MBM - Genetics

Fundamental Mechanisms and cellular processes : Operative Development

1. Gene regulation by TFs 2. Cell-cell signaling by direct contact and by morphogen 3. Induction of cell shape and polarity 4. Cell Migration 5. Programmed cell death

Pattern Formatino and HOX GENES

- Action and Arrangement of HOX Genes - Determination of developmental fate - Unique combinations of HOX gene expression - Small group of cells in particular regions - Number of HOX genes from different clusters used - HOXA and HOXB -> rostral-caudal axis - HOXA and HOXD -> regional identity along the axes of the developing limb - Order of genes in cluster parallels position in embryo in which the gene is expressed - Co linear with timing and location of expression - Illustrates important principles - Genomic organization correlates with function during development - Valproic acid an antiepileptic drug disrupts the expression of HOX genes.

Alzheimer Disease

- Fatal neurodegenerative disease - Most common adult onset neurodegenerative disorder - Affects 1.4% of individuals in developed countries - Presents typically in 6th -9th decade - Clinical features include - Progressive deterioration of Memory Higher cognitive functions - Behavioral changes - Cause: Degeneration of neurons in specific regions of cerebral cortex and hippocampus - Most important pathological abnormalities -Amyloid /senile plaques - Extracellular depositions of mainly Aβ42 and apoE Neurofibrillary tangles -> intracellular (intraneuronal) - Hyperphosphorylated Tau protein - Tau protein promotes assembly and stability of microtubules . Hyperphosphorylation impairs microtubule stability Note: Mutations are not associated with AD -Amyloid Precursor Protein (βAPP) - βAPP - Single pass transmembrane protein - 10% by β-secretase and γ-secretase - Production of either nontoxic Aβ40 or neurotoxic Aβ42 - Normally little Aβ42 is produced - Mutations in secretase genes lead to - Increased production of Aβ42 peptide - Accumulation -> neurotoxicity - Patients with Down syndrome - Early onset of AD by age 40 - 3 copies of βAPP gene - Aβ42 increased in serum of individuals with mutations in βAPP - Four genes are associated with Alzheimer disease (AD) - APP, PSEN1, PSEN2, ApoE - Mutations in 3 of these lead to AD - APP -> encoding βAPP - PSEN1 -> presenilin 1 - PSEN 2 -> presenilin 2 - The more common late-onset form (after age 60) shows familial aggregation and relative risk of complex inheritance - Role of ε4 Allele of apoE -> predisposes to early onset of AD when homozygous - ε4 allele is a major risk factor for development of AD - 40% of patients with AD have the allele - Associated with earlier age of onset 10-15 years earlier - Relationship between ε4 allele and disease is dose dependent - Carriers of ε4 allele also have poor outcomes after - Head injury - Stroke - Other neuronal insults - No role for screening for apoE ε4 - Poor positive and negative predictive values

Limitations in Twin Studies

- Random X chromosome inactivation - Somatic DNA rearrangement - Differences in environmental exposure - Fetal development - Averaging - Volunteer-based ascertainment

Hemoglobin Electrophoresis

-A blood test that can detect different types of hemoglobin -Individuals heterozygous to HbS show 2 bands on electrophoresis (one for HbA & other for HbS)

Acrocentric -Chromosomes 13,14,15,21,22 are acrocentric

-A chromosome in which the centromere is located quite near one end of the chromosome -Chromosomes 13,14,15,21,22 -These chromosomes are involved in ROBERTSONIAN TRANSLOCATIONS

Trinucleotide repeat expansion Fragile X Syndrome - (CCG)n >200 *5' UTR of FMR 1 Friedreich Ataxia - (GAA)n >200 *INTRON of FRDA Huntington Disease - (CAG)n >75 *Mid Exons of HD Myotonic Dystrophy 1 - (CTG)n >50 *3' UTR of DMPK

-3 nucleotides are repeated in tandem -The repeats get amplified Egs. FRAGILE X SYNDROME (Maternal transmission bias): *FRIEDRICH ATAXIA (Maternal transmission bias) *MYOTONIC DYSTROPHY 1 (Maternal transmission bias) *HUNTINGTON DISEASE (Paternal transmission bias) *Spinocerebellar ataxia (Polyglutamine tract)

Sex Chromosomes

-A chromosome involved with determining the sex of an organism -They have: 1. PSEUDOAUTOSOMAL REGION -These regions on both the X and Y chromosome are homologous 2. DIFFERENTIAL REGIONS -These regions on either the X or Y chromosome contain HEMIZYGOUS GENES specialized to that chromosome type (X or Y) -These are the regions that have the X-LINKED or Y-LINKED GENES

Charcot-Marie-Tooth Disease -Duplication of Region in 17p12

-A hereditary DEMYELINATING PERIPHERAL SENSORY & MOTOR NEUROPATHY and peroneal muscular atrophy -Caused by DUPLICATION of a region in 17p12 -Results in increased dosage of PMP22 (Peripheral myelin protein 22) gene in chromosome 17p -Increased dosage of PMP22 causes demyelinating peripheral neuropathy -(Reciprocal deletion of the same region in its homologous chromosome (17p12) results in HEREDITARY NEUROPATHY with LIABILITY TO PRESSURE PALSIES (HNLPP)

Tetraploidy

-A temporary pattern of tetraploidy may be seen during normal cell cycle -Otherwise it may be due failure of completion of an early mitotic division of Zygote

Polysomic Aneuploidy

-A type of Aneuploidy -Addition of one or more chromosome to a diploid set. Addition of one chromosome is called as Trisomy (2n+1)

Monosomic Aneuploidy

-A type of Aneuploidy -One chromosome of a pair is missing in a diploid set - 2n-1

Nullisomic Aneuploidy

-A type of Aneuploidy -One pair of chromosome in a diploid set is missing - 2n-2

Philadelphia Chromosome

-A type of RECIPROCAL TRANSLOCATION -Philadelphia chromosome arises in BONE MARROW CELLS (somatic) and is NOT TRANSMITTED TO OFFSPRING -ABELSON MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL gene (a proto-oncogene) located on chromosome 9. *ABL1 is a TYROSINE KINASE -Breakpoint cluster region protein (BCR) is coded by the BCR gene on chromosome 22, the function of which is not fully understood -When the reciprocal translocation between chromosomes 9 and 22 take place, a fusion gene, BCR-ABL is created which encodes a fusion protein which has tyrosine kinase activity which is continuously active resulting in uncontrolled cell division

Inversions

-A type of chromosome rearrangement -An inversion is a result of TWO BREAKS in a CHROMOSOME -First a fragment is cut off, followed by the reinsertion of the same fragment in the same region of chromosome, but in inverted order -Two types: 1. PARACENTRIC INVERSION: -NOT INVOLVING THE CENTROMERE (both breaks in one arm) -HARD TO RECOGNIZE cytogenetically because arm ratio (sizes) not altered -Crossing over could lead to a chromosome having 2 centromeres, this is inviable 2. PERICENTRIC INVERSTION: -CENTROMERE INVOLVED (breaks involve both arms) Easier to recognize because arm ratio (sizes) altered -Carriers of inversion are generally unaffected, since they do not lose genetic materials -However, this inverted chromosome can give rise to unbalanced gametes & thereby may affect the offspring -PERICENTRIC INVERSIONS leads to the production of unbalanced gametes with either duplication or deletion of genetic information

Ring Chromosomes

-A type of chromosome rearrangement -DELETION occurs at both tips of the chromosome -Resulting new ENDS THEN FUSE to form ring chromosome -If it occurs in a female X chromosome, the karyotype is; 46, X,r(X) -Ring chromosomes are often lost -Loss of ring X chromosome results in TURNER SYNDROME (45 X)

Isochromosome

-A type of chromosome rearrangement -Sometimes a chromosome divides along the axis but PERPENDICULAR to its usual axis of division -Arise from ABNORMAL CENTROMERE DIVISION -The centromere goes to only one arm and the arm without the centromere is lost -This results in the formation of a chromosome with TWO COPIES OF ONE ARM and no copy of the other -The arm with the centromere duplicates and forms the whole chromosome with duplication of genetic material -Isochromosome formed with the long arm (q) of the X chromosome gives rise to the karyotype 46,X, i(Xq) -This genotype pattern is associated with a few cases of TURNER SYNDROME (instead of 45 X)

Translocations

-A type of chromosome rearrangement -Three types of translocations are observed: 1. RECIPROCAL TRANSLOCATIONS 2. ROBERTSONIAN TRANSLOCATIONS 3. INSERTIONS - rare observation *Insertion is a type of non reciprocal translocation that occurs when a segment removed from one chromosome is inserted into a different chromosome -The chromosomes involved are OFTEN NON HOMOLOGOUS, particularly for the reciprocal and Robertsonian translocations

Teratogens

-ALCOHOL -Aminoglycosides (Gentamycin) -Aminopterin -Antithyroid agents (PTU) -Bromine -Cigarette smoke -Cocaine -Cortisone -Diethylstilbesterol (DES) -Diphenylhydantoin -Heroin -Lead -Methylmercury -Penicillamine -RETINOIC ACID (Isotretinoin, Accutane) -Streptomycin -Tetracycline -THALIDOMIDE -Trimethadione -Valproic acid -Warfarin -Ionizing radiation (X-rays) -Hyperthermia -Infection with microorganisms *Coxsackie virus *Cytomegalovirus *Herpes simplex virus *Parvovirus *Rubella (German measles) *Toxoplasma gondii (toxoplasmosis) *Treponema Pallidum (syphilis) -Metabolic condition in the mother *Autoimmune disease (including Rh incompatibility) *Diabetes *Dietary deficiencies *Malnutrition *Phenylketonuria

