THE ROLE OF GENETICS IN MEDICINE & THE ROLE OF GENETICS IN MEDICINE & Chromosomal Basis of HeredityChromosomal Basis of Heredity

Dr S.M.B.TabeiDr S.M.B.Tabei

THE ROLE OF GENETICS IN MEDICIN THE ROLE OF GENETICS IN MEDICIN

1- Genetics as a Medical Specialty 1- Genetics as a Medical Specialty

M e d ic a l g e n e tic s h a s a c h ie v ed a r ec o g n ize d

r o le a s the sp e c ia lty o f m ed ic in e th a t d e a ls

w ith th e :

A - D ia g n o sis ,

B - T re a tm e n t,

C - M a n a g e m e n t o f h e r ed ita r y d iso r d e rs .

Medical and human geneticists are:

1- At the forefront of investigations into human variability and

hum an heredity

2- Also participating in and benefiting from rapid progress in

m olecular biology, biochem istry, and cell biology.

3- Hum an Genome Project (last decade of the 20th century and

the beginning of the 21 st century

Relevance of Genetics to All Medical Practice Relevance of Genetics to All Medical Practice

1- Expanding genetic knowledge. 2- All physicians and their colleagues need to understand principles of human genetics. 3- The existence of alternative forms of a gene (alleles) in the population; 4- The occurrence of similar phenotypes developing from mutation and variation at different loci; 5- The importance of gene-gene and gene environmental interactions in disease;

6- The role of somatic mutation in cancer and aging; 7- The feasibility of prenatal diagnosis, 8- Population screening; 9- Promise of powerful gene therapies

Thus, genetic principles and approaches are not restricted to anyone medical subspecialty.

It fo cu se s n o t o n ly o n th e p a tien t b u t a lso o n th e en tire fa m ily .

Relevance of Genetics to All Medical Practice Relevance of Genetics to All Medical Practice

Disciplines within Human and Medical Genetics Disciplines within Human and Medical Genetics

Human geneticsHuman genetics: is the science of variation and heredity in human beings,,

Medical geneticsMedical genetics : :deals with the subset of human genetic variation that is of significance in the practice of medicine and in medical research.

Within human and medical genetics, there are many fields of interestWithin human and medical genetics, there are many fields of interest : :

1- cytogenetics 1- cytogenetics 2- molecular and biochemical genetics 2- molecular and biochemical genetics 3- genomics 3- genomics 4- population genetics 4- population genetics 5- developmental genetics 5- developmental genetics 5- clinical genetics 5- clinical genetics 6- Genetic counseling 6- Genetic counseling

CLASSIFICATION OF GENETIC DISORDERS CLASSIFICATION OF GENETIC DISORDERS

genetic variation and mutation in the etiology of a large number of disorders genetic variation and mutation in the etiology of a large number of disorders

Three main types of disorders are recognized:Three main types of disorders are recognized:

1- Single gene disorders :1- Single gene disorders :Caused by individual mutant genes. may be present on only Caused by individual mutant genes. may be present on only one chromosome or on both chromosomes. one chromosome or on both chromosomes.

2- Chromosome disorders2- Chromosome disorders : :an excess or a deficiency of the genes contained in whole an excess or a deficiency of the genes contained in whole chromosomes or chromosome segments. chromosomes or chromosome segments.

3- Multifactorial disorders :3- Multifactorial disorders :Multifactorial inheritance is responsible for a number of Multifactorial inheritance is responsible for a number of developmental disorders resulting in congenital malformations developmental disorders resulting in congenital malformations and for many common disorders of adult life and for many common disorders of adult life

Chromosomal Basis of HeredityChromosomal Basis of Heredity T h e h u m a n g en o m e co n sists o f D N A (g en etic in fo rm a tio n , 3 0 ,0 0 0 g en es):

1 - em b ry o g en esis 2- d ev e lo p m en t 3- g ro w th 4- m eta b o lism 5- rep ro d u ctio n

C h ro m a tin : G en o m ic D N A is co m p lex e d w ith sev era l c la sses o f ch ro m o so m a l p ro te in s (E x c ep t d u r in g c e ll d iv is io n ). C h ro m o so m es : R o d sh a p e o rg a n e lle s in th e n u c leu s o f ea ch ce ll. (V is ib le a s d iscre te s tru ctu res o n ly in d iv id in g ce lls )

K a ryo ty p : T h e n u m b er , s ize s, a n d sh a p es o f th e m eta p h a se

ch ro m o so m es

L o cu s : p rec ise p o sitio n o f ea ch g en e in th e ch ro m o so m es.

