Genetics - Chapter 8 - Variation in Chromosome Number and Structure

Euploidy

• The condition of having an integral number of sets of chromosomes

• Most organisms are diploid (two sets), with variation from haploid, monoploid (one set) to octoploid (eight sets) in plants and animals

Aneuploidy

• The condition of not having an integral number of sets of chromosomes (ex. 2n + 1)

• Aneuploidy occurs when a chromosome but not a complete set is lost (monosomy, nullisomy) or gained (trisomy, etc

Termination for variation in chromosome numbers

Euploidy

Complete sets of chomosomes are present

• the number of chromosomes in a set is called the haploid number and is represented by an x

• The number of chromosomes in a gamete is presented by n; this value may be the same or different as x

  • In diploids, x = n

  • In polyploids, x =/= n

• The numbers of sets can vary from one set (haploid) to two sets (diploid) to more than two sets (polyploid)

Haploids

Organisms with one set of chromosomes

ex. plants alternate between haploid (gametophyte) and diploid phases (sporophyte)

• There is mitotic cell division in haploid cells

• Microbes (yeasts) like C. glabrata

• In primative plants, the haploid phase may be free living

Polyploidy

Occurs when more than two sets of chromosomes are present

ex. triploid, three sets

• Bananas, seedless, watermelons, commercial oysters

• 12-15% of spontaneous abortions in humans due to triploidy, ¾ of these have 2 paternal sets of chromosomes

Triploids

Have three sets of chromosomes

Can arise in multiple ways

• Fertilization of an abnormal diploid gamete with a haploid gamete

• Fertilization of an egg by two haploid sperm

• Crossing a diploid with a tetraploid

  • Diploids produce haploid gametes (n) and tetraploids produce diploid gametes (2n); fertilization would generate a triploid

THEY ARE STERILE

• An odd number of homologous chromosomes cannot synapse properly during meiosis

• They will not segregate properly and the developing gametes will not have an integral number of sets of chromosomes

Pairing possibilities and separation in anaphase I of meiosis

If meiosis I can move to anaphase, there would be massively uneven chromosome segregation (each univalent can migrate to either pole, randomly) All gametes have multiple n+1 aneuploidies

Autopolyploidy

2 sets of identical chromosomes from the same species can synapse during meiosis, chromosomes are homologous

Auto = self = same species

Allopolyploidy

2 sets of similar, but not identical chromosomes from different but related species, hybrids formed by interspecies mating cannot synapse during meiosis, chromosomes are homeologous

Allo = other = different species

Differences between autopolyploidy and allopolyploidy

Differences between autopolyploidy and allopolyploidy

Genome doubling (WGD) is a rare mistake

• A catastrophic event due to whole genome non-disjuncture; disruption to the microtubule network that separates chromosomes at anaphase

• This may be more common in plants than in animals

Tetraploids

Can have a regular meiosis

• Because there is an even number of chromosomes, each one can pair with a homologue

  • However, in autotetraploids – because there are 4 identical chromosomes – there can be unusual chromosome pairings during synapsis

    • Can generate two bivalents as well as a trivalent + univalent.

    • Because of the missegregation of chromosomes, autotetraploids have reduced fertility

  • In allotetraploids (amphidiploids), there is only one way to generate homologous pairs between identical members.

    • Identical chromosomes are “homologous” whereas similar ones are termed “homeologous”

    • Amphidiploids are more fertile than autotetraploids

Pairing possibilities and separation in anahase I of meiosis

How do we get tetraploids?

An allotetraploid arises from hybridization of two closely-related diploid species.

• Hybridization is the cross between two species. Generally the hybrid is sterile

• If the sterile hybrid undergoes a natural chromosomal doubling, a fertile amphidiploid is produced

Amphidiploid plants can be produced by somatic cell hybridization.

• ex: triticale wheat is a hybrid of wheat and rye that combines favorable characteristics from both crops

Other polyploids

• Other polyploids, (penta-, hexa-, etc.) are generated by the same mechanisms discussed above for triploids and tetraploids and would have the same issues with fertility.

• Formation of polyploids is a major force in plant speciation

• There are animal polyploids (e.g. amphibians, fish (e.g., salmon), reptiles, flatworms, brine shrimp, leeches)

Endopolyploidy

The condition in which only certain cells or tissues in an otherwise diploid organism are polyploid

• In these cells, replication and segregation of chromosomes occur without nuclear division

  • Ex.

    • cells of the human liver can be 4n (tetaploid), 8n (octoploid) or more

    • the polytene chromosomes found in the salivary glands of some insects have >2000 copies aligned side-by-side in register

Aneuploidy

The condition of having more or fewer chromosomes than in an integral number of chromosome sets

• The loss of one chromosome to produce a 2n – 1 complement is called monosomy.

