01.02.

2009

Human
genetics

Human genetics

• Lectures - 17x2;
• Seminars – 17x3;
–2 concluding tests
–4 mandatory tests
–Final examination (tests + practical part)
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Agricultural revolution – XVII-XVIII century

Industrial revolution – XIX century

Informational revolution – XX century

Genetic revolution – XXI century

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Development
of Human and Medical genetics

• 1956 – identification of number of human

chromosomes (46,XX; 46,XY);
• 1961- relationship between chromosomal
aberrations and human diseases;
• 1966 – decoding of genetic code, description of
inherited metabolic diseases; prenatal diagnosis
via amniocentesis.
• 1980 – cloning of first human gene.

• 1981 - molecular methods used for location of genes in

chromosomes.
• 1985 - PCR used for identification of mutations.
• 1991 – cloning of genes involved in many human diseases:
Dushenne muscle distrophy, cystic fibrosis,
neurofibromatosis, retinita pigmentosum, Marfan sdr.

• 1994 – McKusick published „Mendelian

Inheritance in Man; A Catalog of Human Genes
and Genetic Disorders”.
• 1996 – preimplantation diagnostic of embryos
obtained by in vitro fertilisation.
• 1996 - 2001 more then 1000 genes involved in
human pathology were described.

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In 2001 „Human genome project” starts.

During 2001 -2003 many visions were changed:

– From structure – to function of genes;

– From location of genes in chromosomes – to sequencing of
DNA;
– From diagnostic of genetic diseases – to calculation of
predisposition to genetic diseases;
– From etiology – to mechanisms;
– From analysis of monogenic traits – to analysis of
polygenic traits;
– From genome – to proteome;
– From medical genetics – to genetic medicine;

Cell

Chromosomes
Organism
Nucleus

Amino acids DNA

Protein

CLASSIC VISION GENETIC VISION

Why this patient has this

disease now?

What possibilities are for

What is the prevention or reducing of
problem? effect disease for patient
or/and its family ?
Patient
What to do for
solving of this What is prognostic and
prophylaxis of consequences
problem? of diseases in patient?

What is the risk for this

disease for other members of
the family?

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Human genetics –
Fundamental and applicative science

Genetics is fundamental science because study:

• structure,
• main mechanisms,
• lows,
- Which ensure keeping, transmission and expression of
human traits,
- Ensure formation, development and functions of
human organism.

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Genetics is a clinic science

Which study relationships between heredity and diseases:
- mutations (monogenic, polygenic or chrs) determine
* a disease or
* a predisposition for a genetic disease.
- Genetic diseases are:
* numerous - 9000;
* frequent - 5-8% in newborns.
- Genetic diseases are present in all medical fields.

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Prenatal diagnostic
Prognosis of disease
evolution

Preimplantativ
diagnostic
New methods of
diagnostic
What genetics
gives to
Family planning
contemporaneous
Understanding of doctors?
Etio-pathology

Cell therapy

New etio-pathological
drugs
Gene therapy
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Lymphocytes – 374 Brain – 3195 genes

Endothelial cells – 1031 Eye – 547 genes
Salivary glands – 17 Bons – 904 genes
Thyroid gland – 584 Adipose tissue – 581 genes

Parathyroid glands – 46 Thymus – 261 genes

Esophagus – 76 genes
Smooth muscle – 127
Lungs – 1887 genes
Skeletal muscle – 735
Genes involved in human
Mammal glands – 696
Heart – 1195 genes
Liver – 2091 genes
Pancreas – 1094
development and functions of
Spleen – 1094
Erythrocyte – 8 genes
Trombocytes – 22 genes
Adrenal glands – 658
tissues and organs
Gallbladder – 788
Large intestine – 874 genes
Kidney – 712 genes
Small intestine – 297 Ovary – 504 genes
Placenta – 1290 Testis – 370 genes
Prostate – 1283 Uterus – 1859 genes
Leucocytes – 2164 Embryo – 1989 genes
Skin – 620 Synovial membrane – 813 genes
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All pathologies have a genetic

component
• Mutations (modifications of genetic material)
– Responsible for a disease / syndrome
– Responsible for predisposition to a disease
– Change resistance against infectious agents
– Change the metabolism of drugs
– Influence the regeneration of tissues
– Etc.

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• Genetic diseases are numerous.

• There are known over 10.000 of disease determined or conditioned by genetic

factors.

• Are highly diverse.

• May appear at any age.

• May affect any organ present in all fields of medicine.

• Present in 5-8% of newborns.

• Genetic factors may be responsible for reproductive disorders (sterility,

miscarriage).

• Genetic diseases responsible for infantile mortality and morbidity.

• Genetic diseases are chronic diseases and produce physical or mental

disorders.

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Genetic Types Examples

diseases
47, XX, +21 – (Down sdr.);
Aneuploidies 47, XXY – (Klinefelter sdr.);
 Chromosomal
45,X – (Turner sdr.);
syndromes
Del, dup, izo, r;
> 1000 Chromosomal
ex: cri du chat sdr.; Wolf-Hirschhorn sdr.; DiGeorge sdr.;
aberrations Williams sdr.
FH, ADPKD, neurofibromatosis 1, Marfan sdr., Huntington
Autosomal disease, breast cancer, colon cancer
dominante

 Monogenic
Autosomal Phenylketonuria, chiytic fibrosis, sickle cell anemia,
diseases recesive albinism
> 9000 Hemophilia, muscle dystrophy, color blindness
X-linked

Leber neuropathy
Mitochondrial

Diabetes, hypertension, obesity, cancers

Adult diseases
 Polygenic
diseases Defects of neural tube, cleft lips, heart congenital
Isolated
> 100 malformations
malformations

in children 16

Frequency of genetic diseases

Polygenic
10%
diseases

Monogenic
diseases 2%

Chromosomal
0,70%
sdr.

