6 chromosome mutations variation in number and arrangement

Genetics 4BIO3 J.M 1st SEM 2014-2015

CHROMOSOME MUTATIONS: VARIATION IN NUMBER AND ARRANGEMENT

INTRODUCTION

Mutations and resulting alleles affect phenotype and traits are passed according to Mendelian principles

Chromosome mutations or abberations – change in total chromosome number, deletion or duplication of genes or chromosome segments, rearrangement of genetic material within or among chromosomes

Chromosome aberrations are passed to offspring in predictable manner

Minor alterations in content or location can result to phenotypic variation

1 VARIATION IN CHROMOSOME NUMBER: TERMINOLOGY AND ORIGIN

Chromosome variation – addition or loss of a chromosome to the addition of more haploid sets of chromosomes

Aneuploidy – gain or loss of one or more chromosomes but not a complete set

Monosomy – loss of single chromosome from diploid genome

Trisomy – gain of 1 chromosome

Euploidy – complete haploid sets of chromosomes are present

Polyploidy – more than 2 sets are present

Triploid – with 3 sets of chromosomes

Tetraploidy - with 4 sets of chromosomes Chromosomal variation originates as random error during gamete production Nondisjunction – failure to disjoin during segregation; disrupts normal chromosome distribution


2 MONOSOMY AND TRISOMY RESULT IN VARIETY OF PHENOTYPIC EFFECTS

Monosomy Trisomy

Loss of 1 chromosome; produces 2n-1

Monosomy for X chromosome (45, X Turner syndrome)

Monosomy for autosomes

Not usual in humans

Drosophila - chromosome IV – flies develop more slower, reduced body size, impaired viability; Chromosomes II and III – lethal

Failure of survival can be due to:

If 1 of the genes is a lethal allele – monosomy unmasks the recessive lethal allele that is tolerated by heterozygotes

Single copy of recessive gene may be insufficient to provide life-sustaining function (haploinsufficiency)

Better tolerated in plants – monosomy for autosomal chromosomes (maize, tobacco, evening primrose, jimson weed)

Gain of 1 chromosome, 2n +1

Extra chromosome – more viable individuals in both animal and plant species

In animals – only if chromosome is small

Addition of large autosome to diploid complement has severe effects, usually lethal during development

In plants – individuals are viable, altered phenotype

Jimson weed, Datura – 24 diploid number; alteration in plant’s capsule

Rice plant, Oryza sativa – haploid number of 12

Down Syndrome: Trisomy 21

Discovered by Langdon Down

Trisomy of Chromosome 21 (47, 21+) – found in 1 out of 800 births

Outward appearance of the individuals is very similar, bear striking resemblance to one another – prominent epicanthic fold in each eye and flat face and round head

Can also have protruding, furrowed tongue and short, broad hands

Retarded physical, psychomotor, and mental development

Poor muscle tone, life expectancy – average of 50 years

Prone to respiratory disease and heart malformations; higher risk of leukemia

Death in older adults is due to Alzheimer disease

Critical region of chromosome 21 contains genes that are dosage sensitive - Down syndrome critical region (DSCR)

Decreased risk of having cancer involving tumors – due to presence of extra copy of DSCR1 gene

DSCR1 gene – encodes protein suppressing vascular endothelial growth factor (VEGF)


Origin of Extra 21st Chromosome in Down Syndrome

Condition occurs through nondisjunction of chromosome 21

Failure of paired homologs to disjoin during in anaphase I or II – leads to n+1 gametes

Addition can be from mother or father (ovum – source of 95% of 47,21+ cases) - derived from studies of age of mothers giving birth to infants with Down Syndrome

Increase of the syndrome as age increases

Nondisjunctional event more likely to occur during oogenesis in women over 35 years old

Women 30 or 40 years old produce ova that are significantly older and have been arrested longer

Counselling informs prospective parents about the probability that their child will be affected and educates them about Down Syndrome

Down Syndrome children – known for affectionate, loving nature

Approaches to determine if child will have 47,21+

Amniocentesis - fetal cells obtained from amnion

Chorionic villus sampling (CVS) - fetal cells obtained from chorion

Noninvasive prenatal genetic diagnosis – fetal cells and DNA are derived directly from maternal circulation; requires only 10mL maternal blood sample

