Upendra Sharma.U.SPIMS

introductionNormal human cells contain 23 pairs of chromosomesThis includes one pair of sex chromosome XX or XYDuring cell division we can identify chromosomesLymphocytes incubated for 2-3 days or uncultured bone marrow in 4-24 hours

continueHaploid: set of 23 chromosomesDiploid: normal number of 46 chromosomesAneuploidy: less than an even multiple of 23 usually is 45 or 47 and rarely 48,49Triploidy: 69 chromosomesMosaicismAbnormal in deletion and translocation(balanced and unbalanced)Balanced

Incidence The earlier the abortion the more likely to be chromosomal50% of spontanous abortion are chromosomal abnormalMostly triploidy. 45 XO, trisomy 1698% of fetus with turner abortGenerally 6/1000 the incidence of chromosomal abnormalities

When to suspect itUnexplained infertility/ balanced translocationMultiple abortion >2Prior case of defective baby

When to suspect itcontinuePresence of congenital anomalies45% have minor single anomalies9% 3 minor anomalies1.5% HAVE major anomaly2 or more major anomalies may represent genetic syndrome or chromosomal abnormalities(10%).

Down SyndromeIncidence 1/7002/3 of down fetus spontaneously abortClinical diagnosis depend on gestaltTrisomy 21 in 94% of cases with extra chromosome from mother mostly(95%)Risk correlate with maternal age40 y/0 1/802% are mosaic

Other Clinical featuresHypotonia without weaknessClinodactaly protruded tongue,small ears,brachycephaly,small up turned nose, depressed nasal bridge.Mental retardation, socially do better with good environment (Happy children)

Clinical issuesCardiac and GIHypothyriodismTransient leukemoid reaction Alzheimers disease up to 25% over 40 y/oEarly death relate to cardiac dysfunction

Trisomy 18Incidence 1/8000Overlaps with trisomy 13Sever Mental retardation >90% dead in 1st year

Trisomy 18Small face with prominant occiputSmall sternum and pelvisFlexion deformity of the fingerVSD and horseshoe kidney

triploidyComplete extra set of chromosomesMostly miscarriagesFetal wastage skeleton more than cephalic, 2% survive to be recognizedLarge hydatidiform placentaVSD, ASD, SyndactalyGenital and CNS abnormalities

Trisomy 13Sever developmetal retardationIncidence 1/2000090% dead in the 1st year

Trisomy 13Midline brain defectMalformed earMicroophalmos and colobomaScalp defect

Turner syndromeMost common abnormality in early abortionFemale, short stature, primary amenorrhea, sterility, spares hair and underdeveloped breastNeonatal: wide spaced nipple, lymphedema , shield chest, Coarctation of the aorta

Continue turner syndromeNormal IQ scale with difficulty in spatial orientation such as map Present with short stature or delay sex maturationHormonal therapy

continueMosaisim (15%), remove gonadsRecurrent risk is 1-2%Noonan syndrom AD, fresh mutationPulmonary stenosis, nl stature, microceph, mental retardation

Klinefelter syndrome20% of aspermic adult male (blocked spermatogenesis 47 XXY in 80% and mosaic in 20%IQ is 98 (normal) with mild decrease in verbal IQScoliosis, decrease libido may improve with testesterone, gynecomastia

Fragile X SyndromeModerate to sever mental retardationSpeech delay, short attention, hyperactivityPoor motor coordination and mouthing objectsPoor socialization, temper tantrumMood disorder (bipolar), schizophrenia

Fragile X syndromeLong protruding earsLong face and prominent jawFlattened nasal bridgeHigh arch palateMacroorchidismGenetic is complex, 80% penetration in male and 30% penetration in female

Genetic imprintingMeans: as genomes pass through miosis it is normal for part of it to change.During miosis inactive X chromosome become active and changes on fragiloe X gene (imprinting) make it malignant

Angelman syndromeSever mental retardationInappropriate laughterDecrease pigmentation of choroid or iris (pale blue eyes)Ataxia and jerky eye movementSever speech proplemDeletion of b15q11q13, maternal in originPaternal uniparental disomy

Prader-willi syndrome(A fat red faced boy in state of somnolency) Charles DiickensEarly hypotoniaObesityShort stature as adultAlmond shaped blue eyesMental retardation (mild to moderate)Narrow hands

Amount of genetic information in the chromosome can changeDeficiencies/DeletionsDuplications

The genetic material remains the same, but is rearrangedInversionsTranslocationsVariation In Chromosome Structure

A chromosomal deficiency occurs when a chromosome breaks and a fragment is lostDeficiencies (Deletions)Figure 8.3

Phenotypic consequences of deficiency depends onSize of the deletionFunctions of the genes deleted

Phenotypic effect of deletions usually detrimentalDeficiencies

A chromosomal duplication is usually caused by abnormal events during recombinationDuplicationsFigure 8.5

