Human genetics 2 Human genetics - PowerPoint Presentation

Slide1

Human genetics

Slide2

2Human genetics

Lectures

–

17x2 (Med);

17x1

(

Stom

)

;

Seminars

–

17x3 (Med);

17x2

(

Stom

)

;

3

concluding

tests

(

tests

+

practical part

)

Final

examination

(

tests

+

practical part

)

Consultations

www.biologiemoleculara.usmf.md

http://e.usmf.md

Passkey –

bmgu

Slide3

Average markWritten test 1 (max. 10)Computer test 1 (max. 10)Written test 2 (max. 10)Computer test 2 (max. 10)

Computer

test

3

(max. 10)

Attendance in lectures

(max. 10

)

Scientific report (max. 10, for

Med only)

Slide4

Final gradeAverage per semester – 50%Written (practical) part – 30%Multiple choice test – 20%

Slide5

5

Agricultural revolution

–

XVII-XVIII

century

Industrial revolution

– XIX

century

Informational revolution

– XX

century

Genetic revolution

– XXI

century

Slide6

6Development 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.

Slide7

71981 - molecular methods used for location of genes in chromosomes.

1

985

- PCR used for identification of mutations

.

1

991

– cloning of genes involved in many human diseases:

Dushenne

muscle

distrophy

, cystic fibrosis, neurofibromatosis,

retinita pigmentosum, Marfan

sdr.

Slide8

81994 – McKusick published

„

Mendelian

Inheritance in Man; A Catalog of Human Genes and Genetic Disorders”

.

On-line version OMIM

http://www.ncbi.nlm.nih.gov/omim/

1996 –

preimplantation

diagnostic of embryos obtained by

in vitro

fertilisation.1996

- 2001 more then 1000 genes involved in human pathology were described.

Slide9

9In 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;

Slide10

10

Organism

Cell

Nucleus

Chromosomes

DNA

Amino acids

Protein

Slide11

The “omics” cascade

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Patient

What to do in order to solve this problem

?

What is the problem

?

CLASSIC VISION

GENETIC VISION

Which is the

prognostic and prophylaxis

of complications in this

patient

?

What is

the risk

for this disease for other members of the family

?

Why

this patient

has

this disease

now

?

What possibilities are for prevention

or

reducing

of effect of disease for

patient

or/and

his family

?

Slide13

13

How does

genetics benefit

medicine?

New methods of

diagnostic

New

etiopathological

drugs

Gene therapy

Cell therapy

Prenatal diagnostic

Preimplantation

diagnostic

Family planning

Understanding of

etiopathology

Prognosis of disease

evolution

Slide14

Compartments of genetics

Slide15

15

Human genetics

–

Fundamental and applicative science

Genetics is

fundamental science

because

it is studying

:

structure,

main mechanisms,

main principles, - which ensure keeping,

transmission and expression of human traits, - which ensure formation, development and functions of human organism.

Slide16

16

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

.

Slide17

17

Lymphocytes

–

374

Endothelial cells

–

1031

Salivary glands

–

17

Thyroid gland

–

584

Parathyroid glands

–

46

Smooth muscle

– 127

Mammal glands

– 696

Pancreas –

1094Spleen – 1094Adrenal glands –

658

Gallbladder

– 788

Small intestine

–

297

Placenta

–

1290

Skeletal muscle

–

735

Prostate

–

1283

Leucocytes

–

2164

Brain

–

3195

genes

Eye

–

547

genes

Bons

–

904

genes

Adipose tissue

–

581

genes

Thymus

–

261

genes

Esophagus

–

76

genes

Lungs

–

1887

genes

Heart

–

1195

genes

Liver

–

2091

genes

Erythrocyte

–

8

genes

Trombocytes

–

22

genes

Large intestine

–

874

genes

Kidney

–

712

genes

Testis

–

370

genes

Ovary

–

504

genes

Uterus

–

1859

genes

Embryo

–

1989

genes

Skin

–

620

Synovial membrane

– 813 genes

Genes involved in human development and functions of tissues and organs

Slide18

18

Genetics is a science which study

:

-

heredity and

-

variability of human organism

.

Substrate of heredity and variability

:

Molecular

DNA

Morphologic

Chromosomes

Cellular

Genetic apparatus

Slide19

HeredityHeredity is the passing of traits to offspring (from its parent or ancestors). This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. 

