Blok 2 2011

Genetika Kedokteran

dr. Arfianti, M.Biomed, M.Sc

Basic Concepts• Gene – 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 Structure• Locus – 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

Human Genome

Most human cells contain 46 chromosomes:

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

• 22 pairs of chromosomes named autosomes.

KARIOTIPE

KARIOTIPE • gambaran lengkap kromosom yang telah

disusun berdasarkan pasangan homolog dan jenisnya

• Tujuan mempermudah mempelajari kromosom

• Sampel limfosit, sumsum tulang, kulit, cairan amnion atau vili korion.

TELOMER• Telomer ujung

kromosom sikuen tandem repeat (pada manusia adalah GGGTTA).

• Direplikasi oleh enzim telomerase

• Proses 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 sama

• Meiosis hanya terjadi pada organ kelamin dan berfungsi mereduksi jumlah kromosom menjadi separuhnya.

MEIOSIS• Proses 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.

Genotypes↔Phenotypes

• At 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.

Genotypes Phenotypes

• IA dan IB- dominant allele.• i- recessive allele.

genotypes

phenotypes

Genotypes Phenotypes

IAIA or IAi A

IBIB or IBi B

IAIB AB

ii O

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.

One Locus Inheritance

heterozygote homozygote

2 1A | A a | a

A | a 3 4 a | a

A | a 5 6 a | a

Male

Female

Mendel’s 1st Law

Y / y y / y

½y/y

½Y/y

½y

½Y

all yGamete production

Gamete production

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

Mendel’s 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

Mendel 2nd law cont…

Female GametesGW Gw gW gw

MaleGametes

GWGGWW (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 recessive• Autosomal dominant• X-linked recessive• X-linked dominant• Codominant • Mitochondrial

Autosomal recessive• Manifest only in

homozygous state• Both males and females

affected equally• Carriers (HTZ) unaffected• Consanguinity increases

risk of recessive disorder• e.g., cystic fibrosis: disease

affecting the mucus lining of the lungs, leading to breathing problems and other difficulties

Autosomal dominant• Both males and females have

equal chance to inherit gene• Both can transmit disorder to both

sons and daughters• HMZ 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.

X-linked recessive

• Expressed in males but not usually in females

• Carrier female– 50% risk of affected sons– 50% risk of carrier

daughter • Affected male

– all daughters carriers– all sons unaffected

• e.g., hemophilia: impair the body's ability to control bleeding

X-linked dominant

• Males and females affected, females usually less severely affected than males

• 1 in 2 risk to children of affected female

• All daughters of affected male affected but no male to male transmission

• e.g. fragile X syndrome: a range of developmental problems:learning disabilities and mental retardation

X-linked dominant inheritance

Males and females affected

• Vitamin D resistant rickets

• Fragile X syndrome

Lethal in males• Incontinentia

pigmenti• Rett syndrome• XL

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 #1• PKU 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 ?

Question #2-Solution Highlights

P/p P/p P/p P/p

p/p p/pP-/ P-/

P – the normal allelep – the mutant allele

X-linked dominant disorders

Question #3

1 2 3 4 5 6 7 8 9 10

a. What is the most likely mode of inheritance ?

• The disease is rare.

a. 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

Chromosomes• Number:

– Aneuploidy • Trisomy• Monosomy

– Polyploidy• triploidy (69 chromosomes)

• Structure: deletion/insertion/ inversion/ring

translocation

Trisomy

• Trisomy 21• Trisomy 18• Trisomy 13• No survivable autosomal monosomy• Sex chromosome aneuploidy:• 45X 47XXX 47 XXY 47XYY

Trisomy 21: Down’s Syndrome

• 1 in 700 births - maternal age related

• Learning disability• Hypotonia• Nuchal thickening, short neck• Flat face, brachycephaly• Epicanthic folds, Brushfield

spots• Small mouth and ‘large’ tongue • Small ‘square’ ears• Transverse palmar creases,

sandal gap

45,X• Turner syndrome 1:1000

female births• Cardiac defects

especially coarctatio aorta

• Horseshoe kidney• Short stature• Streak gonads and

infertility• Webbed neck, ptosis• IQ in normal range, some

specific learning diffs

47XXX

• Triple X syndrome• Tall stature in childhood• Normal appearance and fertility• Not associated with structural

abnormalities• Learning disability, speech delay, passive

personality

47,XXY

• Klinefelter syndrome• Males• Tall stature, eunuchoid fat distribution• Small testes and low testosterone• Poor beard growth, gynaecomastia• IQ usually within normal range but < sibs• Some increase in behaviour problems• Increased risk diabetes, varicose veins, breast

cancer

Chromosomal inheritance

• Pedigree doesn’t conform to mendelian pattern

• May be history of miscarriages• Affected children may have different

patterns of physical and developmental abnormality

Genetic conselling• Prenatal testing• “An 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 chorialis– Cairan amnion