Hb Kempsey

-AUTOSOMAL DOMINANT -Caused by point mutation in β globin gene → resulting in replacement of ASPARTATE & ASPARAGINE at residue 99th position in β globin chain. -Locks hemoglobin into relaxed (R) conformation -Exhibits higher affinity for O2 -Impairs O2 delivery to tissues -POLYCYTHEMIA

Methemoglobinemia caused by Hb Hyde Park (Hb M)

-AUTOSOMAL DOMINANT inheritance -Caused by point mutation - HISTIDINE is replaced by TYROSINE at 92 position in β globin chain -Methemoglobin is the one where Heme iron exists in oxidized ferric form (Fe3+) -Methemoglobin cannot bind O2 -Methemoglobinemia results in cyanosis -A small amount of Methemoglobin formed in normal individuals is coverted back to normal Hb by NADH - metHb REDUCTASE -In Hb M (due to genetic defect) heme pocket is affected in such a way that the enzyme NADH - metHb reductase is incapable of reducing ferric iron into ferrous iron -Homozygous state is presumed to be lethal -Acquired methemoglobinemia - may be due to administration of NITRATE DRUGS (treatment of Angina) -Acquired methemoglobinemia may be treated with METHYLENE BLUE (to convert MetHb back to normal Hb)

Hb Hammersmith

-AUTOSOMAL DOMINANT mode of inheritance -Mutation in β globin, PHENYLALANINE -> SERINE at 42nd position -Phe at 42nd position is required to wedge heme into its pocket -Its replacement with serine (small residue) causes dropping out of heme from heme pockets -The resulting Hb is unstable with lower O2 affinity -Forms inclusion bodies (Heinz bodies) Results Hemolysis and Cyanosis

Hemoglobin S (Sickle Cell Anemia)

-AUTOSOMAL RECESSIVE mode of inheritance -Sickle cell disease in HOMOZYGOUS INDIVIDUALS -Single nucleotide substitution in β globin gene (point mutation) -> changes 6th amino acid on β chain from GLUTAMATE to VALINE -This results in loss of a negative charge -DECREASED SOLUBILITY of the HbS under low pO2 -HbS polymerizes into ROD SHAPED FORM -Distorts shape of RBC to sickle shape -RBC unable to squeeze through capillaries -vascular occlusion -Hemolysis -Pain

Prevalence of heterozygous HbS

-About 8% among African Americans -Up to 25% among the population of central Africa -Heterozygous state of HbS confers MALARIA RESISTANCE to the individuals -Heterozygotes: *Are clinically normal in general *RBC may become sickle shaped at VERY LOW OXYGEN TENSION *Risk of splenic infarction while flying at high altitude with reduced cabin pressure of aircraft

Hemoglobin C -HbS - Is an abnormal hemoglobin in which substitution of a glutamic acid residue with a Valine residue at the 6th position of the β-globin chain HbC - Is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 6th position of the β-globin chain

-Also an example for novel property mutation -Mode of inheritance - AUTOSOMAL RECESSIVE -Mutation in β globin, GLUTAMATE -> LYSINE at 6th position -Hb C is LESS SOLUBLE than Hb A -Crystallizes in RBC (mild sickling) -Cause mild hemolysis in capillaries -More cases among west Africans -Compound heterozygotes (Hb SC disease): also exist -SC diseases (Hb SC) show milder hemolytic anemia than HbS -Hb SC may rarely cause vascular occlusion mainly in retina

Sex Chromosome Aneuploidy

-Among live infants 1/400 males and 1/650 females have some form of Sex Chromosome Aneuploidy -The consequences are less severe than Autosomal Aneuploidy -Generally compatible for survival, the exception being the cases where there is complete absence of X chromosome

Type 1 Diabetes Mellitus (DM)

-Auto immune disease -MZ twin concordance is from 30%-70%, indicating that additional factors are involved -HLA (Human Leukocyte antigen) region on chromosome 6 contains genes that encode the class II MHC (Major HistoCompatibility) molecules which are involved in immune response -Most individuals with type 1 DM have HLA DR3 and/or HLA DR4 haplotype -MHC haplotypes only account for a 1/3 of genetic contribution -> There must be other genes that contribute

Centromere Location

-Based on the position of centromere, the chromosomes are classified into: 1. Metacentric - More or less in the middle 2. Sub metacentric - on either side of the mid point 3. Acrocentric - Near the end (Chromosomes 13,14,15,21,22) 4. Telocentric - At the extreme tip (not present in human system)

Dysformations (Deformations)

-Caused by EXTRINSIC FACTORS -Mainly during SECOND TRIMESTER eg: ARTHROGRYPOSIS (contraction of joints)

Fetal Retinoid Syndrome

-Caused by ISOTRETINOIN -Treatment for severe acne -Severe birth defects when taken by pregnant woman -Mimics action of endogenous retinoic acid

Disruptions

-Caused by destruction of normal fetal tissue (irreplaceable) -Difficult to treat - May result from *Vascular insufficiency *Trauma *Teratogens - eg: AMNION DISRUPTION -May present with partial and irregular digit amputations

Cri-Du-Chat Syndrome -Deletion of part of Chromosome 5p (5p15.2, 5p15.3) -Haploinsufficiency - the phenomenon where a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state

-Caused by terminal or interstitial DELETION of PART OF CHROMOSOME 5P -Example for PARTIAL MONOSOMY -Many of the clinical manifestations are a result of HAPLOINSUFFICIENCY *Many clinical findings due to haploinsufficiency of genes within band 5p15.2, -The affected person has severe intellectual disability, a small head (MICROCEPHALY) -Characteristic appearance of face with HYPERTELORISM (increased distance between the orbits), Epicanthal folds -Low-set ears, Micrognathia -Heart defects -CAT'S CRY (Infant's cry sounds like cat meowing) in early childhood *Cat's cry results from deletion in band 5p15.3

Structural Hemoglobin variant with Thalassemia Phenotypes: Hemoglobin E (HbE)

-Caused due to point mutation, GLUTAMATE is replaced by LYSINE at 26th position in β globin chain -Results in β thalassemia, since mutant β chain (present in Hb E) is synthesized at reduced rate -Hb E affects splicing of β globin mRNA -Many cases of Hb E in Southeast Asia -Hb E homozygotes are generally asymptomatic although mildly anemic

Morphogens and Cell-to-Cell Signaling

-Cell-to-cell communication through signaling mechanisms -Cell surface receptor and ligand *Ligands -> e.g., growth factors (FGF, etc.) *Ligand binding -> activates receptor -> signal transmission -Abnormalities can lead to *Achondroplasia *Craniosysnostoses - Hedgehog -Gene originally discovered in Drosophila -Ability to alter orientation of epidermal bristles -Human homolog -> Sonic hedgehog (SHH) -Diffusion of hedgehog protein -> gradient in concentrations of protein -> surrounding cells assume different fates -Secretion of SHH by notochord and floor plate of the developing neural tube -> development of brain and spinal cord -By cells in the limb bud -> zone of polarizing activity -> responsible for the asymmetrical pattern of digits within individuals -SHH in limb development -Morphogenetic action of the Sonic hedgehog protein during limb bud formation. SHH is released from the zone of polarizing activity (labeled polarizing region in B) in the posterior limb bud to produce a gradient (shown with its highest levels as 4 declining to 2). Holoprosencephaly -Dominant mutation in SHH gene -Failure of the midface and forebrain to develop -Cleft lip and palate -Hypotelorism (closely spaced eyes) -Variable expressivity common *Mild/subtle: single central incisor or partial absence of the corpus callosum *Role of modifier factors suspected Variable expressivity of an SHH mutation. The mother and her daughter carry the same missense mutation in SHH, but the daughter is severely affected with microcephaly, abnormal brain development, hypotelorism, and a cleft palate, whereas the only manifestation in the mother is a single central upper incisor

Basic concepts of Developmental Biology

-Cellular Processes -Human Embryogenesis -Human Fetal Development

R - Banding

-Chromosome staining technique -Chromosomes require special treatment such as heating before staining -The Dark and Light band pattern is the reverse of that observed by G banding -Useful for examining regions that stain poorly by G or Q banding *AT rich regions are selectively denatured by heat, leaving the GC rich regions intact which stain dark, thereby showing a reverse staining pattern compared to G-banding

Giemsa Banding (G-banding)

-Chromosome staining technique -Routinely used Banding technique -Here: 1. Slides with chromosome preparation is treated with TRYPSIN to break chromosomal proteins 2. They are then stained with GIEMSA solution 3. The chromosomes show dark and light bands, which can be viewed through microscope -The dark staining regions (which correspond to the late-replicating AT rich heterochromatin), are more condensed and rich in protein disulfide cross links, because of which, they retain the hydrophobic proteins needed for the dye to bind to DNA - The light staining regions (which correspond to the early-replicating GC rich euchromatin) are less condensed and have their protein sulfur predominantly as sulfhydrils

C - Banding

-Chromosome staining technique -Selectively chosen for staining centromere region and other regions containing constitutive heterochromatin

Q Banding

-Chromosome staining technique -Staining with QUINACRINE MUSTARD or related compounds *Examination by fluorescence microscopy -Bright Q bands correspond exactly to dark G bands (of Geimsa banding technique)? -Useful for detecting HETEROMORPHISMS (variants in chromosome morphology). *Heteromorphisms reflect differences in satellite DNA sequences