G en e m a p : T h e m a p o f th e ch ro m o so m a l lo ca tio n o f th e g en es

C y to g en e tic s : T h e stu d y o f ch ro m o so m es, th e ir s tru c tu re , a n d

th e ir in h er ita n ce ( 1 9 5 6 ).

Chrom osom e analysis : im portant diagnostic procedure in clinical

m edicine.

Som e of these applications:

1- Clinical Diagnosis : Num erous m edical disorders, including som e that

are quite com m on, such as Down syndrom e, Chapters 9 and 10).

2- Gene Mapping: m apping of specific genes to chrom o som es as part of

the Hum an Genom e Project. (Chapter 8).

3- Cancer Cytogenetics : Chrom osom al changes in som atic cells are

involved in the initiation and Pro gression of m any types of cancer (see

Chapter 16).

4- Prenatal Diagnosis: Chrom osom e analysis is an essential procedure

in prenatal diagnosis (Chapter 18).

THE HUMAN CHROMOSOMES S o m a tic ce lls (so m a , b o d y ): A ll c e lls th a t c o n tr ib u te to o n e 's b o d y , e x c e p tio n o f c e lls in th e g e r m lin e . T h e 4 6 ch r o m o so m e s o f h u m a n so m a tic c e lls c o n stitu te 2 3 p a ir s . 2 2 p a ir s A u to so m e c h r o m o so m es ( la rg es t is c h ro m o so m e 1 a n d th e sm a lle s t ch ro m o so m e s 2 1 a n d 2 2 ) a n d tw o se x ch r o m o so m e s in h u m a n (X X in fe m a le s a n d X Y in m a le s ) . A ll h a v e : R e p lic a tio n o r ig in s ,T e lo m e r e s e q u en c e s a n d A ce n tr o m e r

H o m o lo g o u s ch ro m o so m es: M em b ers o f a p a ir o f ch ro m o so m es ca rry m a tch in g g en etic in fo rm a tio n ; o r h a v e th e sa m e g en es in th e sa m e seq u e n ce . O n e m e m b er o f ea ch p a ir o f ch ro m o so m es is in h er ited fro m th e fa -th er , th e o th er fro m th e m o th er . A lle le s: A t a n y sp e c ific lo cu s , h o w e v er , th ey m a y h a v e e ith er id en tica l o r s lig h tly d ifferen t fo rm s o f th e sa m e g en e , ca lled a lle le s S o m a tic ce lls h a v e th e d ip lo id (d ip lo os , d o u b le ) o r th e 2 n ch ro m o so m e co m p lem en t ( i.e ., 4 6 ch ro m o so m es), g a m etes h a v e th e h a p lo id (b a p lo o s , s in g le ) o r th e n co m p le m en t (i.e ., 2 3 ch ro m o so m es)

THE HUMAN CHROMOSOMES

                                                                                              

The classification of chromosomes by the position of the The classification of chromosomes by the position of the centromere. A telocentric chromosome has its centromere at centromere. A telocentric chromosome has its centromere at one end; when the chromosome moves toward one pole of the one end; when the chromosome moves toward one pole of the cell during the anaphase of cellular division, it appears as a cell during the anaphase of cellular division, it appears as a simple rod. An acrocentric chromosome has its centromere simple rod. An acrocentric chromosome has its centromere somewhere between the end and the middle of the somewhere between the end and the middle of the chromosome; during anaphase movement, the chromosome chromosome; during anaphase movement, the chromosome appears as a J. A metacentric chromosome has its centromere appears as a J. A metacentric chromosome has its centromere in the middle and appears as a V during anaphase. in the middle and appears as a V during anaphase.

)d (Sub metacentric

P q

Banding pattern of human chromosomesBanding pattern of human chromosomes

THE LIFE CYCLE OF A SOMATIC CELL THE LIFE CYCLE OF A SOMATIC CELL

Phases of the cell cyclePhases of the cell cycle : The division cycle of most eukaryotic cells is divided The division cycle of most eukaryotic cells is divided into into four discrete phasesfour discrete phases: : M, G1, S and G2M, G1, S and G2. M phase (mitosis) is usually followed . M phase (mitosis) is usually followed by cytokinesis. S phase is the period during which DNA replication occurs. The by cytokinesis. S phase is the period during which DNA replication occurs. The cell grows throughout cell grows throughout interphase, which includes G1, S and G2interphase, which includes G1, S and G2 .The relative .The relative lengths of the cell cycle phases shown here are typical of rapidly replicating lengths of the cell cycle phases shown here are typical of rapidly replicating mammalian cells. mammalian cells.

