review of medical genetics

Medical Geneticsbczhao@tsmc.edu.cn

• PART 1: MCQs (40, 1points each, 40 in total)• PART 2: true of false (10, 1points each, 10 in total)• PART 3: Definitions (10, 2points each, 20 in total)• PART 4: Long answer questions (you can choose

some of the 7 questions, but the highest score is 30 in total)

The final marks = The marks of the exam ×80% +The marks of the experiment(karyotype anlysis) ×10% +The marks of attendence (10 + 2 - absent time)

Introduction

Genome

• Difinition: the sum total of the genetic information of our species.

Classification of Genetic Discorderes

Among disorders caused wholly or partly by genetic factors, three main types are recognized :

• Chromosome disorders: A clinical condition caused by an abnormal chromosome constitution in which there is duplication, loss, or

rearrangement of chromosomal material. • Single-gene disorders: A disorder due to one or a

pair of mutant alleles at a single locus. • Multifactorial disorders: The type of non-mendelian

inheritance shown by traits that are determined by a combination of multiple factors, genetic and environmental. Also termed complex inheritance.

• Mitochondrial Disorders

Sickle cell anemia

Mitochondrial Disorders--Maternal inheritance

• Since almost all the mitochondria of fertilized eggs are contributed by the oocyte rather than the sperm, germ-line mutations in the mitochondrial DNA are transmitted to the next generation by the mother.

Homologous and Alleles

• Homologous chromosomes : A pair of chromosomes, one inherited paternally, the other maternally, that pair with each other during meiosis I, undergo crossing over, and separate at anaphase I of meiosis. Homologous chromosomes are generally of similar size and shape when they are viewed under the microscope and contain the same loci, except for the two sex chromosomes in males (X and Y ), which are only partially homologous.

• Alleles : At any specific locus, the homologues may have either identical or slightly different forms of the same gene, call alleles.

DNA structure

DNA structure

• DNA is a polymeric nucleic acid macromolecule of nucleotide.

• There are three components to a nucleotide

a pentose sugar, a phosphate group,

and a nucleotide base

Purines and pyrimidines

DNA:DNA:

A,G,C,T

RNA:RNA:

A,G,C U

Complementary pairing

• complementary: (of two nucleic acid sequences) capable of precisely base-pairing with one another by matching of G ≡C and A T or U, like the two ﹦strands of a DNA double helix.

• Length measurements: bp kb

Organization of human chromosome

• The DNA double helix in the cell nucleus is packaged by special proteins termed histones.

• The formed protein/DNA complex is called chromatin.

Chromatin contains about twice as much protein as DNA.

Nucleosome The nucleosome is the basic structural unit of chromatin.

Organization of the human Genome

Organization of human Genome

• Of the 3 billion base pairs of DNA in the genome:

(1) Single-Copy DNA sequence and Repetitive DNA sequence :

• Single-copy DNA ： The type of DNA that makes up most of the genome.

• Repetitive DNA sequence : DNA sequences that are present in multiple copies in the genome.

• Housekeeping gene: Genes expressed in most or all cells because their products provide basic functions.

CELL DIVISION

• Cell division is the process by which a parent cell divides into two  daughter cells.

Three types of cell division

Five stages of mitosis

• The process of mitosis is continuous, but five stages are distinguished:

♫Prophase

♫Prometaphase

♫Metaphase

♫Anaphase

♫Telophase

Meiosis• Meiosis consists of one round of DNA synthesis

followed by two rounds of chromosome segregation and cell division.

1. Difference in prophase

• Prophase I is a long and complex phase, can be further divided into 5 stages: leptotene, zygotene, pachytene, diplotene, diakinesis.

Condensation

Pairing

Recombination

Coiling

Recondensation

5 stages of prophase I

• Leptotene: In this stage of prophase I, individual chromosomes—each consisting of two sister chromatids—change from the diffuse state they exist in during the cell's period of growth and gene expression, and condense into visible strands within the nucleus. During leptotene, lateral elements of the synaptonemal complex assemble.

• Zygotene: At this stage, the synapsis (pairing/coming together) of homologous chromosomes takes place, facilitated by assembly of central element of the synaptonemal complex The paired chromosomes are called bivalent or tetrad chromosomes.