Autosomal Aneuploidy

-Clinically the most important type of Aneuploidy -Mainly of two types; Monosomy & Trisomy -Autosomal monosomies are usually incompatible for survival *However, trisomies are seen with appreciable frequencies -Trisomies produce less severe consequences than monosomies -This is probably attributed to the general principle ' The body can tolerate excess of genetic materials than deficit'

Hirschsprung Disease

-Complete absence of some or all of the intrinsic colonic ganglion cells -> -Severe constipation -Intestinal obstruction -Massive colonic dilation -May involve mutations in many different genes

Concordance and Discordance

-Concordance: -Two related individuals in a family have the same disease -Share most of the alleles and have the same disease -Concordance in the presence of differing genotypes can be explained by 1. Genocopy -> Phenotype of a genetic origin mimic a phenotype of a different genetic origin 2. Phenocopy -> An environmentally-induced phenotype mimicking one usually produced by a specific genotype -Discordance: -When only one family member of a pair of relatives is affected i.e although they share the alleles, one is affected, the other one is not -Explanation: Unaffected individual has not experienced the other factors (environmental or chance occurrence) necessary to trigger the disease process and make it manifest

Gene regulation by TFs

-Control gene expression -May activate or repress gene expression -Transcriptional regulatory complex *General TF -> found in (almost) all transcriptional complexes -Specific TF -> only in certain cells or at certain times

Programmed Cell Death

-Critical process in development needed for tissue remodeling -Eg: Separation of individual digits Perforation of anal and choanal membranes Establishing communication between uterus and vagin - DiGeorge syndrome - Conotruncal heart defects deletion of TBX1 gene - Defect in apoptosis

Axis Specification and Pattern Formation

-Critical stage -> determines relative orientation of organs and structures -Embryo: *Cranial-caudal axis (= anterior-posterior) *Dorsal-ventral axis (= up-down) -Sonic hedgehog is important for this axis *Left-right axis -Situs inversus -Abnormality in X-linked gene ZIC3 -Failure of proper formation of left-right axis -Some thoracic and abdominal viscerae on wrong side -Within developing Limb: -Individual cells also have axis polarity -Upon axis determination -> patterning program overlay -Patterning -Division of embryo into segments -Assignment of identity to segments -> head, thorax, etc. -Involves HOX genes -Patterning (skeletal morphology) -Pattern Formation and HOX Genes -HOX genes code for transcription factors "HOX proteins" that are important for developmental identity -Regulate downstream genes -> morphogenesis -Located in the -Originally discovered in Drosophila melanogaster -Gene product contains "homeodomain" motif that binds to DNA -Different species contain different number of HOX genes - Drosophila -> 8 (1 cluster) - Humans -> about 40 (4 clusters, HOXA, B, C, D) -In which of the following organelles HOX proteins perform their functions?

Venous Thrombosis (Gene-Gene-Environment interaction)

-Deep Vein Thrombosis (DVT) -Lower extremities -Mutant allele of factor V (factor V Leiden) -A variant of the clotting factor prothrombin -Environmental factors like trauma, surgery, malignant disease, prolonged immobilization, OCP, advanced age -Heterozygosity of individual gene alone little effect on the recurrence -Need to exercise -Care with regard to prescription of oral contraceptives

Clinical significance of LCR (for β globin gene cluster)

-Deletion at LCR results in failure in expression of cluster of β - globin genes -LCR may be essential during gene therapy in cases where β - globin gene expression is defective -Knowledge of LCR may help in treatment of β THALASSEMIA by stimulating the expression of γ- globin genes and thereby producing HbF

Meiosis

-Division that results in gametes with HAPLOID number of chromosomes -PROPHASE I - where crossing over takes place *Dyads come together in homologous pairs, forming TETRADS *They overlap in a process called SYNAPSIS *Crossing over occurs, causing exchange in segments of DNA *Resulting chromosomes have new combinations of maternal and paternal forms of genes *METAPHASE I - tetrads line up along the metaphase plate *ANAPHASE I - Homologous chromosomes separate (sister chromatids remain together) *TELOPHASE I - Each cell has one of the replicated chromosomes from each homologous pair of chromosomes

Genetic Significance of X Inactivation:

-Dose compensation: -Mosaicism: Due to the presence of both paternal & maternal Barr bodies -Variability of Expression for X linked disorders --- as seen in manifesting heterozygotes of X linked recessive disorders

Escape from X Inactivation

-Even in inactive (transcriptionally) X Chromosome, a few genes are found to be transcriptionally active -These transcriptionally active genes are located mainly in PSEUDOAUTOSOMAL REGION of inactive X chromosome (near the terminal regions) -Thus pseudoautosomal genes are transcriptionally active in both active & inactive X chromomosomes -The active pseudoautosomal genes are present sides in Y chromosome

Different types Hb present from embryonic stage to adult state

-Hb Gower 1 (ζ2ε2) → Embryonic Hb Gower 2 (α2ε2) → Embryonic Hb Portland (ζ2γ2) → Embryonic Hb F (α2γ2) → Fetal (minor in adult, constitutes approx. 1%) Hb A2 (α2δ2) → Adult (minor in adult, constitutes approx. 2% ) Hb A (α2β2) → Adult (major in adult)

Turner Syndrome

-Example for sex chromosomal monosomy, Pattern: 45, X -The individuals are females, 1 in 2500 - 4000 female births -Features: -Short stature, webbed neck -Ovarian dysgenesis -Instead of ovaries these patients have streaks of connective tissues -Do not develop secondary sexual characters -Infertility -Impaired social adjustment -Renal and cardiovascular anomalies -Infantile edema of dorsum of the foot -Lymphedema in fetal life -No Barr bodies in somatic cells with pattern 45,X -About 50% of patients have the pattern of 45, X karyotype, whereas 30 to 40% are mosaics - 45,X/46,XX; 45,X/46,XX/47,XXX; 45,X/47,XXX -About 10 to 20% patients have deletion at X chromosome -About 70 to 80% of the cases are caused by the absence of paternally derived X chromosome -However, if paternally derived X chromosome is present (maternally derived is absent) the Turner syndrome individuals have higher IQ scores and better social adjustment comparatively -In few cases the formation of isochromosome of the long arm of X chromosome (Xi) also causes Turner syndrome- 46,X, i(Xq) -Short stature of Turner syndrome is possibly due to the presence of only one copy of SHOX gene (Active SHOX gene is present in short arm of both the X chromosomes. Besides SHOX gene is also present in Y chromosomes) -Formation of ring chromosome r(X) and its subsequent loss may result in Turner syndrome

Example of Uniparental Isodisomy

-Example for uniparental isodisomy: -A female was found to be clinically affected with cystic fibrosis (homozygous), despite the fact that her father being normal and mother being a heterozygote (carrier). DNA analysis revealed that both the abnormal chromosomes (belonging to No. 7 & having mutation in q arm) were identical & maternally derived -The above pattern is attributed to uniparental isodisomy

Prader Willi Syndrome & Angelman syndrome -Deletion is in q arm of chromosome 15 (15q11.2-q13) -If deletion occurs in paternal copy - Prader -Willi (P = P) -If deletion occurs in maternal copy - Angelman's Syndrome (Mom is an Angel) -Both occur due to deletion of an identical segment on chromosome 15 (15q11.2 - q13), but manifest with different phenotypes

-Examples for MICRODELETION SYNDROMES -DELETION is in q arm of chromosome 15 (15q11.2-q13) -If deletion occurs in paternal copy of chr 15- Prader-Willi If deletion occurs in maternal copy of chr 15- Angelman

Nucleotide Repeat Expansion Nucleotide Repeat Expansion Diseases have primarily neurological phenotypes: - Ataxia - Cognitive defects - Dementia - Nystagmus - Parkinsonism and spasticity

-Expansion of repeating tandem nucleotide units within a coding or non coding region of a gene -Repeat unit often triplet -Quadruplet and pentuplet repeats may be associated with disease phenotype -General features -Genes associated with these diseases all have polymorphic wild type alleles -Dynamic mutations: *Number of repeats can increase beyond the normal polymorphic range *Expansion can occur during DNA replication and genome maintenance (DNA repair) -Anticipation - Appearance of the disease at an earlier age as it is transmitted through a family

Cellular Processes

-Four basic cellular processes during development 1. Proliferation -Growth is carefully regulated -Hyperplasia or hypertrophy -Dysregulation can cause severe deformity and dysfunction Ie. Congenital segmental overgrowth -Here: several toes -Cause: Developmental dysregulation 2. Differentiation 4. Apoptosis -Processes governed by morphogens *Growth factors *Cell receptors *Chemicals -Allow for growth and morphogenesis -Creation of embryo *Normal size and shape *Appropriate organ size, shape, location *Cells and tissues with correct architecture

Inactive X

-Gene expression: Most genes silenced; ~15% expressed to some degree -Chromatin State: Facultative heterochromatin; Barr body -Noncoding RNA: XIST RNA expressed from Xi only; associates with Barr body -DNA replication timing: Late-replicating in S phase

Active X

-Gene expression: YES, similar to male X -Chromatin State: Euchromatin -Noncoding RNA: XIST gene silenced -DNA replication timing: Synchronous with autosomes

Abnormal Hemoglobin that causes Hemolytic Anemia Heinz Bodies: Inclusions within red blood cells composed of denatured hemoglobin

-Generally due to point mutation → results in denaturation of globin tetramer in mature RBC -Denatured tetramers form insoluble inclusion bodies (Heinz bodies) → damage to RBC membrane → hemolysis

