Genetics of Human
Marie Černá
Lecture No 422-H
Human Genome Project
• Genome – the complete set of information
in an organism’s DNA
• Human genome (1 haploid set) – 1 m long:
30 000 genes – a gene ~ 30 000 bp long
(dystrophin gene 2 400 000 bp long)
3 x 109 nucleotides (base pairs – bp, b)
3 000 cM (centiMorgans - 1 cM = 1 Mb)
chance of recombination between 2 loci
Human Genome Project
Basic genetic terms:
• GENE - a sequence of DNA molecule that determines
primary structure of another macromolecule
(polypeptide or non-translated RNA)
• GENOME – set of all genes in a cell or in an organism
• GENOTYPE – genetic constitution of a single locus or
genetic constitution of all loci
• PLEIOTROPY – mutation of a single gene has multiple
phenotypic effects - symptoms
(syndrome = set of symptoms)
• MODIFICATION – nonheritable change of phenotype
• PHENOCOPY – nonheritable change of phenotype
imitating certain genotype
(peroxide blonde)
• LOCUS – the position on the chromosome =
the allele localization
• ALLELE – particular (alternative) form of a gene
Allele
• standard, allele polymorphism
= 2 and more standard allele per 1 gene
• mutant, multiple allelia
= 2 and more mutant allele per 1 gene
= allelic heterogeneity
• HETEROGENEITY
- allelic – two and more alleles of one gene in population
lead to the same or similar phenotype
(Duchenne and Becker muscular dystrophy)
- nonallelic (locus) – mutations of different genes lead to
the same or similar phenotype
(congenital deafness ) = GENOCOPY
Monogeny Polygeny
Heterogeny
or
Gene
mutation
Pleiotropy
Gene
linkage
phenylketonuria
hemophilia
daltonism
m.dystrophy
or
Trait
Example
cystic
fibrosis
height
deafness
PHENOTYPE – observed biochemical, physiological and
morphological characters determined by genotype and
environment in which this genotype is expressed
genotype + environment
CHARACTERS :
monogenic, qualitative
- superiority of genotype
– 1 gene of big effect (major gene)
polygenic, quantitative, multifactorial
- significant influence of the environment
– more genes of small and additive effect (minor genes)
Monogenic inheritance
Mendelian genetics – 10%
rare disease = occurrence ≤1:2000
total 7 000 rare diseases
400 mutations per man
• autosomal – independent on the sex,
genes localized on autosomes
• gonosomal – dependent on the sex,
genes localized on gonosomes X or Y
Monogenic inheritance
balanced polymorphism
heterozygote advantage
• complete dominance:
at the level of all organism
• incomplete dominance:
at the biochemical level
• codominance (blood group):
at the molecular level
Sickle cell disease (AR)
Sickle cell disease (AR)
Sickle cell disease (AR)
Sickle cell disease (AR)
Thalassemia alpha (AR)
Thalassemia alpha (AR)
Thalassemia beta (AR)
Thalassemia beta (AR)
Thalassemia beta (AR)
Glucose-6-phosphate dehydrogenase
deficiency (XR)
Polygenic inheritance
multifactorial – 90 %
many genes
environmental effect
on phenotype
Gaussian distribution
quantitative
character
Interaction of
environment and genotype
• Internal environment: hormones
– premature baldness
– atherosclerosis
• External environment: nutrition,
temperature
– quantity + quality of nutrition and height
– termolabile enzyme
for dark pigment in rabbits
Interaction of
environment and genotype
external factor
1
external factor
2
gene pool
1
gene pool
2
external factor
3
external factor
5
external factor
4
gene pool
3
gene pool
5
gene pool
4
Atherosclerosis
is a degenerative disease of the vessel wall.
Clinically, it is manifested by serious and
frequent complications:
• ischemic heart disease
• cerebrovascular accident (stroke)
• ischemic disease of lower limb
Risk factors of atherosclerosis
unaffectable
• personal history - ischemic heart disease or
another manifestation of atherosclerosis
• genetic factors - family history of ischemic heart
disease or another manifestation of
atherosclerosis: in relatives of the first degree, ♂
up to the age of 55 and ♀ up to the age of 65
• sex – higher risk in ♂ than in ♀ - hormones
• age – higher risk in ♂ above 45 years of age and
in ♀ above 55 years of age
Risk factors of atherosclerosis
affectable
• hyperlipoproteinemia (↑LDL and ↓HDL cholesterol)
• smoking cigarettes
• arterial hypertension
• disorder of saccharide tolerance (diabetes mellitus)
• obesity of central type
• lack of physical activity
• increased level of homocystein
• increased level of uric acid (gout)
• increased level of thrombogenic factors (fibrinogen)
Heritability of atherosclerosis
• in 80-90% of population is a tight
balanced state between genetic and
environmental factors (multifactorial)
• 5-10% of population has a considerable
genetic predisposition (polygenic)
• 5-10% of population has a considerable
genetic resistance (polygenic)
• 1% of population carries gene mutation
(monogenic)
Lipoprotein particles
macromolecules formed by
• fat
• protein (apolipoprotein, apoprotein)
apo A → HDL, chylomicrons
apo B → LDL, VLDL, chylomicrons
apo C → chylomicrons, VLDL, LDL, HDL
apo E → chylomicrons, VLDL, LDL, HDL
alleles 2, 3, 4
Lipoprotein particles
The compartment of production:
apo A
intestine, liver
apo B - apo B-48
intestine
- apo B-100
liver
apo C
liver
apo E
liver
Lipoprotein particles
Lipoprotein particles
apo(a)
apo B-100 + apo(a) form the lipoprotein Lp(a)
The individual isoforms of apo(a) present
an important factor determinative the
concentration of Lp(a), while between the size
of isoprotein apo(a) and the concentration of
Lp(a) is a reversal relation.