• Pachytene: Nonsister chromatids of homologous chromosomes may exchange segments over regions of homology.  At the sites where exchange happens, chiasmata form. The exchange of information between the non-sister chromatids results in a recombination of information;

• Diplotene: The chromosomes themselves uncoil a bit, allowing some transcription of DNA. However, the homologous chromosomes of each bivalent remain tightly bound at chiasmata, the regions where crossing-over occurred.

• Diakinesis: Chromosomes condense further during the diakinesis stage, This is the first point in meiosis where the four parts of the tetrads are actually visible. Sites of crossing over entangle together, effectively overlapping, making chiasmata clearly visible.

(1) Leptotene

• The chromatin begin to condense into chromosomes.

• The initial association of homologous chromosomes.

Chromosomes have already replicated.

The two chromatids are so closely aligned that they cannot be distinguished.

(2) Zygotene-1• The close association of homologous

chromosomes called synapsis.

At this stage, homologous chromosomes begin to align along their length.

The process of pairing or synapsis is normally precise, bringing corresponding DNA sequences into alignment along the length of the entire chromosome.

Pachytene: Bivalent ≈ tetrad

• A bivalent, sometimes referred to as a tetrad, is a pair of associated homologous chromosomes held together by Synaptonemal complex.

• Each replicated chromosome is composed of two chromatids.

• DiploteneDiplotene is the fourth stage of meiotic prophase I. The synapsed chromosome pairs consist of four chromatids (tetrad) each. Chiasmata are visible.

(4) Diplotene

After recombination, the synaptonemal complex begins to break down, and the two component of each bivalent now begin to separate from each other .

The average number of chiasmata seen in human spermatocytes is about 50, that is several per bivalent.

• DiakinesisDiakinesis is the last stage of meiotic prophase I. The chromatin has continued to condense, so that the chromosomes are as short and thick as they will get before metaphase I.

(5) Diakinesis

Chromosomes condense further during the diakinesis stage.

Other than this observation, the rest of the stage closely resembles prometaphase of mitosis; the nucleoli disappear, the nuclear membrane disintegrates into vesicles, and the meiotic spindle begins to form.

From prophase to Metaphase Ⅰ Ⅰ

2. Difference in metaphase

Metaphase(46 chromosomes)

Metaphase I(23 pairs)

Metaphase II(23 chromosomes)

3. Difference in anaphase

Anaphase(separate the sister

chromatids )

anaphase I(separate the

homologus )

anaphase II(separate the sister

chromatids )

4. Difference in telophase

• Here, the chromosomes at the equatorial plate are separated and pulled towards the opposite ends of the cell by the spindle apparatus. Spindle fibers also cause the poles to move farther from each other, thus giving the cell an oval shape.

Centromeres split and the sister chromatids are separated in this phase. These sister chromatids are then pulled towards the opposite ends, to be assorted into the resultant daughter cells.

The centromeres remain intact. Chromosomes separate from their homologous partners, but the pairs of sister chromatids remain intact during anaphase I. These pairs split up during anaphase II.

The differences between meiosis and mitosis

The human karyotype

Stucture of chromosome

①chromotid：②centromere ， ki

netochore③arm④secondary

constriction⑤satellite⑥telomere

Short arm（ p）

Long arm（ q）

chromotid

secondary constriction

euchromatic 

region

heterochromatin region

satellite

② Centromere (primary constriction)

• The centromere is apparent as a primary constriction , a norrowing or pinching-in of the sister chromatids due to formation of kinetochore.

telomere

• A telomere is a region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes.

Telomere and telomerase

• Telomerase is a ribonucleoprotein that is an enzyme that adds DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere regions.

karyotype analysis

• Karyotypes describe the number of chromosomes, and what they look like under a light microscope. Attention is paid to their length, the position of the centromeres, banding pattern, any differences between the sex chromosomes, and any other physical characteristics. The preparation and study of karyotypes is part of cytogenetics.

Details of Denver system

gruop chromosome size position of the centromeres

satellite secondary constriction

A 1 ～ 3 biggest Metacentric (1,3) no 1

Submetacentric(2)

B 4 、 5 Second biggest

Submetacentric no

C 6 ～ 12, X Medium  Submetacentric no 9

D 13 ～ 15 Medium  acrocentric yes

E 16 ～ 18 small metacentric no 16

Submetacentric

F 19 、 20 Second smallest

metacentric no

G 21 、 22 、Y

smallest acrocentric 21, 22 yes

Y 无

• Chromosomes are often classified by the position of the centromere into four types:

• metacentric

• Submetacentric

• Subtelocentric

• telocentric

Chromosome staining methods

• The 24 types of chromosome found in the human genome can be readily identified at the cytological level by a number of staining procedures.