α -Thalassemias

-Genetic disorders caused by insufficient or stoppage of α-globin production -Constitute both intrauterine and postnatal disease, since the formation of both fetal and adult Hb are affected -4 copies of α-globin genes are present in chr. 16 -Mutation of one copy - silent carriers -Mutation of 2 copies - heterozygous - may show mild symptoms, common in southeast Asia -Mutation of 3 copies - severe, Hb H disease -Mutation of all 4 copies - Hydrops fetalis - Fetal death, common in southeast Asia -In the absence (deficiency) of α- globin chain unusual chain combinations take place -Hb Bart's - γ4 -Hb H - β4 -Both are ineffective as oxygen carriers -Gradual precipitation of HbH in RBC - Leads to formation of inclusion bodies (Heinz bodies) in RBC - premature destruction - Anemia -High level of Hb H cause severe intrauterine hypoxia and the infant is born with massive fluid accumulation - Hydrops fetalis -Most common forms of α thalassemia are caused due to DELETIONS

β-Thalassemias

-Genetic disorders of β-globin production -Decreased ( or stoppage) β-globin production -Imbalance in globin chain production of Hb -Excess α -globins precipitate in RBC causing RBC destruction -Hypochromic , microcytic anemia -Clinical features seen only a few months after birth because β-globin is important only in postnatal period (to form Hb A) -Elevation of Hb A2 is unique because δ globin production is not affected -Hb F is also increased (because of selective survival)

Multifactorial Inheritance

-Genetics of common disorders with complex inheritance -Diseases that result from the complex interactions between a number of genetic and environmental factors -Multifactorial disorders affect nearly 2/3 of people during their lifetime -Examples include congenital birth defects, MI, cancer, mental illness, diabetes, and Alzheimer disease -Complicated and unknown -"Empirically derived risk figures"

Hereditary Persistence of Fetal Hb (HPFH)

-Hb F is the major Hb at fetal life, constitutes about 70% of Hb at birth -In adult it contributes only about 2% -Synthesis of β chain becomes significant near the time of birth and then continues after birth -HPFH is caused by disruption of perinatal globin switch from γ globin to β globin (Possibly due to the deletion at β globin gene) -Synthesis of δ chain also continues after birth. However the conc. of Hb A2 is kept only around 2% in normal adult -γ Globin gene remains intact, however, thereby continuing post-natal Hb F synthesis and compensating for the deficiency of Hb A Higher production of γ Globin chains results in HPFH

Possible Selective Advantage of the Heterozygous State

-Heterozygotes are less susceptible to the severe malaria caused by the parasite Plasmodium falciparum -This organism spends an obligatory part of its life cycle in the RBC -These erythrocytes have shorter life span than normal -Parasite cannot complete the intracellular stage of its development -Compounds that increase the production of HbF: 1. Hydroxyurea (Hydroxycarbamide): 2. Decitabine (a cytidine analogue): -This drug stimulates the gene coding for the synthesis of HbF (by hypomethylation) -Presence of fairly high level of HbF inhibits severity of complications of sickle cell anemia (HbS) -Coexistence of HbF is also reported to reduce the severity of complications in β- thalassemia

Malformations

-INTRINSIC ABNORMALITIES in one or more genetic programs in development -Often but not always associated with malformations in other organs -Eg: GREIG CEPHALOPOLYSYNDACTYLY *LOF mutation of a transcription factor GLI3 *Involved in hand development *Insertional polydactyly *Postaxial polydactyly with severe cutaneous syndactyly of digits two through five

Y Chromosome

-Inherited from father to son -Human Y chromosomes contain over 50 genes (Holandric genes), code for about 23 different proteins -Examples: i) SRY gene located at its p arm. It codes for TESTIS DETERMINING FACTOR (TDF) ii) AZF genes, the mutation of which leads to azoospermia & oligospermia iii) Pseudoautosomal genes

Fetal Alcohol Syndrome

-Involves primarily CNS -Alcohol more toxic to developing brain than to other structures

Patau Syndrome (Trisomy 13)

-Karyotype Pattern: 47, XY +13 and 47, XX +13 -Prevalence: 1/12000 to 20000 live births (approx) -Features: -Growth retardation & intellectual disability -Holoprosencephaly -Sloping forehead, Microcephaly & wide sutures -Cleft lip, cleft palate & microphthalmia. -Post axial polydactyly in hands & feet, fist clench, rocker bottom feet -Cardiac and urogenital abnormalities -Survival rate is almost similar to trisomy 18 -About 80% of cases are due to conventional trisomy, remaining cases mainly due to chromosomal translocation -Caused mostly by maternal nondisjunction (usually during meiosis I) -Maternal age dependent

Edwards Syndrome (Trisomy 18)

-Karyotype: 47, XY +18 or 47,XX +18 -Prevalence: 1/6000 to 8000 live births -Features: -Intellectual disability & failure to thrive -Hypertonia -Clenched fist with overlapping fingers -Feet with rocker - bottom appearance -Head has prominent occiput -Short sternum -Severe heart malformation - Ventricular -Septal defect, Atrial septal defect & Coarctation of the aorta -Postnatal survival is very poor (usually < 1 yr) -Most children are not able to walk -More than 95% of Edwards syndrome children have complete trisomy 18. Only a few incidences of mosaicism -Over 90% of cases are caused by non disjunction during meiosis in mother -Maternal age dependent

Trisomy XYY

-Karyotype: 47, XYY -Incidence: 1 in 1000 male births -Generally not associated with any obvious phenotypic abnormalities -Relatively taller and have reduced IQ Minor behavioral disorders, such as attention deficit, hyperactivity and learning disabilities -Sexual development normal

Other forms of α- Thalassemia

-Less common 1. Due to ZF deletion: -Leads to transcription of an antisense RNA which in turn silences α 2 globin gene 2. ATRX syndrome (α thalassemia associated with intellectual disability): -Due to mutation in X- linked ATRX gene *ATRX gene codes for a chromatin remodeling protein required for normal expression of α- globin genes -Mutation leads to α thalassemia

Regulation of β-Globin Gene Expression

-Locus control region (LCR) present upstream to β -globin gene plays a significant role in the expression of all members of β-Globin gene cluster in CHROMOSOME 11 -It facilitates access for transcriptional factors to bind at regulatory elements -It facilitates the expression of all the genes of β- gene cluster during globin switching

Tetranucleotide Repeat Expansion Diseases

-MYOTONIC DYSTROPHY 2 *(Genocopy of myotonic dystrophy 1)

Disease Concordance of MZ vs DZ Twins

-MZ and same-sex DZ twins -Share a common intrauterine environment & sex -Usually raised together in the same household by the same parents -Comparison studies will show how frequently disease occurs when relatives share the environment but have only 50% of their genes common -"Greater concordance in MZ vs DZ is strong evidence of a GENETIC COMPONENT to the disease"

Disease Concordance in MZ Twins Reared Apart

-MZ twins with identical genotypes reared in different environment -Important in psychiatric disorders, eating disorders etc - eg; Alcoholism

Cell Shape and Organization

-Many cells need to organize themselves in their microenvironment -Polarity -> apical, basolateral part - Eg: Renal tubule cells -> reabsorption of solutes -Mediated by cilia -> sense fluid flow -Adult polycystic kidney disease (PKD) -Loss of function (LOF) of one of two protein components of primary cilia -Polycystin 1 or polycystin 2 -Failure to sense fluid flow -Cells continue to proliferate -No polarization -Formation of cysts (fluid filled spaces) lined by renal tubular cells

"Familial Aggregation" (Cluster) -The clustering of certain traits, behaviors, or disorders within a given family

-May not be totally because of genetic contribution -May be due to sharing of environmental factors - Ethnicity (cultural attitudes) - Food habits - Exposure to environment - Behaviors - Socioeconomic status - May be due to a chance

Twin Studies

-Monozygotic twins -Cleavage of a single fertilized zygote into 2 separate zygotes early in embryogenesis -Share same alleles at every locus -Always same sex -Mostly share same environment -Dizygotic twins -Simultaneous fertilization of 2 eggs by 2 sperms -Share, on average, 50% of the alleles at all loci -Share a womb -Not always same sex -Mostly share same environment -Siblings -A pair of siblings inherits the same 2 alleles at a locus 25% of the time, no alleles in common 25% of the time and 1 allele in common 50% of the time -Mostly share same environment

Synpolydactyly and HOXD13 Mutations

-Mutations usually caused by expansion of polyalanine tract *Normal: 15 alanines *Mutant: 22-24 alanines

Disruption of Limb Development Associated with Amniotic Bands

-Nearly complete disruption of thumb -Third and fifth digit -> constriction rings -Fourth digit -> distally amputated

Down Syndrome (Trisomy 21)

