Genetika Kedokteran

Blok 2 2011Genetika Kedokterandr. Arfianti, M.Biomed, M.Sc

Basic ConceptsGene basic unit of genetic information. Genes determine the inherited characters.

Genome the collection of genetic information.

Chromosomes storage units of genes.

DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life

Chromosome StructureLocus location of a gene on the chromosome.

Allele one variant form of a gene at a particular locus.

Locus1Possible Alleles: AA,Aa, aa

Locus2Possible Alleles: BB,Bb,bb

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Human GenomeMost human cells contain 46 chromosomes:

2 sex chromosomes (X,Y):XY in males.XX in females.

22 pairs of chromosomes named autosomes.

KARIOTIPE

5Image from http://www.accessexcellence.com/AB/GG/

KARIOTIPE gambaran lengkap kromosom yang telah disusun berdasarkan pasangan homolog dan jenisnya Tujuan mempermudah mempelajari kromosomSampel limfosit, sumsum tulang, kulit, cairan amnion atau vili korion.

TELOMERTelomer ujung kromosom sikuen tandem repeat (pada manusia adalah GGGTTA). Direplikasi oleh enzim telomeraseProses penuaan aktivitas telomerase akan semakin menurun panjang dari telomer akan semakin berkurang.

TELOMER

BARR BODY Wanita salah satu kromatin X-nya mengalami inaktivasi kondensasi kromatin di inti sel pada saat interfase barr body atau kromatin X. Apus mukosa pipi (buccal smear) Kromatin seks 1-10% sel neutrofil wanita dalam bentuk drumstick.

MITOSIS DAN MEIOSIS Mitosis seluruh sel tubuh dan berfungsi membentuk sel dengan jumlah kromosom yang samaMeiosis hanya terjadi pada organ kelamin dan berfungsi mereduksi jumlah kromosom menjadi separuhnya.

MEIOSISProses gametogenesis spermatogenesis dan oogenesis sel gamet dengan jumlah kromosom separuh dari jumlah kromosom sel somatik. 2 tahap meiosis yaitu Meiosis I dan Meiosis II. Meiosis I diploid menjadi haploid. Meiois II = mitosis. Antara meiosis I dan meiosis II tidak terjadi sintesis DNA.

GenotypesPhenotypesAt each locus (except for sex chromosomes) there are 2 genes genotype at the locus.

The expression of a genotype phenotype. E.g: hair color, weight, or the presence or absence of a disease.

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Genotypes PhenotypesIA dan IB- dominant allele.i- recessive allele.genotypesphenotypes

GenotypesPhenotypesIAIA or IAiAIBIB or IBiBIAIBABiiO

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Dominant vs. Recessive A dominant allele is expressed even if it is paired with a recessive allele.

A recessive allele is only visible when paired with another recessive allele.

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One Locus Inheritanceheterozygotehomozygote 2 1

A | Aa | aA | a 3

4a | aA | a

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a | aMaleFemale

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Mendels 1st Law

Y / y

y / y

y/y Y/y y Yall yGamete productionGamete production

The law of segregation: Allele pairs separate or segregate during gamete formation, and randomly unite at fertilization.

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Mendels 2nd LawThe law of independent assortment: during gamete formation the segregation of the alleles of one allelic pair is independent of the segregation of the alleles of another allelic pair

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Mendel 2nd law contFemale GametesGWGwgWgwMaleGametesGWGGWW (Yellow,round)GGWw (Yellow,round)GgWW (Yellow,round)GgWw (Yellow,round)GwGGWw (Yellow,round)GGww (Yellow,wrinkled)GgWw (Yellow,round)Ggww (Yellow,wrinkled)gWGgWW (Yellow,round)GgWw (Yellow,round)ggWW (Green,round)ggWw (Green,round)gwGgWw (Yellow,round)Ggww (Yellow,wrinkled)ggWw (Green,round)ggww (Green,wrinkled)

Genetic Disorders6 general patterns of inheritance are observed:

Autosomal recessiveAutosomal dominantX-linked recessiveX-linked dominantCodominant Mitochondrial

Autosomal recessiveManifest only in homozygous stateBoth males and females affected equallyCarriers (HTZ) unaffectedConsanguinity increases risk of recessive disordere.g., cystic fibrosis: disease affecting the mucus lining of the lungs, leading to breathing problems and other difficulties

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Autosomal dominantBoth males and females have equal chance to inherit geneBoth can transmit disorder to both sons and daughtersHMZ often more severely affected than HTZ Affected males and females appear in each generation of the pedigree.Affected mothers and fathers transmit the phenotype to both sons and daughters.e.g., Huntington disease.