①Conventional banding②G banding ③Q banding ④R banding ⑤C banding ⑥ High-resolution Banding

G-banding method• Chromosomes stained by the Giemsa-staining

method, the technique most widely used in clinical cytogenetics laboratories.

High-resolution Banding

• This type of banding is achieved through G-banding or R-banding techniques to stain chromosomes that have been obtained at an early stage of mitosis, when they are still in relatively uncondensed state.

• Prometaphase chromosome reveal 550 – 850 bands or event more in a haploid set, whereas standard metaphase preparations show only about 450.

Applications of chromosome analysis

• (1) Clinical diagnosis: Numerous medical disorders, including some that are common, such as Down syndrome (trisomy 21 ), are associated with microscopically visible changes in chromosome number or structure and require chromosome or genome analysis for diagnosis and genetic counseling .

• (2) Gene Mapping and identification: A major goal of medical genetics today is the mapping of specific genes to chromosomes and elucidating their roles in health and disease.

• (3) Cancer cytogenetics: Genomic and chromosomal changes in somatic cells are involoved in the initiation and progression of many types of cancer.

• (4) Prenatal Diagnosis: Chromosome and genome analysis is an essential procedure in prenatal diagnosis.

gene structure and functiongene structure and function

Genomic imprinting

• a small number of genes in the genome that are exceptions to this general rule and are expressed only from one of the two copies.

• Examples of this unusual form of genetic regulations, celled genomic imprinting.

• Prader-Willi syndrome (PWS) and Angelman syndrome (AS).

• Both of these conditions are caused by deletions or other mutations in the same region of chromosome 15. However, part of this region is imprinted (or inactivated) on the maternally inherited chromosome (the PWS region), and part is imprinted on the paternal chromosome (the AS gene, which is called UBE3A).

The central dogma

Split gene

Exons and introns

Flanking sequence

Exon

intron

promoter

enhancer

polyA signal

TATA boxCAAT boxGC box

1. Eukaryotic Gene Structure

• Most genes of eukaryotic genome are split genes.• The majority of genes are interrupted by one or

more nonconding regions.

Exons and intron • Exons: the sequence exist in the mature mRNA. \• intron :A noncoding segment in a length of DNA that

interrupts a gene-coding sequence or nontranslated sequence, the corresponding segment being removed from the RNA copy before transcription.

• GT-AG rule: The splicing reations are guided by specific sequences in the primary RNA transcript at both the 5’ and the 3’ ends of introns.

Promoter

• There are several different types of promoter found in the human genome.

TATA box; CAAT box; GC box; Octamer transcription element

Fundamentals of gene expression

• Chromatin Remodeling The region of the chromosome must be

opened up in order for eznymes and transcription factors to access the gene

• Transcription Control The most common type of genetic regulation Turning on and off of mRNA formation • Post-Transcriptional Control Regulation of the processing of a pre-mRNA

into a mature mRNA • Translational Control Regulation of the rate of Initiation • Post-Translational Control (protein activity

control) Regulation of the modification of an

immature or inactive protein to form an active protein

• Somatic rearrangement (DNA rearrangement or gene rearrangement)

Regulating gene expression

• Note: Prokaryotes exhibit transcriptional control (as seen in regulation of operons) and post-translational control (protein modification). They do not exhibit chromatin alteration (since they have naked DNA). They exhibit very little post-transcriptional control and translational control.

Transcription Control

Gene mutation

Mutation

• Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

gene mutation and chromosome aberration

2. Causes

Mutations result from unrepaired damage to DNA or to RNA genomes, errors in the process of replication, or from the insertion or deletion of segments of DNA by mobile genetic elements.

• (1) spontaneous mutations (molecular decay); (It arises naturally and not as a result of exposure to mutagens)

• (2) induced mutations caused by mutagens; (caused by exposure to a mutagen)

• (3) mutations due to error prone replication by-pass of naturally occurring DNA damage (also called error prone translesion synthesis),

• (4) errors introduced during DNA repair.