Slide20

Heredity is based on

Slide21

Importance of heredity

Slide22

Variability

Slide23

Importance of variability:

Slide24

Slide25

Mutations

Slide26

26All pathologies have a genetic component

Slide27

27Genetic 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.

Slide28

Causes of mutations

Slide29

Types of mutations

Slide30

30Frequency of genetic disorders

Slide31

31

Genetic diseases

Types

Examples

Chromosomal syndromes

> 1000

Aneuploidies

47, XX, +21 – (Down sdr.);

47, XXY – (Klinefelter sdr.);

45,X – (Turner sdr.);

Chromosomal aberrations

Del, dup,

izo

, r;

ex:

cri du chat

sdr

.

; Wolf-

Hirschhorn

sdr

.;

DiGeorge

sdr

.; Williams

sdr

.

Monogenic diseases

> 9000

Autosomal dominante

FH, ADPKD, neurofibromatosis 1, Marfan sdr., Huntington disease, breast cancer, colon cancer

Autosomal recesive

Phenylketonuria, cystic fibrosis, sickle cell anemia, albinism

X-linked

Hemophilia, muscle dystrophy, color blindness

Mitochondrial

Leber neuropathy

Polygenic diseases

> 100

Adult diseases

Diabetes, hypertension, obesity, cancers

Isolated malformations in children

Defects of neural tube, cleft lips, heart congenital malformations

Slide32

Types of mutations

Slide33

Expression of mutations in phenotype

Slide34

Slide35

Migration

Slide36

Slide37

Norm of reaction is under control of genotypeUnder the pressure of environment gene expression changes to ensure optimal activity of organismShort-time adaptationsLong-time adaptations

Adaptive modifications in the limit of norm of reaction

Slide38

Spontaneous abnormalities induced by environment

Abnormalities produced during development caused by destructive factors

Congenital abnormalities

Determined by teratogen factors

Mime genetic disorders



PHENOCOPIES

Postnatal abnormalities

Slide39

Slide40

40

Levels of organization of genetic material

Genome

–

complement of cell DNA

(

nuclear

+

mitochondrial

)

Chromosome

–

a linkage group of genes

Gene –

elementary unit responsible for synthesis of a protein and expression of a trait

Slide41

Slide42

42

Peculiarities of the human genome

Haploid nuclear genome

3,2 x 10

9

bp

~

30000

genes

Mitochondrial genome

16,6

kb

37

genes

Gene DNA

25%

Extra-gene DNA

75%

Coding DNA

10

%

Non-coding DNA

90%

Single copy or low number copies sequences

60%

Moderate or highly repetitive sequences

40%

Slide43

43

Slide44

Sequences of the Human genome

Slide45

Alternation of genome elementsStructural genesCoding sequence in tandem (e.g., Nucleolar

organizer

)

Spacers

Satellite DNA

(

e.g.

,

centromeric

DNA

)

LINEs

(Long Interspersed Repeated Elements) – 16%SINEs (Short Interspersed Repeated Elements) – 11%LTRs (L

ong Terminal Repeats)VNTRs (Variable Number Tandem Repeats)SSRs (Simple Sequence Repeats)etc.

Slide46

Repetitive elements in human geneHGO (homogentisate 1,2-dioxygenase)Deficiency of enzyme encoded by

HGO

leads to

alkaptonuria

Slide47

47

Human chromosomes

dynamic structures with different shape, level of condensation, gene activity

:

single-chromatid

or two-chromatid

;

chromatin or chromosome

;

transcriptional active or inactive

.

morphologic substrate of H and V

;

supramolecular level of organization of genetic material (

DNA + histones + non-histones + RNA)

Slide48

48

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

Slide49

49Origin of gonosomes

Slide50

50

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)

Slide51

51

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

Slide52

52

The shape of chromosome depends on position of centromere

Structure of metaphase chromosomes

.

R

chromosomal landmarks

Secondary constriction

Satellite

Centromere

Primary constriction

Sister chromatids

Slide53

53

Slide54

54

Human karyotype

Slide55

55

Classification of chromosomes

By length

:

Large

Medium

Small

By shape

:

Metacentric

Submetacentric

Acrocentric

By type

:

Autosomes

Gonosomes

By presence of other

landmarks:

h on

p arm

h on q armsatellites

Groups:A 1-3 B 4,5C X, 6-12D 13-15E 16-18

F 19,20

G 21, 22, Y

Slide56

56

Human karyotype and chromosomal formula

46,XX

46,XY

47,XXY

45,X

47,XY,+21

45,XY,-21

46,XX,5p-