Huntington disease Huntington's chorea is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory. 5 to 8 per 100,000. the New York physician George Huntington who first described it precisely in 1872.

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X-linked recessive

Expressed in males but not usually in femalesCarrier female50% risk of affected sons50% risk of carrier daughter Affected maleall daughters carriersall sons unaffectede.g., hemophilia: impair the body's ability to control bleeding

X-linked dominant

Males and females affected, females usually less severely affected than males1 in 2 risk to children of affected female All daughters of affected male affected but no male to male transmissione.g. fragile X syndrome: a range of developmental problems:learning disabilities and mental retardation

X-linked dominant inheritance Males and females affectedVitamin D resistant ricketsFragile X syndrome Lethal in malesIncontinentia pigmentiRett syndromeXL chondrodysplasia punctata

Codominant inheritance

Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein Both alleles influence the genetic trait or determine the characteristics of the genetic condition. E.g. ABO locus

Mitochondrial inheritance

Mitochondria are exclusively maternally inherited Genes in mitochondrial DNA Mitochondrial disorders can appear in every generation of a family and can affect both males and females E.g. Leber's hereditary optic neuropathy (LHON)

Question #1PKU is a human hereditary disease resulting from inability of the body to process the chemical phenylalanine (contained in protein that we eat).

It is caused by a recessive allele with simple Mendelian inheritance.

Some couple wants to have children. The man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families. What is the probability that their first child will have PKU ?

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Question #2-Solution Highlights

P/pP/pP/pP/pp/pp/p

P/-P/-P the normal allelep the mutant allele

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X-linked dominant disorders

Question #3

12345678910What is the most likely mode of inheritance ? The disease is rare.

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Observations:After the disease is introduced into the family in generation #2, it appears in every generation dominant!Fathers do not transmit the phenotype to their sons X-linked!

Question #3-Solution Highlights

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ChromosomesNumber: Aneuploidy TrisomyMonosomyPolyploidytriploidy (69 chromosomes)Structure: deletion/insertion/ inversion/ring translocation

TrisomyTrisomy 21Trisomy 18Trisomy 13No survivable autosomal monosomySex chromosome aneuploidy:45X 47XXX 47 XXY 47XYY

Trisomy 21: Downs Syndrome1 in 700 births - maternal age relatedLearning disabilityHypotoniaNuchal thickening, short neckFlat face, brachycephalyEpicanthic folds, Brushfield spotsSmall mouth and large tongue Small square earsTransverse palmar creases, sandal gap

45,XTurner syndrome 1:1000 female birthsCardiac defects especially coarctatio aortaHorseshoe kidneyShort statureStreak gonads and infertilityWebbed neck, ptosisIQ in normal range, some specific learning diffs

47XXXTriple X syndromeTall stature in childhoodNormal appearance and fertilityNot associated with structural abnormalitiesLearning disability, speech delay, passive personality

47,XXYKlinefelter syndromeMalesTall stature, eunuchoid fat distributionSmall testes and low testosteronePoor beard growth, gynaecomastiaIQ usually within normal range but < sibsSome increase in behaviour problemsIncreased risk diabetes, varicose veins, breast cancer

Chromosomal inheritancePedigree doesnt conform to mendelian patternMay be history of miscarriagesAffected children may have different patterns of physical and developmental abnormality

Genetic consellingPrenatal testingAn education process that seeks to assist affected (and/or at risk) individuals to understand the nature of the genetic disorder, the nature of its transmission and the options open to them in management and family planning.Tests in pregnancy- Villi chorialisCairan amnion