Spontaneous mutation and induced mutations

• (1) spontaneous mutations (molecular decay); (It arises naturally and not as a result of exposure to mutagens)

• (2) induced mutations caused by mutagens; (caused by exposure to a mutagen)

Ultraviolet (UV) radiation

Pyrimidine dimersPyrimidine dimers

3. Classification of mutation types

• ⑴ By effect on structure• ⑵ By effect on function• ⑶ By effect on fitness• ⑷ By mutation location• ⑸ By impact on protein sequence • ⑹ By inheritance

Loss-of-function mutations and Gain-of-function mutations• Loss-of-function mutations: A mutation 　 associated with

a reduction or a complete loss of one or more of the normal function of protein

• Gain-of-function mutations: A mutation associated with an incerese in one or more of the normal functions of a protein. To be distinguished from novel property mutation.

dominantrecessive

Dynamic mutation

• Dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product (progeny) of a dynamic mutation has a different likelihood of mutation than its predecessor.

• These mutations, typically short sequences repeated many times, give rise to numerous known diseases including the Trinucleotide repeat disorders.

Fragile X syndrome

• Mutations in the FMR1 gene cause fragile X syndrome.

• Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene.

By impact on protein sequence

• Affect only one codon– Silent mutations– Missense mutations– nonsense mutation– Termination codon

mutation (UAA/UAG/UGA)

• Affect many codons– frameshift mutation

By impact on protein sequence

• nonsense mutation

Frameshift mutations

• Frameshift mutation: A mutation involving a deletion or insertion that is not an exact multiple of three base pairs and thus changes the reading frame of the gene downstream of the mutation.

Mutation rates

• Mutation rates vary across species. Evolutionary biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population (mutator strains).

• According to one study, two children of different parents had 35 and 49 new mutations. Of them, in one case 92% were from the paternal germline, in another case, 64% were from the maternal germline.

chapter 4

Single Gene Disorders

Single gene diorders: The type of DNA that makes up most of the genome.

Terminology 

• Allele: one of the alternative versions of a gene or DNA sequence at a given locus.

• Genotype and Phenotype

• Homozygous and Heterozygous• Homologous chromosomes (homologues) : A pair of chromosomes, one

inherited paternally, the other maternally, that pair with each other during meiosis I, undergo crossing over, and separate at anaphase I of meiosis. Homologous chromosomes are generally of similar size and shape when they are viewed under the microscope and contain the same loci, except for the two sex chromosomes in males (X and Y ), which are only partially homologous.

• Dominant and Recessive

Genotype and Phenotype

• Genotype:is the set of alleles that make up a persons genetic constitution at a single locus.  

• Phenotype:is the observable expression of a genotype as a morphological, clinical or molecular trait.

Homozygous and Heterozygous

• Homozygous: when a person has a pair of identical alleles in a locus,he is said to be homozygous. 

• Heterozygous: when the alleles are different, he is said to be heterozygous. 

Dominant and Recessive

• Dominant: with a dominant genetic disorder ,one abnormal copy of the gene will cause the disease.

• Recessive: both copies of the gene must be abnormal in order for a person to be affected by the Disease.

Pedigree and proband

• Pedigree: is a family tree which made up by symbols and lines, represent a patient's genetic family History.

• Proband: The affected family member through whom the family is ascertained. Also called the propositus or index case.

Pedigress Symbols

Patterns of single gene disorders

• ⑴ Factors determined the classification

Chromosome location

Dominant or recessive• ⑵ Basic patterns of single gene disorders

Autosomal Dominant (AD)

• Definition:AD diseases are those in which a single copy of a mutant gene on autosome is enough for the trait to be expressed or shown.

• ⑴ Complete dominance • ⑵ Incomplete dominance (semi-dominance)• ⑶ Codominance• ⑷ Irregular dominance• ⑸ Delayed dominance • ⑹ anticipation• ⑺ sex-conditioned inheritance

⑴ Complete dominance

• The phenotype of the heterozygote (Aa ) will be indistinguishable from the phenotype of the homozygous (AA ) dominant.

Penetrance and expressivity

• Penetrance: The fraction of individuals with a genotype known to cause a disease who have any signs or symptoms of the disease. Contrast with expressivity.