Cell cycle checkpointsCell cycle checkpointsSeveral checkpoints function to ensure that complete genomes are transmitted Several checkpoints function to ensure that complete genomes are transmitted to daughter cellsto daughter cells. . One major checkpoint arrests cells in G2One major checkpoint arrests cells in G2 in response to in response to damaged or unreplicated DNA. The presence of damaged DNA also leads to cell damaged or unreplicated DNA. The presence of damaged DNA also leads to cell cycle arrest at a checkpoint in cycle arrest at a checkpoint in G1G1. Another checkpoint, in. Another checkpoint, in M M phase, arrests phase, arrests mitosis if the daughter chromosomes are not properly aligned on the mitotic mitosis if the daughter chromosomes are not properly aligned on the mitotic spindle. if the damage is excessive, until the cell is instructed to die by spindle. if the damage is excessive, until the cell is instructed to die by programmed cell death (programmed cell death (a process called apoptosisa process called apoptosis). ).

Replication of chromosomesReplication of chromosomes

Replication is the Replication is the process of duplicating a process of duplicating a chromosomechromosome

• Occurs prior to division

• Replicated copies are called sister chromatids

• Held together at centromere

Mitosis In m ito tic p h a se to en su re th a t ea ch o f th e tw o d a u g h ter ce lls rece iv es

a co m p lete se t o f g en etic in fo rm a tio n .

T h e p ro cess o f d is tr ib u tin g a co p y o f ea ch ch ro m o so m e to ea ch

d a u g h ter ce ll is ca lled ch ro m o so m e seg reg a tio n .

Five stages of mitosis: 1- Prophase 2- Prometaphase3- Metaphase4- Anaphase5-Telophase

ProphaseProphase - Replicated - Replicated

chromosomes condense.chromosomes condense. - the beginning of the - the beginning of the

formation of the mitotic formation of the mitotic spindle. spindle.

- Microtubules organize - Microtubules organize (centrosomes )into a (centrosomes )into a spindlespindle

- The centrosomes - The centrosomes gradually move to take up gradually move to take up positions at the poles of positions at the poles of the cell the cell

PrometaphasePrometaphase- - -nuclear membrane breaks upnuclear membrane breaks up

- - -allowing the chromosomes to disperse within the cell and to attachallowing the chromosomes to disperse within the cell and to attach

- , ,via their kinetochores, to microtubules of the mitotic spindlevia their kinetochores, to microtubules of the mitotic spindle

- - -The chromosomes begin to move toward a point midway betweenThe chromosomes begin to move toward a point midway between

- the spindle poles, a process called congressionthe spindle poles, a process called congression

MetaphaseMetaphase - Chromosomes line - Chromosomes line

up on the metaphase up on the metaphase plate.plate.

- the chromosomes - the chromosomes reach maximal reach maximal condensation. condensation.

- Spindle - Spindle microtubules are microtubules are attached to attached to centromeres of centromeres of chromosomeschromosomes..

AnaphaseAnaphase - Centromeres of - Centromeres of

sister chromatids of sister chromatids of each chromosome each chromosome separateseparate

- Chromosomes - Chromosomes move to opposite move to opposite ends of the cellends of the cell

TelophaseTelophase Nuclear membranes Nuclear membranes

formform

Spindle disappearsSpindle disappears

Division of Division of cytoplasm occurs cytoplasm occurs (cytokinesis)(cytokinesis)

CytokinesisCytokinesis

Cytoplasmic division Cytoplasmic division

occurs after nuclear occurs after nuclear

division is complete. division is complete.

Two cells are formed.Two cells are formed.

The Human Karyotype

MEIOSISMEIOSIS - Meiosis is the type of cell division by which the diploid cells of the germline (primary spermatocytes or primary oocytes, ) give rise to haploid gametes.

-Meiosis consists of one round of DNA synthesis followed by two rounds of chromosome segregation and cell division

The two successive meiotic divisions are called meiosis I and meiosis II The two successive meiotic divisions are called meiosis I and meiosis II

Meiosis I is also known as the reduction divisionMeiosis I is also known as the reduction division because it is the division because it is the division in which the chromosome number is reduced from diploid to haploid in which the chromosome number is reduced from diploid to haploid

In Meiosis I occur In Meiosis I occur genetic recombinationgenetic recombination (also called meiotic crossing (also called meiotic crossing over) occurs .over) occurs .

thus ensuring that none of the gametes produced by meiosis is not thus ensuring that none of the gametes produced by meiosis is not identical to another. identical to another.