Human Aneuploidy

Patau Syndrome (47, 13+)

Edwards Syndrome (47, 18+) Survival of aneuploidy conditions, karyotype analysis of spontaneously aborted foetuses:

1. Approximately 20 percent of all conceptions terminate in spontaneous abortion

2. 30 percent of all spontaneously aborted foetuses have some form of chromosomal imbalance (at least 6% of conceptions have abnormal chromosome complement)

Gametes lacking a single chromosome are functionally impared to a serious degree or embryo dies early in the development

Normal embryonic development requires precise diploid complement of chromosomes to maintain equilibrium in genetic information expression


3 POLYPLOIDY (2 HAPLOID CHROMOSOME SETS) IS PREVALENT IN PLANTS

Polyploidy – more than 2 multiples of haploid chromosome set

Naming based onset number (triploid, 3n…)

Well known in lizards, amphibians, fishes, and plants

Odd numbers are not maintained in generations

Originate in 2 ways: 1. Addition of 1 or more extra chromosome set identical to normal haploid

complement – autopolyploidy 2. Combination of chromosome sets from different species; due to

hybridization – allopolyploidy

Autopolyploidy

Each additional set of chromosomes – identical to parent species

Triploids – represented as AAA; tetraploids – AAAA … Autotriploids

Failure of all chromosomes to segregate during meiosis

If a diploid gametes is fertilized by haploid gamete – zygote has 3 sets of chromosomes; 2 sperm may fertilize an ovum

Autotetraploids – theoretically more likely to be found

Produce balanced gametes when involved in sexual reproduction If chromosomes have replicated but parent cell never divides and reenters interphase – double chromosome number Tetraploid cells can be produced experimentally from diploid cells – apply cold or heat shock or apply colchicine


Colchicine – alkaloid derived from autumn crocus; interferes with spindle formation – replicated chromosomes cannot separate at anaphase and migrate to poles

Autopolyploids – larger than diploid relative

Increase is due to larger cell size rather than greater cell number – can have increased flower and fruits in plants

Important triploid plants – Solanum, Winesap apples, bananas, seedless watermelons, tiger lily Lilium tigrinum

Tetraploids – alfafa, coffee peanuts, McIntosh apples

Gerald Fink – create strains of S. cerevisiae with 1,2,3 or 4 copies of the genome and examined expression levels of all genes during cell cycle

Using stringent standard – ploidy increase

Gene expression either increased or decreased at least tenfold

Repressed when ploidy increases – G1 cyclins

G1 cyclins – facilitate cell’s movement through G1; if delayed, gene expression is repressed

Stay in G1 phase – cell grows larger before moving to S phase

Allopolyploidy

Hybridizing 2 closely related species

Haploid ovum from species with AA chromosome is fertilized by sperm from species with BB set, results to AB chromosome set

Organism may be sterile – inability to produce viable gametes (especially when some or all a and b chromosomes are not homologous and cannot synapse in meiosis)

If AB combination undergoes natural or induced chromosomal doubling – 2 copies of all a and b chromosomes will be present (results to fertile AABB tetraploid)

Allotetraploid -polyploidy contains 4 haploid genomes from separate species

Amphidiploid - describes allotetraploid; both original species are known; plants like these are found in nature (success based on forming balanced gametes)

Meiosis proceeds – 2 homologs of each specific chromosome are present

Amphidiploids from closely related species- can have homology between a and b chromosomes

Rare in animals – fertilization is species specific


Amphidiploid example: cotton Gossypium

26 chromosome pairs : 13 large, 13 small

Amphidiploid exhibit traits of both parental species

Ex. Wheat (2n=14; 4n=28) and Rye (2n=14)

Cross of tetraploid whet and diploid rye – produced Triticale

4 VARIATION OCCURS IN CHROMOSOME COMPOSITION AND ARRANGEMENT

2nd class of chromosome aberration – delete, add, or rearrange substantial portions of 1 or more chromosomes