• Expressivity ： The extent to which a genetic defect is expressed. If there is varialbe expressivity, the trait may vary in expression from mild to severe but is never completely unexpressed in individuals who have the corresponding genotype.

Pedigree Characteristics of AD

• The phenotype usually appears in every generation, each affected person having an affected parent.

• Any child of an affected parent has a 50% risk of inheriting the trait (50% of offspring are affected).

• 50% of sibs are affected.

• Phenotypically normal family members do not transmit the phenotype to their children.

• Males and females are equally likely to transmit the phenotype, to children of either sex.

• A significant proportion of isolated cases are due to new mutation.

ABO blood group

• Alleles IA, IB and i located on 9q, are concerned to the blood group ABO.

Autosomal Recessive (AR)

• Definition ： AR are presented only in individuals who are homozygous for the mutant gene on autosome.

Carrier of AR

• Carrier (Aa ) ： An individual who carries one gene for a particular recessive trait.

• Carrier : An individual heterozygous for a particular mutant allele. The term is used for heterozygotes for autosomal recessive alleles, for females heterozygous for X-linked alleles, or, less commonly, for an individual heterozygous for an autosomal dominant allele but not expressing it (e.g. , a heterozygote for a Huntington disease allele in the presymptomatic stage).

Pedigree Characteristics of AR

• ⑴ Affects both sexes equally• ⑵ A child of unaffected carrier parents has

25% risk of disease• ⑶ Few affecters, usually only in one

generation• ⑷ Increased risk in consanguineous mating

Coefficient of relationship

• Coefficient of relationship: The probability that any two individuals share a given gene at a random locus from a common ancestor.

• Types of Consanguineous mating

Consanguineous and Inbreeding

• Consanguineous: Related by descent from a common ancestor (the noun is consanguinity).

• Inbreeding : The mating of closely related individuals. The progeny of close relatives are said to be inbred. (Note that some consider the term inbreeding to be pejorative when it is applied to human populations).

Consanguineous mating VS random mating

• Consanguineous mating could increase the risk of affected.

• More rarer the autosome recessive is, more higher the risk inceresed.

X-linked Inheritance

• X-linked diseases are single gene disorders that reflect the presence of defective genes on the X chromosome.

Hemizygous

• Hemizygous: A term for the genotype of an individual with only one representative of a chromosome or chromosome segment, rather than the usual two; refers especially to X-linked genes in the male but also applies to genes on any chromosome segment that is deleted on the homologous chromosome.

Pedigree Characteristics of XR

• ⑴ Affects almost exclusively men• ⑵ Affected men born from carrier mother,

with 50% risk to be affected• ⑶ No male to male transmission

Genetic heterogeneity

• Genetic heterogeneity: The production of the same or sililar phenotypes by different genetic mechanisms. See allelic heterogeneity, clinical heterogeneity, locus heterogeneity.

– 1. Allelic heterogeneity : In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different muatant allelels rather than by identical alleles at the locus.

– 2. Locus heterogeneity : Many mutations in different gene expressed at different loci (autosomes and sex chromosomes).

– 3. Phenotypic heterogeneity: Different mutation in the same gene leading to different phenotypes.

X-linked dominant inheritance ， XD

• X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder.

Pedigree Characteristics of XD

• More females affected than males, the ratio is approximately 2 to 1

• All daughters of affected males are affected, all sons of affected males are normal

• A child of an affected female has 50% risk to be affected

• Each affected individual has one affected parent, passed in a vertical fashion

chapter 6 Disorders of the Autosomes and Sex

Chromosomes

Polymorphism

• Polymorphism: a more than one version of a trait being actively present in a population, a heritable difference between individuals in the same species.

• For example:

– ABO blood group,

– immunogloulins,

– DNA sequence polymorphism, and

– minor variants in chromosome structure.

• Exactly we should call these variants chromosome heteromorphism.

Chromosomal polymorphism

• Chromosomal polymorphism is a condition where one species contains members with varying chromosome shapes or counts.

• Common positions forms of chromosome hetermorphism﹠– Size of chromosome: About 10% of clinically normal

males have longer or short Y.