MEIOSISMEIOSIS

The First Meiotic Division (Meiosis I) The First Meiotic Division (Meiosis I)

PROPHASE 1 PROPHASE 1

The prophase of meiosis I is a complicated process that differsThe prophase of meiosis I is a complicated process that differs from mitotic prophase in a number of ways, with important genetic from mitotic prophase in a number of ways, with important genetic consequences. consequences.

Several stages are defined: Several stages are defined:

1- Leptotene. 1- Leptotene. 2- Zygotene 2- Zygotene

3- Pachytene 3- Pachytene 4- Diplotene 4- Diplotene 5- Diakinesis 5- Diakinesis

The chromosomes, replicated during the preceding S phaseThe chromosomes, replicated during the preceding S phase and beginning to condense.and beginning to condense. two sister chromatids of each chromosome are so closelytwo sister chromatids of each chromosome are so closely aligned that they cannot be distinguished. aligned that they cannot be distinguished.

homologous chromosomes begin to pair closely along their entire lengthhomologous chromosomes begin to pair closely along their entire length(synapsis ). (synapsis ). DNA sequences into alignment along the length of the entire chromosome. DNA sequences into alignment along the length of the entire chromosome.

The chromosomes become much more tightly coiled. The chromosomes become much more tightly coiled.

Synapsis is complete, Synapsis is complete,

Each pair of homologs appears as aEach pair of homologs appears as a bivalent bivalent (tetrad four chromatids) (tetrad four chromatids) Crossing over takes place Crossing over takes place

the synaptonemal complex disappears, the two components of each bivalent now begin to separate from each other. Although the homologous chromosomes separate, each of their centromeres remains intact. Eventually the two homologs of each bivalent are held together only at points called chiasmata (crosses),

In this stage, the chromosomes reach maximal condensation. In this stage, the chromosomes reach maximal condensation.

Metaphase I begins, as in mitosis Metaphase I begins, as in mitosis

T h e tw o m em b ers o f ea ch b iva len t m ov e ap ar t, an d th e ir resp ectiv e cen trom eres w ith th e a tta ch ed s is ter ch rom a tid s a re d raw n to o p p osite p o le s o f th e ce ll, a p rocess term ed d isju n c tion .

M a n y e r r o r s c a n o c c u r in c e ll d iv is io n . A n a p h a se o f m e io sis I is th e m o st e rr o r ste p , th e e r r o r r e su ltin g in b o th h o m o lo g s o f a c h r o m o so m e p a ir g o in g to th e sa m e , r a th e r th a n o p p o site , p o le s . T h is p a th o g e n ic p r o c e ss is te r m e d n o n d isju n c tio n .

TELOPHASE I

The tw o haplo id sets o f ch rom osom es have norm ally grouped a t

opposite po les o f the ce ll

Cytokinesis

T h e c e ll d iv id es in to tw o h a p lo id l d a u g h te r c e lls a n d en te r s m e io tic in te rp h a se .

In sp e r m a to g e n es is , th e cy to p la sm is m o r e o r le s s e q u a lly d iv id e d b etw e en th e tw o d a u g h te r

c e lls (F ig . 2 -9),

In o o g en es is , o n e p ro d u ct (th e s e c o n d a r y o o cy te ) r e c e iv es a lm o st a ll th e c y to p la sm , a n d th e

r e c ip r o c a l product becomes the first polar body (Fig. 2 -10) .

Mitosis, interphase is brief, and meiosis II begins.

The notable point that distinguishes meiotic and mitotic interphase is that there is no S

phase (i.e., no DNA synthesis) between the first and second meiotic divisions.

Meiosis IIMeiosis II

- Is similar to mitosis except that the chromosome number of

the cell entering meiosis II is haploid.

- The end result is four h a p lo id c e lls , e a c h c o n ta in in g 2 3

c h r o m o so m e s (F ig . 2 - 7 ) .

- B e c a u se o f c r o s s in g o v e r in m e io s is I , th e c h r o m o so m e s o f

th e r e su ltin g g a m e te s a r e n o t id e n t ic a l .

HUMAN GAMETOGENESIS AND FERTILIZATION HUMAN GAMETOGENESIS AND FERTILIZATION

Spermatogenesis Spermatogenesis

Oogenesis Oogenesis