genetics 1-csbrp
TRANSCRIPT
Genetic Disorders
Dr.CSBR.Prasad, M.D.
Incidence of genetic disorders
We all carry genes that are potentially hazardous:
1. Some manifest even before our birth
2. Some are recessive3. Some will be triggered by
environmentA working party of the Royal College of Physicians has estimated that 2-3% of births result in babies with either congenital or genetically-determined abnormalities.
Incidence of genetic disorders
~5% of individuals will develop some form of genetic disorder by the age of 25 years
The lifetime risk of genetic diseases is estimated to be 670 per 1000
Some facts <2% of the human genome codes
for proteins >½ represents blocks of repetitive
nucleotide codes whose functions remain mysterious
Humans have a 30,000 genes Any two individuals share 99.9% of
their DNA sequences Humans differ from chimps by 1%
genetic uniqueness
Some terms
GenomicsProteomicsHereditary,
Congenital, Familial
MutationTranslation /
Transcription
HeterozygousHemizygousHomozygusAutosome RecessiveDominant
Genetic Disorder
Advances in Molecular biology involving recombinant DNA technology
Molecular basis of human diseases Functional Cloning - Classical Positional Cloning
Production of human biologically active agents Eg. Growth hormone, Erythropoietin.
Gene therapy Disease diagnosis
Karyotype
Study of chromosomes A karyotype is used to display the
number, types and appearance of chromosomes
Human somatic cell – 46 chromosomes 22 pairs of autosomes 2 sex chromosomes Diploid numbers – 2N
Karyotype
Male – 46, XY Female – 46, XX Human Germ cells – Haploid
cells –N 23 chromosomes Sperms – 23 X or 23 Y Ovum – 23 X
Karyotype - preparation & analysis
1. Cells (from blood, amniotic fluid, etc) are grown in vitro to increase their number
2. Cell division is then arrested in metaphase with colchicine
3. Cells are centrifuged and lysed to release chromosomes
4. Chromosomes are stained, photographed, and grouped by size and banding patterns
Normal karyotype
KaryotypeChromatid - An arm
of a chromosomeCentromere is the
place where two chromatid meet each other
TelomereTelomere – is the distal end of chromosome
Karyotype
Based on the location of centromere chromosome grouped into 4 types – Metacentric – Central centromere Submetacentric - Short arm (p) , Long arm
(q) Acrocentric – Eccentric centromere Telocentric
Karyotype
Each arm is divided into 2 or more regions
Each region is divided into bands and sub bands
They are numbered from centromere outwards ex. Xp 21.2
Karyotype Banding techniques for karyotype study
G Banding – Giemsa stain (400 – 800 bands) Q Banding – Quinacrine florescent stain R Banding – Reverse Giemsa stain C Banding
Based on the length of chromosomes they are divided into 7 groups – A to G (Denver classification)
Normal karyotype
Numerical abnormality
Diploid – 46 (2N)
Haploid – 23 (N)
Numerical abnormality
Polypoidy – No. of chromosomes which is EXACT multiple of haploid numbers
• Triploid – 3N (69 ch)• Tetraploid – 4N (92 ch)
Aneuploidy – No of chromosomes which is not an exact multiple of haploid numbers
Monosomy – 45 Ch - 45 XO (Turner’s) Trisomy – 47 Ch - 47 XY + 21 (Down’s)
Name a normal cell with polyploidy?
Megakaryocyte
Mechanism of Aneuploidy Non disjunction – Failure of
chromosome to separate normally during cell division result in monosomy or trisomy
Anaphase lag - One chromosome fail to reach the pole of dividing cell at the same time and is left out of nucleus of daughter cell
Mosaicism – Individual has 2 or more types of cell lines derived from same zygote
ex. cancers
Structural abnormalities
Structural abnormalitiesStructural abnormalities
Deletion
Inversion
Duplication
Translocation
Ring chromosome
Isochromosome
Structural abnormalities
Translocation – Transfer of a segment of one chromosome to another non-homologous chromosome
1. Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11)
2. Robertsonian translocation
Structural abnormalities - Translocation Balanced translocation
Structural abnormalities
2. Robertsonian translocation – When two acrocentric chromosome lose their short arm and fuse at the centromere so that eventually the cell is left with 45 chromosomes.