– Satellite: presence or absence, size

mainly on 13, 14, 15, 21 and 22

– Secondary constriction of chromosome 1, 9 and 16

presence or absence, length

– Banding pattern polymorphis: Fluorescence intensity of chromosome 3, 4

Chromosomal Mutations

• Numerical– Euploid---multiple of haploid number (N)– Aneuploid---trisomy or monosomy– pseudodiploid

• Structural

– Deletion– Duplication– Inversion– Translocation

1. Euploid

• Euploid describing a nucleus, cell, or organism that has an exact multiple of the haploid number (n) of chromosomes. For example,

• Most animal species are diploid

• Polyploidy in animals is generally lethal

– Haploid: n, only found in sperms and eggs

– Tetraploid: 4n,

– Triploid: 3n

2. Aneuploid

• A cell or organism whose nuclei possess a chromosome number that is greater by a small number than the normal chromosome number for that species.

• Instead of having an exact multiple of the haploid number of chromosomes, one or more chromosomes are represented more times than the rest.

Classification of aneuploid

• 1. Hyperdiploid– Somatic cells in which

chromosome numbers are more than 46.

– Those cells with an extra chromosome show trisomy for the chromosome involved.

– Trisomy is the most common type.e.g. 47, XX(XY), +21 (Down Syndrome)

• 2. Hypodiploid

Mechanism of numerical aberration

⑴ Diandry and digyny

⑵ Endoreplication and

endomitosis

⑶ Meiotic nondisjunction

⑷ Mitotic nondisjunction

⑸ Loss of chromosome

The reason for triploid

The reason for tetraploid

The reason for aneuploid

The reason for mosaicism

Also the reason for mosaicism

Meiotic Nondisjunction Generates Aneuploidies

abnormal gametes

Zygotic Ploidy Zygotic Ploidy

Mosaicism

• A condition in which tissues of genetically different types occur in the same organism.– Sometimes individuals are found who have both

normal and abnormal cell lines. These people are called mosaics.

– In the vast majority of these cases the abnormal cell line has a numerical chromosome abnormality. Structural mosaics are extremely rare.

– The degree to which an individual is clinically affected usually depends on the percentage of abnormal cells.

• E.g. 46 ， XX/47 ， XX ， +21

Different kinds of Structural Aberration

• 1. deletion• 2. inversion• 3. translocation• 4.duplication• 5. ring chromosome• 6. isochromosome• 7. dicentric

chromosome

Description of Structural Aberration

• Description: number, sex chromosomes, abnormalities– Brief pattern ： using the breakpoints– Detailed pattern ： using the form of the bands

in rearranged chromosomes

1. Deletion,del

• Deletions involve loss of material from a single

chromosome. The effects are typically severe since

there is a loss of genetic material.

terminal deletion: A terminal segment of a

chromosome is deleted.

interstitial deletion: An intermediary segment, i.e.,

excluding a centromere and terminal ends

(telomeres), of a chromosome is deleted.

Terminal deletion

• Brief pattern： – 46, XX(XY), del(1)(q21)• Detailed pattern： – 46, XX(XY), del(1)(pter→q21:)

2. Inversion , inv

• Inversions occur when there are two breaks within a single chromosome and the broken segment flips 180° (inverts) and reattaches to form a chromosome that is structurally out-of-sequence.– Paracentric Inversion: An inversion of a

chromosome segment that excludes the centromere.

– Pericentric Inversion: An inversion of a chromosome segment that includes the centromere.

Inversions Prevent Generation of Recombinant Offspring Genotypes

• Only parental chromosomes (non-recombinants) will produce normal progeny after fertilization

3.Translocation, t

• Translocations involve exchange of material

between two or more chromosomes.

Reciprocal translocation: is a translocation in

which the segments of chromosomes have been

exchanged.

Robertsonian translocation: Translocations

involving the centromeric regions and with both

long arms of acrocentric chromosomes.

Example : Translocation (2;15) Karyotype

• This karyotype is an example of a balanced translocation between two chromosomes.

• In this case a large segment in the p, or short arm of the right chromosome 2 has been exchanged with basically the entire q, or long arm of the right chromosome 15.

• Because the size of the exchanged segments is about equal, this particular structural rearrangement would be almost impossible to detect without banding techniques.