Gene or chromosome part deletions and duplications

Rearrangement of genetic material in a chromosome segment - transferred to another chromosome, translocations (gene locations are altered within the genome)

Due to breaks along chromosome axis followed by loss or rearrangement of genetic material

Sticky – ends produced at points of breakage, can rejoin other broken ends

If breakage and rejoining do not established – can be inherited

Heterozygous for aberration – aberration found in 1 homolog but not the other; unusual pairing are formed during synapsis

If no loss or gain of genetic material – “heterozygous” aberrations has no effect on phenotype; offsprings can be carriers of certain aberrations


5 DELETION IS A MISSING REGION OF A CHROMOSOME

Chromosomes break in 1 or more places and portions can be lost

Deletion (deficiency) – missing piece

Terminal deletion - occur at near one end

Intercalary deletion - within chromosome interior

Formation of deletion (compensation loop)

Chromosome portion retaining the centromere is usually maintained when cell divides ; Segment without centromere – lost in progeny cells following mitosis or meiosis

If small part of a chromosome is deleted – organism can survive

Large deletion – lethal

Cri du Chat Syndrome in Humans

Deletion of small terminal portion of Chromosome 5 (46, -5p)

Case of partial monosomy but region of missing is too small – considered as segmental deletion

Reported by Jerome LeJeune

May exhibit anatomic malformations – gastrointestinal and cardiac complication, mentally retarded, abnormal development of glottis and larynx (leads to eerie cry)

Not inherited; results from sporadic loss of chromosomal materials in gametes

Longer deletions – greater impact on physical, psychomotor, and mental skill levels

Portion of the chromosome missing contains TERT gene

TERT – encodes telomerase reverse transcriptase; essential for telomere maintenance during DNA replication


6 DUPLICATION IS REPEATED SEGMENT OF A CHROMOSOME Duplication – part of the gene (locus, chromosome piece) is present

more than once

Heterozygous pairing can produce compensation loops

May result of unequal crossing between synapsed chromosomes or through replication error

3 aspects of duplications

1. Result in gene redundancy 2. May produce phenotypic variation 3. Important source of genetic variability during evolution

Gene Amplification – Ribosomal RNA Genes The Bar Mutation in Drosophila

Presence of abundant rRNA – supports protein synthesis

More metabolically active – higher demand for rRNA

Single copy of gene encoding rRNA is inadequate in many cells

rDNA – genome encoding specific RNA sequences

Gene amplification is used

In oocytes – normal amplification of rDNA – insufficient to provide adequate rRNA amounts needed to construct ribosomes

rDNA genes - found in chromosome area – nucleolar organizer region (NOR)

Duplications can cause phenotypic variation –might appear to be caused by simple gene mutation

Bar-eye phenotype of Drosophila

Phenotype – inherited same like dominant X-linked mutation

Normal wild-type females – 800 facets in each eye

Heterozygous female – 350 facets

Homozygous females – 70 facets

Female with fewer facets – double Bar Polytene X chromosome of Bar flies contain specific banding patterns – 1 copy of the region designated as 16A is present on both X chromosomes; duplicated in Bar flies; tripled in double Bar flies


7 INVERSIONS REARRANGE LINEAR GENE SEQUENCE Inversion – chromosome segment is turned 180degrees within a

chromosome ; does not involve loss of genetic information; only rearranges linear gene sequence

Requires breaks at 2 points along chromosome length and reinsertion of inverted segment

Inverted segment can be short, long and may or may not include a centromere

Paracentric inversion -centromere not part of rearranged chromosome segment

Pericentric inversion – centromere is part of inverted segment

Consequences of Inversions during gamete Formation

Normal linear synapsis during meiosis – not possible if only 1 member of homologous pair has inverted segment

Inversion heterozygotes – organisms with 1 inverted chromosome and a noninverted homolog

Formation of inversion loop – aids in pairing between inversion heterozygotes in meiosis

If no crossing over in inverted segment of the inversion loop – homologs segregate; normal and inverted chromatids

If crossing over happens – abnormal chromatids In crossing over of paracentric inversion

1 recombinant dicentric chromatid (2 centromeres)

1 recombinant acentric chromatid (lacks chromatid)