-Most common trisomy -Chromosomal Karyotype: 47, XY +21 or 47, XX +21 -Prevalence: 1 in 850 live births -Most of the conceptions are spontaneously aborted, thus risk of producing affected live child is considerably lower -Only 20 - 25% of trisomy 21 conceptuses survive to birth -Phenotypic Features: *Characteristic appearance of Face (MONGOLOID appearance), Slanting eyes, small open mouth with a protruding tongue, Flat nasal bridge -Hypotonia (Decreased muscle tone) -Short stature -Single transverse crease in the palm of the hand -Wide gap between 1st & 2nd toes -Incurved fifth digits (clinodactyly) -Moderate to severe intellectual disability -Several patients have structural heart defects -Increased risk for hypothyroidism -Increased risk for leukemia -Characteristic neurological complications of Alzheimer disease appear much earlier in life in Down syndrome patients compared to general population -Survival rates of Down syndrome children are significantly lower- possibly due to CONGENITAL HEART DEFECTS -However, the survival rate is better in recent years because of medical care -Approx. 95% of Down Syndrome cases are caused by nondisjunction, 47, XX/XY + 21 -In more than 90% of cases nondisjunction occurs in the mother (predominantly during meiosis I) & 10% cases paternal nondisjunction (mostly during meiosis II) -Risk for having a child with trisomy 21 increases with maternal age, especially >30 yrs of age -Amyloid precursor protein gene is located on chromosome 21 -Congenital malformations such as duodenal atresia and tracheoesophageal fistula are more common in Down syndrome than in other disorders -About 4% of DS patients exhibit Robertsonian translocation (usually involving Chr.14 & 21) - they are trisomic with respect to the genes present in q arm of chr.21 -Translocation Down syndrome shows no relation to maternal age but has a relatively high recurrence rate in families, when a parent, especially the mother, is a carrier of the translocation -MOSAICISM is seen in approx. 2% of trisomy 21 live births -These individuals have some normal & some trisomy 21 somatic cells -Karyotype: 47 XX +21/46 XX, or 47 XY +21/46 XY -Here clinical manifestations are milder, comparatively -The most common cause of mosaicism in trisomy is - trisomic conception followed by loss of extra chromosome in some cells during embryonic development -A small % of patients with Down syndrome have a 21q21q translocation chromosome, in which the q arm of chromosome 21 is present in duplicate (thought to originate as an isochromosome) and along with a normal chromosome 21 results in trisomy for the genes present in q arm of chromosome 21. -Partial trisomy 21: rarely, Down syndrome is diagnosed in a patient in whom only a part of the long arm of chromosome 21 is present in triplicate.

Neural Tube Defect

-Multifactorial Congenital Malformation (MCM) - Anencephaly - Still born with absent forebrain, overlying meninges, vault of the skull, and skin - Spina bifida - Failure of fusion of the arches of the vertebrae. - Varying degrees of severity - Maternal Folic Acid deficiency is the single greatest factor causing NTD Cleft Lip and Cleft Palate - One of the most common congenital malformations - Failure of fusion of the frontal process with the maxillary process - Nonsyndromic, sporadic form displays familial aggregation - Recurrence risk in family increases if more relatives are affected or the proband has more severe disease phenotype - Maternal smoking during pregnancy is risk factor Congenital Heart Defects (CHD) - Frequency of about 4-8/1000 births - Heterogenous group (single gene or chromosomal mechanism) that is believed to be multifactorial

Pleiotropy: Syndrome

-Multiple abnormalities in PARALLEL -Ie. BRACHIO-OTO-RENAL DYSPLASIA SYNDROME -Ie. RUBENSTEIN-TAYBI SYNDROME

Congenital Arthrogryposis with Amyoplasia:

-Multiple symmetrical joint contractures due to abnormal muscle development -Severe fetal constraint complicated by oligohydramnios -Normal intelligence -Orthopedic rehabilitation frequently successful

Hb variants with Altered Oxygen Transport

-Mutation impairs oxygen binding/release -Generally have little effect on stability -Examples: Hb Kempsey Hb Hyde Park (Hb M) that causes Methemoglobinemia

Myotonic Dystrophy (Dystrophia Myotonica) (DM) Myotonic Dystrophy 1 - (CTG)n >50 *3' UTR of DMPK

-Mutations in 3'-UTR -> Novel properties on RNA - Mode of inheritance -> AD - 2 types: DM1 and DM2 -Reduced penetrance, Pleiotropy and variable expressivity common - Mutated gene - DMPK (Myotonic Dystrophy Protein Kinase)/ Myotonin - Located on chromosome 19 - Mutational Mechanism: - CTG repeat expansion at 3' UT region -> affects mRNA stability and "quenches" RNA-binding proteins - The most pleiotropic phenotype of all the repeat expansion diseases. - Severity and age of onset correlated with repeat size (Anticipation) - Clinical features: 1. Most frequent muscular dystrophy of ADULT LIFE - Progressive neuromuscular weakness and wasting of muscle with myotonia - Myotonia -> electrophysiological disturbance -> delayed relaxation and muscle stiffness - Cardiac conduction defect and cardiomyopathy - Disturbed GI peristalsis - Lack of facial expression - Frontal balding - Testicular atrophy 2. CONGENITAL FORM - Infants present with hypotonia - Respiratory distress (can be life threatening) - Surviving infants show myotonic faces - Lack of facial expression - Tented upper lip with fish mouth appearance - Mild mental retardation -Hatched-like faces -ASSOCIATED WITH: - Anticipation - Maternal transmission bias

Fragile X Syndrome -(CCG)n >200 -5' UTR of FMR 1

-Mutations in 5'-UTR -> impairing transcription -X-linked disorder with reduced penetrance -Frequency -> 1 in 4000 (males) -Second most common cause of moderate mental retardation in males -CGG triplet repeat expansion in the 5' untranslated region (5'UTR) of the first exon of FMR1 (Fragile X mental retardation 1) gene -Name due to a cytogenetic marker on X chromosome at Xq27.3 -> "fragile site" where chromatin fails to condense properly during mitosis -A small gap near the tip of X chromosome -Lymphocytes, folate-free media culture - Normal function of FMR Protein: *RNA-binding protein *Associates with polyribosomes to suppress protein synthesis *RNA targets appear to be involved in cytoskeletal structure, synaptic transmission, and neuronal maturation -Mutational Mechanism: *CGG repeats in 5' UTR (promoter) -> Hypermethylation -> "Gene Silencing" -> No FMR1 mRNA -> No FMR1 protein -Maternal transmission bias -Increased risk of mental retardation in grandchildren of normal males with premutation Clinical Features: A. PREPUBERTAL: -Developmental delay, -Abnormal temperament:tantrums, -hyperactivity, autism -Mental retardation: IQ 40-85 -Abnormal craniofacies: long face, -prominent forehead, large ears, -prominent jaw, cleft palate -Flat feet B. POSTPUBERTAL: -Macro-orchidism -Abnormal behavior: shyness, gaze aversion -Ophthalmologic: strabismus -Orthopedic: joint, hyperextensibility, C. OTHER: -Cardiac: mitral valve prolapse -Dermatologic: usually soft -and smooth skin

Huntington Disease

-Mutations in coding region -> Novel properties of the encoded protein -Mode of inheritance -> AD - Heterozygous and homozygous individuals equal severity - Homozygotes may have a more rapid progress of the disease - Paternal transmission bias - Juvenile form of HD (70-121 repeats) almost always inherited from an affected father -The expression of mHTT has global effects on the transcriptome suggesting that transcriptional dysregulation is a key feature of HD pathogenesis. mHTT interacts with, and disrupts, major components of the general transcriptional machinery, affecting both general promoter accessibility and recruitment of RNA polymerase II. Studies in pre-symptomatic HD brains have shown that soluble mHTT oligomers interact with and impede the function of specificity protein 1 (SP1), TATA box binding protein (TBP), the TFIID subunit TAFII130, the RAP30 subunit of the TFIIF complex, and the CAAT box transcription factor NF-Y, all of which are important mediators of general promoter accessibility and transcription initiation. -The expression of mHTT also disrupts the activity of histone acetyl transferases (HATs), such as CBP/p300 and p300/CBP associated factor (PCAF), which results in histone hypoacetylation and increased heterochromatin formation. Strategies that utilise histone deacetylase (HDAC) inhibitors to correct transcriptional dysregulation by restoring or enhancing histone acetylation have been shown to ameliorate mHTT toxicity in flies and mice, thereby supporting a central role for transcriptional dysregulation in HD . However, because of the broad action of many HDAC inhibitors and the promiscuous nature of HDAC activity, the precise mechanisms by which these molecules influence mHTT toxicity remain unclear .Yet, genetic studies in flies and worms suggest HDACs 1 and 3 are required for mHTT toxicity and could be the primary targets of HDAC inhibitors .function - Mutational mechanism: ]- CAG nucleotide repeat expansion in the coding region of the huntingtin gene - Normal gene product -> Huntingtin. - Widely expressed - Carries polyglutamine tract - Abnormal gene product (mutant Huntingtin protein/mHTT) - CAG repeat translated into stretch of glutamine residues - When expanded - Increased interaction with transcriptional regulators including TATA box binding protein - Changes transcription of many proteins - Huntington Disease -Clinical Features -Age dependent penetration, depending on repeat size - Mean age of onset is about 40 - Early signs and symptoms -> Minor motor abnormalities - Clumsiness - Hyperreflexia - Eye movement disturbances - Gradually progression to: - Involuntary movements - Chorea (most prominent) - Parkinsonism - Dystonia - Involuntary motor impairment - Progressive dementia - Psychological disturbances - Mood disorder and personality changes - Cellular hallmark of disease - Insoluble aggregates of mutant proteins (inactive) and other polypeptides clustered in nuclear inclusions - Normal cellular response to misfolding of huntingtin - Soluble nonaggregated form of mutant huntingtin (active) is responsible for pathogenesis - Neuropathological hallmark -> degeneration of striatum and cortex