8-41

• 1. Alternate segregation– Chromosomes on opposite sides of the translocation cross segregate

into the same cell

– Leads to balanced gametes

• Both contain a complete set of genes and are thus viable

• 2. Adjacent-1 segregation– Adjacent non-homologous chromosomes segregate into the same cell

– Leads to unbalanced gametes

• Both have duplications and deletions and are thus inviable

• 3. Adjacent-2 segregation– Adjacent homologous chromosomes segregate into the same cell

– Leads to unbalanced gametes

• Both have duplications and deletions and are thus inviable

Meiotic segregation can occur in one of three ways

gametes karyotype of zygote after fertilized with normal gemate

Alternate AB CD 46 ， XX （ XY ） AD CB 46 ， XX （ XY），－ 2, － 5, ＋ der(2), ＋ der(5) ， t(2 ； 5) (q21 ；

q31)

Adjacent1 AB CB 46 ， XX （ XY），－ 5，＋ der(5) ， t(2 ； 5) (q21 ； q31)

AD CD 46 ， XX （ XY），－ 2，＋ der(2) ， t(2 ； 5) (q21 ； q31)

Adjacent2 AB AD 46 ， XX （ XY），－ 5，＋ der(2) ， t(2 ； 5) (q21 ； q31)

CB CD 46 ， XX （ XY），－ 2，＋ der(5) ， t(2 ； 5) (q21 ； q31) 交换 1 AB AB 46 ， XX （ XY），＋ 2，－ 5 CD CD 46 ， XX （ XY），－ 2，＋ 5 交换 2 CB CB 46 ， XX （ XY），－ 2，－ 5 ＋ 2der(5) ， t(2 ； 5) (q21 ；

q31) AD AD 46 ， XX （ XY），－ 2，－ 5 ＋ 2der(2) ， t(2 ； 5) (q21 ；

q31) 3 ： 1 AB CB CD 47 ， XX （ XY），＋ der(5) ， t(2 ； 5) (q21 ； q31)

AD 45 ， XX （ XY），－ 2, － 5 ，＋ der(2) ， t(2 ； 5) (q21 ；

q31) CB CD AD 47 ， XX （ XY），－ 2, ＋ der(2)，＋ der(5) ， t(2 ； 5)

(q21 ； q31) AB 45 ， XX （ XY），－ 5 CD AD AB 47 ， XX （ XY），＋ der(2) ， t(2 ； 5) (q21 ； q31)

CB 45 ， XX （ XY），－ 2, － 5，＋ der(5) ， t(2 ； 5) (q21 ；

q31) AD AB CB 47 ， XX （ XY），－ 5，＋ der(2) ， t(2 ； 5) (q21 ； q31)

CD 45 ， XX （ XY），－ 2

Robertsonian translocation

• Translocations involving the centromeric regions and with both long arms of acrocentric chromosomes.

• Centricfusion or Balanced translocation

Robertsonian translocation

• A chromosomal duplication is usually caused by abnormal events during recombination.

Figure 8.5

4. Chromosomal Duplication

SYNDROMES ASSOCIATED WITH ANEUPLOIDY OF AUTOSOMAL CHROMOSOMES

Karyotype Syndrome Clinical Features

47,XX, +13 Patau Severe mental retardation andphysical deformities.

47,XX,+18 Edward Severe mental retardation andphysical deformities.

47,XX,+21 Down Mental retardation, flat face, simiancrease.

• Down syndrome, is due to three copies of chromosome 21.

• It affects one in 700 children born in the United States.• Although chromosome 21 is the smallest human chromosome, it

severely alters an individual’s phenotype in specific ways.

PART 4 The sex chromosomes and their

abnormalities

Dosage Compensation

• Dosage Compensation : decrease X gene products by half in females (e.g. humans called X-inactivation)

• XX females “compensate” by inactivating one of their X chromosomes to make a single “dosage” of X-linked genes.

The Lyon Hypothesis

• ① In normal females, only one of the two X chromosomes is genetically active.

• ②X chromosome inactivation occurs early in development(late blastocyst stage of embryogenesis).

• ③ X inactivation is random. The inactive X can either be maternal or paternal in origin and the choice is random in each cell and independent of the choice in other embryonic cells.

• ④ X inactivation is irreversible in somatic cells- the inactive X in a particular cell remains in active in all descendents of that cell.

Nonrandom X Chromosome Inactivation

• The cells with deleted X:• The cells carry X-autosomal translocation

Barr Bodies are Inactivated X Chromosomes in Females

• Normal male,

• Turner female

• Normal female,

• Klinefelter male

Barr bodies=N-1 ruleBarr bodies=N-1 rule