Predisposition to atherosclerosis
1) decreased level of apoA
2) increased level of apoB and
apo(a) - small molecules
3) increased level of apoE4
Monogenic form
Familial hypercholesterolemia
• autosomal dominant disease
• in 5% of myocardial infarction patients under 60y.
• cause: dysfunction of LDL receptors (gene on 19p)
• variable expressivity
- allelic heterogeneity - 300 mutations in the gene
- locus heterogeneity – apoB gene
Familial hypercholesterolemia
Heterozygotes: occur with a frequency of 1 : 500
have elevated serum cholesterol 7-10 mmol/l
up to the age of 30 – manifest clinical symptoms of HLP
up to the age of 50 – manifest cardiovascular diseases
Homozygotes: occur with a frequency of 1 : 1 000 000
have very high serum cholesterol 15-30 mmol/l
in childhood – manifest heart failures
up to the age of 20 – die of coronary artery disease
Gene dosage of LDL receptor
in dependence on concentration of cholesterol
Various mutations of the LDL receptor gene
are grouped into five functional classes:
Class 1 – accounting for about 20% of the total, do not
produce any detectable LDL receptor protein (null alleles)
Class 2 – block the transport of the nascent LDL receptor
protein from the endoplasmic reticulum to the Golgi
apparatus
Class 3 – encode receptors that reach the cell surface, but
fail to bind ligand
Class 4 – encode receptors that reach the cell surface and
bind LDL, but are not localized to clathrin-coated pits and
fail to internalize bound LDL
Class 5 – encode receptors that bind and internalize LDL
receptor in coated pits, but fail to release the ligand in
endosomes and fail to recycle back to the cell surface
(recycling – defective mutants)
Biological role of LDL receptor in the cell
and 5 classes of its mutations
The structure of gene for LDL receptor
with localization of its mutations
Xanthoma of Achilles tendon
Comparison of severity of symptoms
in homozygotes (hands) and in heterozygotes (legs)
Affection of FH course by sex
Use of resin
and inhibitor of HMG-CoA reductase
in therapy of FH
Heritability of type 2 diabetes
• in 80-90% of population is a tight
balanced state between genetic and
environmental factors (multifactorial)
• 5-10% of population has a considerable
genetic predisposition (polygenic)
• 5-10% of population has a considerable
genetic resistance (polygenic)
• 1% of population carries gene mutation
(monogenic)
Risk factors of type 2 diabetes
Insulin secretion disorder
• transcription factor 7 - like 2 gene (TCF7L2 gene)
• genes of cell cycle regulation
• genes for development of liver and pancreas
• genes for apoptosis
• genes for ion channels/transporters (K+, Ca2+ / Zn2+)
Insulin resistance
• fat mass and obesity-associated gene (FTO gene)
• peroxisome proliferator-activated receptor gamma gene
(PPARG gene)
– transcription factor for binding
fatty acids, prostaglandins, thiazolidinediones
Monogenic forms
MODY
neonatal diabetes
– permanent
– transient
- kalium inward rectifier 6.2 KIR6.2 (KCNJ11 gene)
- sulfonylurea receptor SUR1 (ABCC8 gene)
diabetes with deafness
- mitochondrial DNA mutations
MODY
(MATURITY–ONSET DIABETES OF THE YOUNG)
• Autosomal dominant type of heredity
• Onset at least in one family member up to the age
of 25
• Adjustment of hyperglycemia fasting
at least two years without insulin
• Non-ketosis diabetes
• Disorder of insulin secretion without dysfunction
Mutations in the gene coding glucokinase
- glucokinase, GCK-MODY (chromosome 7 p)
• this enzyme changes glucose into glucose-6phosphate, which stimulates the -cells to an
insulin secretion  glucokinase = glucose sensor
• diabetes with mild course without complications
Mutations in the genes coding
transcription factors
hepatocyte nuclear factor-1, HNF-1,
HNF1A-MODY
(chromosome 12 q), the most frequent form
hepatocyte nuclear factor-4, HNF-4,
HNF4A-MODY
hepatocyte nuclear factor-1β, HNF-1β,
HNF1B-MODY
insulin promoter factor, IPF1,
IPF1-MODY
insulin transcription factor NEUROD1, NEUROD1-MODY
insulin transcription factor KLF11,
KLF11-MODY
(KLF11 = Krüppel-like zinc finger 11)
Literature - basic
Genetics in Medicine, sixth edition, revised reprint
Thompson & Thompson
Saunders, 2004
Chapter 11: Lessons from the hemoglobinopathies
pages 181 – 202
Chapter 15: Genetics of D.with Complex Inheritance
pages 289 – 310
Clinical Case Studies: 9, 17, 21, 28, 30
Literature - additional
Medical Genetics at a Glance, second edition,
Dorian J. Pritchard & Bruce R. Korf
Blackwell Publishing, 2008
Part 2: Medical genetics 30-32
pages 76 – 83