Friedreich Ataxia Friedreich Ataxia - (GAA)n >200 *INTRON of FRDA

-Mutations in introns -> impairing transcription -Mode of inheritance -> AR -Most common inherited spinocerebellar ataxia -Prevalence -> 2 to 4 /100,000 in individuals from Europe, Middle East and India -GAA repeat expansion in the first intron of the FRDA gene -FRDA gene located on chromosome 9 - Codes for FRATAXIN -Mitochondrial iron binding protein -Regulates iron homeostasis in mitochondria -Mutational mechanism: -GAA expansion -> Impairs gene function by impairing transcriptional elongation -Loss of frataxin function -Increased levels of mitochondrial free iron -Impaired heme synthesis (not in RBC) -Reduced activity of Fe-S containing protein like complexes I to III - Clinical features: - Onset before adolescence - Impaired coordination of limb movements - Speech difficulty - Diminished or absent tendon reflexes - Impairment of position and vibration sense - Cardiomyopathy - Scoliosis and foot deformities - Type 2 diabetes

Prader-Willi Syndrome

-Neonatal hypotonia -Obesity, excessive & indiscriminate eating habits -Small hands & feet -Short stature, hypogonadism, Intellectual disability -Results from the absence of certain paternally expressed imprinted genes -In 70% of the cases, due to deletion of 15q11.2 - q13 only on the paternally inherited chromosome 15 -Patients have genomic information in 15q11.2 - q13 derived only from their mother -Syndrome results from loss of expression of one or more of the normally paternally expressed genes in this region

Hemoglobin Structure Adult - HbA - 2α & 2β Fetal - HbF - 2α & 2γ HbA2 - 2α & 2δ HbA1c - 2α & 2β

-Normal adult hemoglobin (Hb) is HbA -Tetrameric protein - 2 α & 2 β chains with 141 & 146 amino acid residues respectively -Extensive α helical structure (7 helical regions in each α chain & 8 in each β chain) -There is interaction of (Fe2+) with PORPHYRIN NITROGEN and importance of proximal & distal HISTIDINE residues

Karyotype

-Number & appearance of chromosomes in a cell -Standard chromosome set of an individual -The process of preparing a chromosome spread - 'to karyotype'

Barr Bodies

-Number of Barr bodies in a cell depends upon number of X chromosomes -No. of Barr bodies = No. of X Chromosomes - 1 -Examples: i) If the pattern is XX, No. of Barr body 2-1 = 1 ii) If the pattern is abnormal, eg. XXX; No. of Barr body 3-1 = 2 iii) If the pattern is XO (Turner syndrome), No. of Barr body 1-1 = 0 *In males there is only one X chromosome, so no Barr body is formed

DiGeorge Syndrome -Deletion in chromosome 22q11 -Haploinsufficiency of TBX1 gene -CATCH-22 Cardiac Abnormality Abnormal faces Thymic aplasia Cleft palate Hypoparathyroidism with Hypocalcemia

-One of the most common cytogenetic deletions -Frequency: 1 in 2000 to 4000 live births -Caused by a DELETION in CHROMOSOME 22q11, removes several genes (approximately 30) -HAPLOINSUFFICIENCY of TBX1 gene (codes for transcription factor T-Box 1, involved in the normal development of muscles and bones of the face and neck, large arteries that carry blood out of the heart, structures in the ear, and glands such as the thymus and parathyroid) -Salient Features of DiGeorge syndrome: CATCH-22 (Cardiac Abnormality, Abnormal faces, Thymic aplasia, Cleft palate & Hypoparathyroidism with Hypocalcemia) -Mental disability is also seen

X-Chromosome Inactivation (Lyonization)

-One of the notable features seen in female SOMATIC CELLS -In each somatic cell of women only one X chromosome is transcriptionally active -Whereas the second X chromosome is almost transcriptionally inactive and exists in the form of heterochromatin -This inactive chromosome constitutes BARR BODY in the female somatic cells -X-inactivation occurs early in embryonic life -In general inactivation is random but fixed *Ie. The inactive X chromosome may be either maternal or paternal in different cells of same individual. -Once the decision is made on inactivation of a particular X chromosome in a cell it is binding to all its descendents -Non random type of inactivation is observed in cases of unbalanced structural abnormality of X- chromosomes *Here the structurally abnormal chromosome (X) is preferentially inactivated, thereby rendering natural advantages to the female individual -Mechanism of inactivation: Involves DNA METHYLATION. This results in the formation of transcriptionally inactive genes in chromosomes

Pleiotropy: Sequence

-Only one single organ system at one point in time affected AND rest of pleiotropic defects caused by perturbation of THAT organ system -Ie. ROBIN SEQUENCE

X Inactivation Centre -XIST: Inactive X (Xi) specific transcripts -XIST GENE plays key role in X Inactivation

-PROXIMAL PART OF LONG ARM (q) of X chromosome takes part in barr body formation -Contains an unusual gene XIST, plays a key role in X inactivation -This XIST gene is transcriptionally silent in the active X chromosome but expressed (transcriptionally active) in inactive X chromosome

Trisomy X

-Pattern: 47, XXX -Occurs in approx. 1/1000 female births -Hypotonia, delayed milestones, tend to be taller than average -Sometimes suffer from reduced fertility, premature ovarian failure and intellectual disability -Presence of 2 Barr bodies in somatic cells Variant karyotypes: 48, XXXX, 49, XXXXX

Klinefelter Syndrome

-Pattern: 47, XXY -Example for Sex Chromosomal Trisomy -Prevalence: Approx. 1/600 male births -Features: -Taller than average with disproportionate long arms and legs -Hypogonadism - small testis, azoospermia, infertility -Testosterone levels are quite low FSH & LH levels are high -Tendency for poor social adjustment -Gynaecomastia is seen approx. 1/3 of the patients - Tendency for breast cancer. This risk may be reduced by mastectomy -Body hair is typically sparse -Muscle mass tends to be reduced IQ is lower (No mental disability, however) -Presence of Barr body in somatic cells -Despite the mild clinical phenotypic features, at least 50% conception cases undergo spontaneous abortion -About 50% cases result from nondisjunction during paternal meiosis & the remaining from maternal meiosis. The incidence increases with the advancing age of the mother -Mosaicism is seen in about 15% of the cases 46,XY/47,XXY-increases the chance of viable sperm production -Variant Karyotypes of Klinefelter syndrome (other than 47,XXY) ---- 48,XXYY, 48,XXXY, 49,XXXXY, 49,XXXYY

Disease Concordance in MZ Twins

-Powerful method for determining whether genotype alone is sufficient to produce a particular disease -"Disease concordance less than 100% in MZ twins is strong evidence that play a role in disease"

Human Hemoglobin Genes

-Present in chromosome 16 & 11 -α Globin gene cluster: Genes for α chain (α1 and α2) and 'α like chain' (ζ) are clustered at CHROMOSOME 16 in tandem arrangement (ζ, α2 and α1) -Both α1 and α2 genes are identical β Globin gene cluster: Similarly Genes for β chain and 'β like chains' (γ,δ and ε) are clustered at CHROMOSOME 11 in tandem arrangement (ε,γ, δ and β)

Introduction to Developmental Biology

-Single cell-zygote -> Human being via DEVELOPMENTAL BIOLOGY -Process must occur in a reliable & predictable pattern and time frame -Development results from the action of genes interacting with cellular and environment cues -Everything is a chance!!!!!!!!!!!

Pleiotropy *Syndromes and Sequences

-Single underlying causative agent -Abnormalities in *More than one organ system or *Multiple structures that arise at different times -Causative agent *Mutant gene *Teratogen

Cell Migration

-Programmed cell movement critical for development -Mainly (but not only) for development of CNS -Lissencephaly ("smooth brain") -Severe brain maldevelopment -> mental retardation -One component of Miller-Dicker syndrome -Contiguous gene syndrome on chromosome 17p -Involves LIS1 gene -Loss of LIS gene -> progressive waves of cell migrations do not occur -Thickened, hypercellular cerebral cortex -Undefined cellular layers -Poorly developed gyri -"Smooth appearance of brain" -Neural crest cell migration -From dorsal/lateral surface of neural tube to distant sites - Ventral aspect of face - Ears - Heart - Intestine - Skin, etc. -Failure of migration may lead to diseases -Hirschprung Disease -Mutations in RET gene in 50% of patients -Waardenburg syndrome *AD *Heterozygous for loss of function mutations of PAX3 (transcription factor) -Type 1 -> decrease or deficiency of neural crest derivatives -Hypertelorism -Pigmentary disturbances -Two different colored eyes -White forelock and eyelashes -Some degree of cochlear deafness -Type 3 -> Like type 1 plus upper limb defects -Type 2 -> Abnormalities limited to derivatives of pigment cells

Proteus Syndrome

-Rare congenital disorder that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body -Segmental overgrowth disorder affecting the face, abdomen and right leg

Triploidy

-Rare, may be seen in infants but they do not survive long -Mostly results from fertilization of an ovum by two sperms (dispermy) -Failure of one of the meiotic division - formation of diploid sperm or ovum can also account for triploidy on fertilization

Human Embryogenesis

-Refer Embryology/ cell biology -Germ cell compartment: Refer Embryology/ cell biology -Stem cells: Refer Embryology/ cell biology

Aneuploidy Aneuploidy is of three kinds: 1. Monosomic 2. Nullisomic 3. Polysomic Aneuploidy may be Autosomal or Sex chomosomal