Phenotypic consequences of duplications correlated to size & genes involved

Duplications tend to be less detrimental

Duplications

Bar-Eye Phenotype in DrosophilaPhenotype: reduced number of ommatidiaUltra-bar (or double-bar) is a trait in which flies have even fewer facets than the bar homozygoteBoth traits are X-linked and show intermediate dominance

Majority of small duplications have no phenotypic effect

However, they provide raw material for evolutionary change

Lead to the formation of gene familiesA gene family consists of two or more genes that are similar to each otherderived from a common gene ancestorDuplications and Gene Families

Genes derived from a single ancestral geneFigure 8.9

Gene FamiliesWell-studied example is the globin gene familyGenes encode proteins that bind oxygen

Globin gene family 14 homologous genes derived from a single ancestral geneAccumulation of mutations in the members of generated Globin genes expressed during different stages of development Globin proteins specialized in their function

Figure 8.10DuplicationBetter at binding and storing oxygen in muscle cellsBetter at binding and transporting oxygen via red blood cellsExpressed after birth

A segment of chromosome that is flipped relative to that in the homologueInversionsFigure 8.11Centromere lies within inverted regionCentromere lies outside inverted region

InversionsNo loss of genetic informationMany inversions have no phenotypic consequencesBreak point effectInversion break point is within regulatory or structural portion of a genePosition effectGene is repositioned in a way that alters its gene expressionseparated from regulatory sequences, placed next to constitutive heterochromatin~ 2% of the human population carries karyotypically detectable inversions

Individuals with one copy of a normal chromosome and one copy of an inverted chromosome Usually phenotypically normalHave a high probability of producing gametes that are abnormal in genetic contentAbnormality due to crossing-over within the inversion intervalDuring meiosis I, homologous chromosomes synapse with each otherFor the normal and inversion chromosome to synapse properly, an inversion loop must formIf a cross-over occurs within the inversion loop, highly abnormal chromosomes are produced

Inversion Heterozygotes

Inversions Prevent Generation of Recombinant Offspring GenotypesOnly parental chromosomes (non-recombinants) will produce normal progeny after fertilization

When a segment of one chromosome becomes attached to another

In reciprocal translocations two non-homologous chromosomes exchange genetic material Usually generate so-called balanced translocationsUsually without phenotypic consequencesAlthough can result in position effect

Translocations

Fig. 8.13b(TE Art)Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.Nonhomologous chromosomesReciprocaltranslocation1177Nonhomologous crossover17Crossover betweennonhomologouschromosomes

Fig. 8.13a(TE Art)Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.22Environmental agent causes 2 chromosomes to break.Reactive ends2222DNA repair enzymesrecognize broken ends and connect them. Chromosomal breakage and DNA repair

8-38Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or displayIn simple translocations the transfer of genetic material occurs in only one directionThese are also called unbalanced translocations

Unbalanced translocations are associated with phenotypic abnormalities or even lethalityExample: Familial Down SyndromeIn this condition, the majority of chromosome 21 is attached to chromosome 14 (Figure 8.14a)

8-39Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or displayFamilial Down Syndrome is an example of Robertsonian translocation

This translocation occurs as suchBreaks occur at the extreme ends of the short arms of two non-homologous acrocentric chromosomesThe small acentric fragments are lostThe larger fragments fuse at their centromeic regions to form a single chromosome

This type of translocation is the most common type of chromosomal rearrangement in humans

8-40Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or displayIndividuals carrying balanced translocations have a greater risk of producing gametes with unbalanced combinations of chromosomesThis depends on the segregation pattern during meiosis I

During meiosis I, homologous chromosomes synapse with each otherFor the translocated chromosome to synapse properly, a translocation cross must formRefer to Figure 8.15

Balanced Translocations and Gamete Production

Figure 8.158-42

8-41Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or displayMeiotic segregation can occur in one of three ways1. Alternate segregationChromosomes on opposite sides of the translocation cross segregate into the same cellLeads to balanced gametesBoth contain a complete set of genes and are thus viable2. Adjacent-1 segregationAdjacent non-homologous chromosomes segregate into the same cellLeads to unbalanced gametesBoth have duplications and deletions and are thus inviable3. Adjacent-2 segregationAdjacent homologous chromosomes segregate into the same cellLeads to unbalanced gametesBoth have duplications and deletions and are thus inviable

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or displayConsider a fertilized Drosophila egg that is XXOne of the Xs is lost during the first mitotic divisionThis produces an XX cell and an X0 cell8-71The XX cell is the precursor for this side of the fly, which developed as a femaleThe X0 cell is the precursor for this side of the fly, which developed as a maleThis peculiar and rare individual is termed a bilateral gynandromorphFigure 8.26

*Figure: 07-12a

Caption:(a) Genotypes & phenotypes.