Both contain duplications and deletions of chromosome segments


1. During anaphase, acentric chromatid moves randomly to 1 pole or other may be lost 2. Dicentric chromatid is pulled in 2 directions 3. Polarized movement produces dicentric bridges 4. Dicentric chromatid breaks at some point – a part goes to each gamete during meiosis I 5. Gametes with recombinant chromatid are deficient in genetic material

Offspring bearing crossover gametes –inviable and not recovered

Inversion suppresses crossing over

In heterozygotes – inversion has effect of suppressing recovery of crossover products

Can be inherited

Evolutionary Advantages of Inversions

Since crossover recovery in products is suppressed in inversion heterozygotes – groups of specific alleles at adjacent loci within inversions can be preserved from generations

If alleles confer survival advantage – beneficial

Example: set of alleles ABcDef is more adaptive than AbCdeF or abcdEF Effective gametes contain favourable set of gametes Same principle applied using balancer chromosomes – contain inversions

8 TRANSLOCATIONS ALTER LOCATION OF CHROMOSOMAL SEGMENTS IN THE GENOME

Translocations – movement of chromosomal segment to a new location in the genome; does not directly alter individual viability

Reciprocal translocation – exchange of segments between 2 nonhomologous chromosomes (2 nonhomologous chromosome arms come close to each other to facilitate exchange)

If includes internal chromosome segments – 4 breaks

Consequence – like inversions; genetic information is not lost or gained; rearrangement only

Synapsis of translocation heterozygote - pairing results in crosslike configuration

Genetically unbalanced due to unusual alignment

Does not necessarily result to aberrant gametes


2 possible segregation patterns leading to gamete formaton

Centromere 1 migrates randomly toward 1 pole of spindle during anaphase I; travels along with either centromere 3 or centromere 4

Centromere 2 moves to other pole with either centromere 3 or centromere 4

1,4 combination – not involved in translocation

2,3 combination – with translocated chromosomes; with complete complement of genetic information

1,3 and 2,4 have duplicated and deleted segments Meiotic products are unbalanced; participation in fertilization results to lethality Semisterility – 50% of the parent’s progeny that are heterozygous for reciprocal translocation survive

Translocations in Humans: Familial Down Syndrome

Beaks at extreme ends of short arms of 2 nonhomologous acrocentric chromosomes

Small segments are lost; larger segments fuse at centromeric region

Produces large submetacentric or metacentric chromosomes

Robertsonian translocation

Parents contain 14/21, D/G translocation – one parent has majority of G-group chromosome 21 translocated to 1 end of the D-group chromosome 14

Individual - phenotypically normal even having only 45 chromosomes

In meiosis – ¼ of the individual’s gametes has 2 copies of chromosome 21 (offspring will have down syndrome)

Other offspring can have standard diploid genome (normal) or balanced translocation (normal)


9 FAGILE SITES IN HUMAN CHROMOSOMES ARE SUSCEPTIBLE TO BREAKAGE Fragile sites – susceptible to chromosome breakage when cultured in

absence of certain chemicals (folic acid); failed are of a chromosome to stain

Cause of fragility – unknown

May indicate regions where chromatin is not tightly coiled

Fragile-X Syndrome (Martin-Bell Syndrome)

Individuals bearing folate-sensitive site on X-chromosome

Most common form of inherited mental retardation

Affects 1 of 4000 males, 1 of 8000 females

Females – carry only 1 fragile X chromosome can be affected; dominant trait

Affected males – long, narrow faces with protruding chins, enlarge ears, increased testicular size

FMR-1 – can be responsible for the syndrome

Trinucleotide repeats – sequence of 3 nucleotides repeated many times

In FMR- 1 – CGG sequence is repeated in an untranslated are adjacent to coding sequence of the gene (upstream region)

Repeats vary

High number correlates with expression of fragile-X syndrome

6-54 repeats – normal

55-230 repeats –carriers

230+ repeats – expression of the syndrome Normal product of the gene – RNA-binding protein (FMRP) expressed in the brain Genetic anticipation – number of repeats increase in future generation

6 chromosome mutations variation in number and arrangement

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