-Refers to an addition or deletion of one or more chromosomes from the normal set (mostly diploid) of chromosomes -Results from nondisjunction during meiosis (Anaphase) -It may occur during first or second meiotic division -However, the distribution pattern of extra chromosome is different when nondisjunction occurs at 1st or 2nd meiotic divisions -Nondisjunction at Meiosis II: gametes with extra chromosome: either paternal or maternal (but not both) -Rarely a gamete may contain more than one extra chromosome -Rarely nondisjunction can also take place at two successive meiotic divisions -There is also possibility of simultaneous nondisjunction in both male and female gametes resulting in zygote with unusual chromosome number. However this case is very rare

Measuring Familial Aggregation

-Relative risk -Case control studies -Relative Risk (λr ) = Ratio of frequency of disease in relatives of affected proband to frequency (prevalence) in general population -Relative Risk = Prevalence of the disease in RELATIVE "r" of an affected person/Population prevalence of the disease -The larger λr the GREATER the familial aggregation -A value of λr = 1 indicates that a relative is no more likely to develop the disease than is any individual in the population

Reciprocal Translocations

-Relatively common, estimated frequency of 1 in 600 newborns. -Breakage of non-homologous chromosomes, and reciprocal exchange of the resulting segments -TWO CHROMOSOMES are involved

Thalassemias

-Represent heterogeneous group of disorders affecting hemoglobin synthesis -Collectively predominant among human SINGLE GENE DISORDERS -First discovered in persons of Mediterranean origin -Two types - α & β thalassemia -Carrier individuals acquire protective advantage against MALARIA -Coexistence - Structural Hb variant (Hb E) may also lead to thalassemia like features -Prevalence: -Mainly in Mediterranean, Middle East, Parts of Africa and Asia

Globin Switching

-Represents change in expression of different globin genes during development -These genes are expressed sequentially during development (time dependent) -This is because both α and β gene clusters are arranged in the same order in which they are expressed during development -Normally production of α group and β group chains are equimolar -Switching of globin synthesis is also accompanied by changes in site of synthesis *In Yolk sac (3rd - 8th week) *In Liver (till birth) *In Spleen (~12th wk - till birth) *In Bone marrow (~ 12th wk- adult )

RFLP Pattern of HbA, HbS Homozygous and HbS Heterozygous RFLP - Restriction Fragment Length Polymorphism

-Restriction enzyme Mst II cuts HbA and HbS gene differently -Mutation in beta globin gene abolishes a recognition site , meant for cleavage by the restriction enzyme Mst II

Robin Sequence

-Restriction of mandibular growth prior to 9th week of gestation *Tongue more posterior than normal *Interferes with normal closure of palatal shelves -> cleft palate -Can be isolated birth defect of unknown cause -Can be caused by extrinsic impingement on developing mandible -Phenotype also part of the features of Stickler syndrome *Mutations in type II collagen *Abnormally small mandible *Other defects -> stature, joints, eyes *Mutant collagen gene NOT responsible for failure of palatal closure rather: secondary to primary defect in jaw growth

Digenic Retinitis Pigmentosa (Gene-Gene interaction) -Harrison: Progressive night blindness. The name is misnomer as there it is not an inflammatory process. Also present in Refsum's disease.

-Retinal degeneration (Gene-Gene interaction) -Caused by two rare mutations in two different unlinked genes that encode for photoreceptor proteins PERIPHERIN and Rom1. -Individuals heterozygous for both Rom1 and peripherin photoreceptor membrane proteins develop the disease -ADDITIVE EFFECT

Robertsonian Translocation

-Short arms of two non homologous chromosomes are lost and the two long arms fuse at the centromere to form a single chromosome -Confined to ACROCENTRIC CHROMOSOMES (13,14,15, 21 and 22) -The short arms of acrocentric chromosomes contain SATELLITE DNA and rRNA GENES; loss is not deleterious -May be pseudodicentric (a chromosome with TWO CENTROMERES of which one is epigenetically inactivated) -Relatively common Robertsonian translocations involve: 1. Chromosomes 13 & 14 - rob (13;14)(q10;q10) 2. Chromosomes 14 & 21 - rob (14;21)(q10;q10) -The carriers of Robertsonian translocation are phenotypically normal but have only 45 chromosomes along with the translocation chromosome -Their offspring by inheritance may gain an extra long arm or may lose an acrocentric chromosome -Robertsonian translocation involving chromosomes 14 & 21 accounts for approx. 4% of DOWN SYNDROME cases

Parent-of-origin Genomic During gametogenesis, imprints erased by removal of epigenetic marks ↓ New imprints established, determined by the sex of the parent ↓ Gametes carry a monoallelic imprint (paternal or maternal) ↓ Somatic cells in the embryo and adults carry one copy of chromosome with paternal imprint & one copy with maternal imprint ↓ Paternally imprinted genes expressed only from maternal copy & vice versa

-Some genes are monoallelically expressed; either from paternal or maternal copy -Choice of allele to be expressed determined by PARENTAL ORIGIN (NONRANDOM) -Introduction of epigenetic marks in the germline of one parent but not the other, at specific locations in the genome -OCCURS DURING GAMETOGENESIS, marks certain genes as having come from the mother or father -After conception, parent-of-origin imprint is maintained in some or all somatic tissues of the embryo- silences gene expression from alleles within the imprinted region -Imprinted genes show MONOALLELIC gene expression; maternally imprinted gene is expressed only from the paternal allele and vice versa -Genomic imprinting is controlled by a DNA element called IMPRINTING CENTER

Human Fetal Development

-Specification, Determination and Fate -Axis Specification and Pattern Formation -Undifferentiated Cells -> Specification -> Determination -> Fate Specification: - Acquires specific characteristics - Reversible - Influenced by environmental cues - Responsible for Regulative Development Determination: - Acquires attributes (environmental cues) - Irreversible - Responsible for Mosaic Development Fate: - Ultimate destination - Specific functions -Specific fate -> a region of the embryo that regularly gives rise to same structure -Fate map -> A collection of how all the different regions of an embryo develop -Gene expression profile for differentiated cells normally not the result of permanent changes to DNA *Epigenic gene regulation *Stable transcription complexes *Modification of histones in chromatin *DNA methylation -Epigenetic control of gene expression is responsible for the loss of developmental plasticity -Exception to this rule *Lymphocyte precursor cells -> rearrangements in T-cell Receptor -Immunoglobulin genes -> somatic rearrangements to increase antibody diversity -Regulative and Mosaic Development -Regulative Development *Ability to compensate for loss or injury of cells *Early human embryogenesis is regulative *Exposure to teratogens in the 2 weeks after conception carries low risk of causing birth defects *Evidence: Prenatal diagnosis by biopsy of pre implantation embryo is possible - Male and female gametes collected -> IVF - Biopsy at 8 cell stage - FISH or PCR - Remaining seven cells -> implanted -Mosaic Development -Inability to compensate for loss or injury of cells -Fate of particular cells specified independently of environment -Eg: Rubella virus induced congenital cataracts and microphthalmia from loss of fetal lens cells -Exception: Regeneration in adult salamanders (Limb, Heart, Spinal cord, Retina, Tail) -Inability to compensate for loss or injury of cells -Fate of particular cells specified independently of environment -Eg: Rubella virus induced congenital cataracts and microphthalmia from loss of fetal lens cells -Exception: Regeneration in adult salamanders (Limb, Heart, Spinal cord, Retina, Tail)

Structural Chromosomal Abnormalities

-Structural chromosomal abnormalities less common than numerical chromosomal abnormalities -Induced by breaking agents (Clastogens) such as VIRAL INFECTIONS, IONIZING RADIATION, CHEMICALS -Can occur either in somatic cells or germ line cells -Can be transmitted to the OFFSPRING if it occurs in GERM LINE CELLS -In somatic cells, structural alteration of chromosomes may lead to CANCER -Person may exhibit MOSAICISM (Some cells with normal some other with abnormal chromosome) with respect to structural chromosome abnormality -In chromosomes, some of the structural alterations are STABLE, capable of passing through mitotic division unaltered -To become STABLE, the altered/rearranged chromosome should have functional CENTROMERE and TELOMERES

Clinical Dysmorphology

-Study of congenital birth defects that alter shape or form of one or more parts of the body during development - Categories: *Malformations, Dysformations and Disruptions

Thalassemias (Pathophysiology)

-Synthesis of either the α or the β chain is defective (Decreased rate of synthesis or occasionally not synthesized at all) -Imbalance in the ratio between α & β chains -Excess normal chains eventually get precipitated within the cell -Defect in production of hemoglobin -Damage to cell membrane -Premature red cell destruction -Hemolytic anemia - hypochromic, microcytic

Fluorescence In Situ Hybridization (FISH)

-The FISH technique is required to: 1. Examine presence or absence of a particular DNA sequence in chromosomes 2. Evaluate number or organization of a chromosome or chromosomal region -In FISH technique specific DNA probes (such as gene specific, locus specific & repetitive DNA probes) are used to detect a particular chromosomal rearrangement, existence of abnormal chromosome numbers or existence of satellite DNA

Case Control Studies

-The cases (individuals affected by a disease) are compared with the controls (suitably chosen individuals without the disease) -The controls: 1. Spouses, adoptees (genetically different, environmentally same/similar) 2. Patients with unrelated diseases matched for age, occupation and ethnicity -Compares frequency of disease in extended families of cases (positive family history) with frequency of positive family history among controls -Eg: Multiple Sclerosis (MS) ~3.5% siblings of patients with MS also had MS ~0.2% relatives of controls had MS -Conclusion? -Some familial aggregation is occurring in MS -Limitations: -Ascertainment bias (selection of individuals for inclusion in a genetic study) -Recall bias -Controls should differ from the cases only in their disease status -An association found in a case-control study does not prove causation -If 2 factors are dependent on each other eg: Ethnicity and food habits -Frequency of coronary artery disease among Japanese and Japanese immigrated to North America

