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