Robertsonian Translocation
Structural abnormalitiesTranslocation: Ex: Acute Myelogenous
Leukemia Philadelphia chromosome t(9,22)
Structural abnormalities
Deletion Loss of part of the DNA from a
chromosome. Deletion may be from terminal portion/ Middle portion
Deletion – Terminal deletion of short arm
Deletion – Terminal deletion of long arm
Deletion –Deletion of long arm
Can you give one best example for deletion resulting in disease?
Alfa-Thalassemia
Structural abnormalities
Ring chromosome: When both ends of a chromosomes are lost and the damaged ends join together, they form Ring chromosomes
Deletion – Ring
chromosome
Diseases in which ring chromosomes are seen
include:
Some tumors of adipose tissueFanconi’s anemia
Structural abnormalitiesDuplications: Ex: Fragile X syndrome The most common form of mental
retardationThe X chromosome have over 700
repeats due to duplications (Normal upto 29)
Affects 1:1500 males, 1:2500 females
Structural abnormalitiesDuplications: Ex: Fragile X syndrome
Structural abnormalities
Isochromosome formation result when the centromere divides in a tranverse plane rather than in a normal long axis of the chromosomeEx. One with 2 short arms & one with 2 long arms
Isochromosome
Structural abnormalities
Inversion: Rearrangement that involves two breaks within a single chromosome with reincorporation of inverted segment Paracentric Pericentric
Inversion – (long arm)
Paracentric Pericentric
Mutation
Permanent change in the DNA Mutation in germ cell –
Inherited diseases Mutation in somatic cells –
Cancer, congenital malformation
Mutation
Genomic Mutation – Monosomy/ trisomy
Chromosomal Mutation – rearrangement of genetic material with visible structural changes in chr.
Gene Mutation – Submicroscopic1. Point mutation2. Frame shift mutation
Mutation
Point mutation – single nucleotide base is substituted by different base.
e.g. sickle cell disease – glutamic acid replaced by valine at 6th position from the aminoterminal of beta globin chain of Hemoglobin
Mutation
Frame shift mutation One or two base pairs may be
inserted/ deleted from the DNA, leading to alterations in the reading frame of the DNA strand
Frameshift Mutation
(1-2 bp(s) deletion) (1-2 bp(s) insertion)
Insertion
Duplication
Down’s Syndrome
Down’s Syndrome
Trisomy 21, 47 XY + 21 Most common chromosomal
disorder 1 in 700 live births Due to non disjunction Or
Robertsonian translocation Parents – Normal karyotype Risk factor Mother over 35 years
The fertilization of a genetically abnormal egg carrying an extra chromosome 21 (orange) by a normal sperm (green) produces an embryo
with Down syndrome (purple).
Trisomy 21 -- Down’s syndome
Click to see animation on Non-Disjunction
Down’s Syndrome
Clinical Features Major cause of mental retardation IQ 25-
50 Very gentle, shy & friendly Diagnosed at birth by “mongol” look –
Flat facial profile, oblique palpebral fissure, epicanthic folds
40 % of patients – CHD ASD, Ostium primum, A-V valve
malformation, VSD
Down’s syndromeDown’s syndrome
Normal Mongols Down’s baby
With Mongoloid look
Down’s syndrome
Down’s syndromeDown’s syndrome
Normal hand Simian crease
Down’s syndromeDown’s syndrome
Simian creaseSimian crease
Down’s syndromeDown’s syndrome
Simian crease
Down’s syndrome
Down’s syndrome
Umbilical hernia
Down’s syndromeDown’s syndrome
Down’s Syndrome
Acute Leukemia – 10 to 20 fold ^ risk Alzheimer’s disease < 40 years of age Abnormal immune response – Infection Simian crease, Hypotonia, Umbilical
hernia
Down’s Syndrome
Acute Leukemia – 10 to 20 fold increased risk
Transient Myeloproliferative Transient Myeloproliferative SyndromeSyndrome
END
KlinefelterKlinefelter’s ’s
SyndromeSyndromeChromosomes
In sperms:
X (green)
Y (red) &
18 (aqua)
END
Marfan’s syndrome
Normal
: Tricuspid valve : Pulmonary valve : Aortic valve : Mitral valve
Marfan’s
Marfan’s syndrome
Aortic aneurysm and Aortic dissection
Chromosomes 23
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y
first meiotic division: prophase: leptotene
normal trisomy 21
chromosome 21
other chromosomes
© 2003 H. NUMABE M.D.
second meiotic division: second polar bodies
normal trisomy 21
chromosome 21
other chromosomes
© 2003 H. NUMABE M.D.
Marfan’s syndrome
Autosomal dominant fibrillin-1(FBN1) gene mutation