmental delays Increased risk of autoimmune disorders, breast cancer, osteoporosis, leg ulcers, depression, and dental problems Larger craniofacial dimensions Severe acne in adolescence Behavior problems Learning disabilities Slightly lower IQ than normal Characteristics normally associated with Klinefelter syndrome include being tall, sexually underdeveloped, and infertile, though in some case testicular function is preserved. Sparse facial and body hair is also a common characteristic. Klinefelter’s can also cause delays in speech and motor skills as well as deficits in attention, auditory processing and social skills. Learning disabilities, anxiety, and depression can also result. Treatment for these problems includes testosterone therapy and assisted learning. Finally, people with Klinefelter’s have an increased chance of certain health problems including autoimmune disorders such as type II diabetes, breast cancer, osteoporosis, leg ulcers, depression, and dental problems. (10,11)

Klinefelter syndrome

Turner syndrome Cytogenetics: 45, XO, FEMALE Incidence: 1/5000 Features Lymphedema of hands and feet in newborn Short stature Webbing of neck Wide carrying angle Gonadal dysgenesis (1ry amenorrhea) Renal anomalies and cardiac anomalies

Turner Syndrome

Turner Syndrome, webbed neck Lymphedema

Turner syndrome (Gonadal Dysgenesis) At Birth .. Edema of dorsum of hand & feet .. Webbing of neck. Childhood period - Short stature - Head .. Low posterior hairline - Neck .. Webbing of the neck - Chest .. Broad chest & wide spaced nipples - Limbs .. Cubitus valgus

Turner syndrome Adolescence - Failure of development of 2ry sex characters - 1ry amenorrhea (streaked ovary) - Normal mentality, Some learning disability Associated anomalies & complications: 1- Cardiac anomalies: Bicuspid aortic valve – AS - coarctation of aorta 2- Renal anomalies: Horseshoe kidney 3- Ear: Recurrent OM – SNH loss

Thank you…..