Developmental Genetics Introduction

-The genetics, including the mechanisms responsible for normal human development in utero -Focuses on action of genes and their interaction with cellular and environmental cues *Transcriptional regulators that direct specific developmental pathways *Signaling molecules -Developmental disorders caused by mutations in 1. Genome 2. Chromosomes 3. Single genes -Congenital anomalies also major cause of long-term Morbidity, Mental retardation, and other dysfunctions -The practitioner to develop a rational approach to the diagnostic evaluation of a patient with a birth defect -The practitioner *Predictions about prognosis *Recommended management options *Recurrence risks -Public health goal of reducing disease should NOT be interpreted ONLY as prevention of birth of children with anomalies through voluntary pregnancy termination -Sometimes prevention of birth defects may be accomplished by nutritional adjustments Folic acid -> NTDs

β - Thalassemia Major

-The individuals with two β thalassemic alleles → with severe anemia and require lifelong medical attention -Infants become severely anemic after birth, in the first or second year -Skeletal changes (Chipmunk faces and pathological fractures) occur due to extramedullary erythropoiesis -Require regular blood transfusions -β0 thalassemia - associated with absence of β-globin synthesis -β+ thalassemia - associated with reduced but detectable β-globin -β - Thalassemia minor: *Carriers of one β thalassemic allele are clinically normal but have hypochromic, microcytic RBC with slight anemia *β thalassemia minor may be initially misdiagnosed as iron deficiency anemia -The disorders are named according to the genes deleted; -δβ thalassemia, γδβ thalassemia etc .. -Some deletions within β globin cluster do not cause thalassemia but results in Hereditary Persistance of Fetal Hemoglobin (with the expression of γ globin gene throughout life) -Hereditary Persistence of Fetal Hb (HPFH): Hb F is the major Hb at fetal life, constitutes about 70% of Hb at birth In adult it contributes only about 2% Synthesis of β chain becomes significant near the time of birth and then continues after birth HPFH is caused by disruption of perinatal globin switch from γ globin to β globin (Possibly due to the deletion at β globin gene)

Globin Gene dosage:

-There are 4 copies of α globin genes and 2 copies of β globin genes per diploid genome -Hence a genetic disease due to mutation in β globin gene is likely to be more common compared to the disease due to the mutation of α globin gene -Fetal life remains unaffected if mutation occurs in β globin gene, since γ globin gene plays dominant role in fetus

Classification of Hemoglobinopathies

-Three groups: 1. STRUCTURAL VARIANTS - Having altered globin polypeptide without affecting rate of synthesis -Mostly due to point mutations -Over 400 types of abnormal Hb -About half of which are clinically significant -Structural variants of Hb may be associated with 1) HEMOLYTIC ANEMIA 2) ALTERED OXYGEN TRANSPORT 3) THALASSEMIA TYPE PHENOTYPES 2. THALASSEMIAS - Decreased synthesis of one or more globin chains, resulting in imbalanced amount of α and β globin chains 3. Hereditary Persistence of fetal hemoglobin (HPFH) - Due to impaired perinatal switch from γ to β-globin synthesis

Organization of Globin Gene Families

-Two copies of the ALPHA globin gene are designated ALPHA 1 and ALPHA 2 -Each can provide ALPHA-GLOBIN chains that combine with BETA-GLOBIN chains -ALPHA GLOBIN genes are on CHROMOSOME 16 -Hemoglobins are formed by combinations of ALPHA GLOBIN-LIKE chains and BETA-GLOBIN like chains

Rubenstein-Taybi Syndrome

-Type of PLEIOTROPY SYNDROME -AD -Clinical features: -Broad toes and thumbs -Loss-of-function of transcriptional coactivator gene CBP (CREB-binding protein) -Bridges regulatory transcription factors with general transcription factors & RNA polymerase -CREB: cAMP responsive element binding protein. TF imp. For neuronal survival and has an imp. Role in the memory in the hippocampus..

Brachio-oto-renal dysplasia syndrome

-Type of PLEIOTROPY SYNDROME -Cause: Mutations in EYA1 gene *Codes for protein phosphatase *Involved in ear and renal development

Duplication

-Type of chromosome rearrangement -Occurs mainly due to UNEQUAL CROSSOVER during meiotic synapsis -Duplication, in general, is LESS HARMFUL than deletion -May result in phenotypic abnormalities, because chromosomal breakage may disrupt certain genes

Deletion

-Type of chromosome rearrangement -Results from CHROMOSOME BREAKAGE -Deletion may be TERMINAL or INTERSTITIAL -A person of chromosomal deletion is MONOSOMIC for certain genetic information -Incidence of cytogenetically visible autosomal deletions --- 1/7000 -Consequences depends on the size of deletion and number, nature and functions of genes that are lost

Types of Structural Abnormalities of Chromosomes

-UNBALANCED REARRANGEMENTS *Deletion *Duplication *Ring chromosomes -Isochromosomes -BALANCED REARRANGEMENTS *Translocations *Inversion

Uniparental Disomy in Genetic Diseases

-Uniparental disomy refers to presence of two chromosomes derived from only one parent -Some cases of PWS and AS do not have detectable deletions in chr 15 -Some PWS patients have two cytogenetically normal chromosomes 15, both inherited from their mother (uniparental disomy) ↓ Lack of expression of paternally expressed imprinted genes Some AS patients have two cytogenetically normal chromosomes 15, both inherited from their father (uniparental disomy) ↓ Lack of expression of maternally expressed imprinted genes -If both homologues from one parent are present - heterodisomy -If the two chromosome are derived from identical sister chromatids - isodisomy

Angelman Syndrome

-Unusual facial appearance -Wide stance -Short stature, intellectual disability -Spasticity, seizures -In 70% of the cases, due to deletion of 15q11.2 - q13 only on the maternally inherited chromosome 15 -Patients have genomic information in 15q11.2 - q13 derived only from their father -Syndrome results from loss of expression of two normally maternally expressed genes in this region -Mutations in the imprinting center also can cause PWS or AS

Chromosome & Genome analysis with Microarrays (DNA Chips)

-Uses microarrays that contain either complete representation of entire genome or cloned fragments of the genome -Genome-wide screening for copy number variations -Consists of tens of thousands of short sequences of DNA ('probes') arranged in a precise grid on a glass slide ('chip') -Makes use of control & patient samples

Thalidomide Syndrome

-Widely used sedative in 1950s -Causes malformed limbs

Action and Arrangement of HOX Genes

An ancestral HOX gene cluster in a common ancestor of vertebrates and invertebrates has been quadruplicated in mammals, and individual members of the ancestral cluster have been lost. The combination of HOX genes expressed in adjacent regions along the anteroposterior axis of developing embryos selects a unique developmental fate (as color-coded in the segments of the fly and human embryo shown at bottom). In the developing limbs (top right), different combinations of HOXA and HOXD genes are expressed in adjacent zones that help select developmental fate along the proximal-distal and anterior-posterior axes.

Structural Rearrangements

Can be either: 1. BALANCED REARANGEMENTS -The resulting chromosome has generally NORMAL GENETIC INFORMATION -Does not cause loss or gain of chromosomal materials UNBALANCED REARRANGEMENTS -The resulting chromosome has ADDITIONAL or MISSING genetic information -Abnormal phenotype may be observed

Mitosis

Division that results in SOMATIC CELLS with DIPLOID number of chromosomes

Numbering bands in chromosomes Ie. The CFTR GENE is 7q31.2

Eg: 16 p 2 3 refers to 3rd band, in 2nd region of p arm of chromosome 16. 7 q 3 2.2 refers to 2nd sub band of 2nd band in 3rd region of q arm of chromosome 7.

Disruption of Histone Acetyl Transferase (HAT) function by mHTT

In the MUTANT HUNTINGTIN PROTEIN (mHTT): HISTONE ACETYL TRANSFERASE (HAT) is unable to work therefore there is no acetylation of the histones (leaving the DNA in a condenced/heterochromatin form *Acetylation opens DNA up for transcription *Deacetylation closed DNA up for transcription

Waardenburg syndrome

Patients with type I Waardenburg syndrome. A, Mother and daughter with white forelocks. B, A 10-year-old with congenital deafness and white forelock. C, Brothers, one of whom is deaf. There is no white forelock, but the boy on the right has heterochromatic irides. -Type I and type III WS in humans caused by dysfunction of PAX3 -Type II WS is due to a mutation in the microphthalmia-associated transcription factor (MITF) -Expression of MITF is limited to pigment cells and their precursors and is dependent on transactivation by PAX3

Pentanucleotide Repeat Expansion Diseases

SPINOCEREBELLAR ATROPHY 10

46 -There are 23 pairs -Chromosomes 1 - 22 (each is present in pair) are AUTOSOMES *The two members of each pair represents homologous chromosomes -23rd pair is a SEX CHROMOSOME *XX in females XY in males -The chromosome possesses two arms, one on both sides of centromere. The short arm is 'p' and long arm is 'q'

Total number of chromosomes

Chromosomal Abnormalities

Two types: 1. Structural - Abnormalities in structure 2. Numerical - Abnormality in either chromosome set (Euploidy) or number (Aneuploidy) -Euploidy: Change in whole set of chromosomes Examples: *Triploidy: 3 sets of chromosomes *Tetraploidy: 4 sets of chromosomes