0,00% 2,00% 4,00% 6,00% 8,00% 10,00%

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The direction in human genetics which study genetic diseases is

called medical genetics.
Clinical genetics is a part of medical genetics.

Human genetics

Medical genetics

Clinical genetics

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Genetics is a science which study:

- heredity and
- variability of human organism.
Substrate of heredity and variability:

Molecular Morphologic Cellular

DNA Chromosomes Genetic

apparatus

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Genetic apparatus of human cells

Genetic material: Cell components ensure:

a) 46 mol. Nuclear DNA;
b) 2-10 mol. mtDNA
Realization of GI Transmission of GI
a) Transcription a) Replication
apparatus; apparatus;
Nucleus
b) Translation b) Mitotic
Mitochondria
apparatus apparatus
Ribosomes
!!! RIBOSOMES !!! CENTRIOLS
Centriols 20

Levels of organization of genetic material

I. Genome – complement of cell DNA
(nuclear + mitochondrial)
II. Chromosome – a linkage group of genes
III.Gene – elementary unit responsible for
synthesis of a protein and expression of a
trait

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Peculiarities of human genome

Haploid nuclear genome Mitochondrial genome
3,2 x 109 p.b. 16,6 kb
~ 30000 genes 37 genes

Gene DNA Extragenic DNA

25% 75%

Coding Noncoding Single and low Moderate and

DNA DNA copy sequences highly repetitive
10% 90% sequences
60%
40%

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Chromosome 1 2 3 4 5 6 7 8
No. of genes 2782 1888 1469 1154 1268 1505 1452 984
Length, Mb 247 243 200 191 180 171 159 146

Chromosome 9 10 11 12 13 14 15 16
No. of genes 1148 1106 1848 1370 551 1276 945 1109
Length, Mb 140 135 134 132 114 106 100 89

Chromosome 17 18 19 20 21 22 X Y
No. of genes 1469 432 1695 737 352 742 1336 307
Length, Mb 79 76 64 62 46,9 50 155 58
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Obligatory elements Facultative elements

Structural genes; Mobile elements

tRNA, rRNA genes; Pseudogenes
Palindroms; Foreign DNA
Satellite DNA

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Non-coding sequences of human genome

SINEs – transposones, initiation of replication

LINEs – retrotransposones, conjugation of chromosomes

during meiosis I
Satellite DNA – structural role, constitutive
heterocrhromatin (c, t, h, s)

Minisatellite DNA – markers of chromosomes

Microsatellite DNA – individual genetic markers

LINEs (Long interspersed elements) – 16%

SINEs (Short interspersed elements) – 11%

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Human chromosomes
• morphologic substrate of H and V;
• supramolecular level of organization of genetic material (DNA +
histones + non-histones + RNA)

• dynamic structures with different shape, level of condensation,

gene activity:
• single-chromatid or two-chromatid;
• chromatin or chromosome;
• transcriptional active or inactive.

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• self-reproduction of chromosomes takes place during S phase

of interphase (replication).

• chromosomes represent linkage groups of genes :

- each chrs contains a specific number of genes;
- each gene has a specific place in chrs - locus;
- genes of one chromosome are inherited together

• a diploid set of chromosomes is called karyotype:

23 pairs: 22 pairs of autosomes +
1 pair of gonosomes (XX or XY).
Pair of chromosomes = homolougus chromosomes 27

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Origin of gonosomes

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• landmarks of karyotype:
relative and absolute length of chrs,
position of centromere = primary constriction - c,
presence of secondary constrictions - h,
presence of satellites - s

• chromosomes may be analyzed during:

• metaphase (homogenous painting or banding)
• prometaphase (banding)
• interphase (hybridization with fluorescent probes)

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• chromosomes have heterogeneous structure :

- Coding and non-coding sequences;
- euchromatin and heterochromatin,
- single copy and repetitive sequence;
-GC and AT reach sequences;
- transcribed and non-transcribed sequences;
- sequences associated with basic and basic proteins .
!!! This explains origin of chromosomal bands

• Chromosomal number and structural abnormalities induce

developmental abnormalities - sundromes

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Structure of metaphase chromosomes.

Rchromosomal landmarks
Satellite

Secondary
constriction

Centromere Primary
constriction

Sister
chromatids

The shape of chromosome depends on position of

centromere
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Ic p p q x100

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Human karyotype

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Classification of chromosomes

By length: By shape: By type:

-Large -Metacentric -Autosomes

-Medium -Submetacentric -Gonosomes

-Small -Acrocentric

Grupes:
By presence of
other lendmarks: A 1-3 E 16-18
-h on p arm B 4,5 F 19,20
-h on q arm C X, 6-12 G 21, 22, Y
-satellites D 13-15
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Human karyotype and chromosomal

formula

46,XX
46,XY
47,XXY
45,X
47,XY,+21
45,XY,-21
46,XX,5p-

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