• The loss of two members of an homologous pair of chromosomes to produce a 2n – 2 complement is called nullisomy.

• The gain of one chromosome to produce a 2n + 1 complement is called trisomy.

Aneuploidy can occur in…

• Meiosis, leading to genetic disorders upon fertilization. All organs in the body are affected; problems in developmental pathways.

• Mitosis, leading to cancer. Cellular overgrowth.

Mistakes in meiosis

Nondisjunction is a cell division error in which homologous chromosomes or the sister chromatids fail to separate and migrate to opposite poles.

• Nondisjunction can occur during meiosis I or II.

  • Failure to crossover or crossovers too close to (or too far away from) the centromere

  • Loss of sister chromatid cohesion

  • Defects in spindle assembly/disassembly

• This leads to gametes with abnormal numbers of chromosomes and can lead to abnormal offspring after fertilization.

Human monosomy

Monosomy for any of the autosomes is not tolerated in humans and other animals

• Monosomic gametes themselves may be very functionally impaired

Monosomy for the X chromosome occurs in humans

• Turner syndrom, X0

  • This is the only human monosomy that survives

Trisomy

Trisomy (2n + 1 chromosomes)

• Trisomy for the sex chromosomes has a less dramatic phenotype than trisomies for autosomes, which are often lethal.

  • XXX, XXY (Kleinfelter syndrome), XYY

• Trisomy for the autosomes leads to

  • Down syndrome (trisomy 21), Patau syndrome (trisomy 13), Edward syndrome (trisomy 18)

• In trisomy, three copies of one chromosome are present, so pairing configurations in meiosis are usually irregular.

  • At any particular region along the chromosome length, only two of the three homologs may synapse, though different regions of the trio may be paired

Down syndrome

Nondisjunction of the maternal chromosome 21 during meiosis.

Nondisjunction shows an increased incidence with increasing maternal age.

• Most trisomies are due to material meiotic errors; maternal age affects some of these errors.

• The first meiotic division begins in the fetal ovary but isn’t completed until ovulation(!); a pregnant woman can affect her grandchildren’s phenotypes

Aneuploidies in Cancer

Aneuploidy is consistently observed in virtually all cancers. Some examples:

• trisomy 12 in chronic lymphocytic leukemia (CLL)

• trisomy 8 in acute myeloid leukemia (AML).

Alteration of normal mitotic checkpoints are also important tumorigenic events, and these may directly lead to aneuploidy.

• Loss of p53 creates genomic instability that most often results in the aneuploidy genotype.

Genetic syndromes that predispose an individual for chromosome breakage are associated with increased risk for various types of cancer.

• Aneuploidy contributes to carcinogenesis by disrupting the asymmetric division of adult stem cells.

Structural abnormalities

Four classes

• Deletions (deficiencies)

• Duplications

• Inversions

• Translocations

Two basic mechanisms

• Breakage and reunion

  • Two DNA breaks - incorrect resealing

• Recombination between non-homologous sites

  • Cross-overs between repeated DNA at different sites

Deletions

Loss of genetic information

• Sometimes is called a partial monosomy (if large)

• Deletions occur after repair of chromosomal damage or by unequal crossing over

Consequences

• Generally deleterious or lethal

  • Ex. cri-du-chat syndrome

• Creates “null” alleles

  • Recessive lethals if affect essential genes

• Deletions may by “haplo-insufficient”

  • If ½ normal gene dose not enough for normal phenotype

  • Acts like a dominant mutation

• Phenotype is dependent on size

  • Small deletions may have no phenotype

  • Some may by deleterious (depends on genes)

  • Large deletions → major gene imbalance

    • Lethal in metazoans (partial monosomy)

• When homologous chromosomes pair wild-type DNA loops out

  • Reduces map distance - no crossovers possible in deleted DNA

    • Can be used to determine location and size

  • Also visible in polytene chromosomes in mitosis

Uses

• Useful for mapping

  • Uncovers recessive alleles

  • Effectively homozygous loss of function

  • Ex. Drosophila

    • Different known deletions crossed to various mutations

    • Extents mapped on polytene

    • Different deletions express different recessive traits “prune” and “facet”

Deletion Summary

Definition: Loss of genetic information

• Sometimes is called a partial monosomy (if large)

• Deletions occur after repair of chromosomal damage or by unequal crossing over.

Consequences:

• Generally deleterious or lethal

  • Examples: cri-du-chat syndrome; deletion of the end of chromosome 5

Identified by genetic behavior & microscopically

• May behave as dominant alleles (haploinsufficiency)

• Lack of reversion

  • The inability to convert a mutant phenotype back to the normal

• See the recessive phenotype

  • the recessive allele is on one chromosome and a deletion on the other chromosome; in principle, same situation as X-linked recessive alleles being expressed in males, except here it is on an autosome.

• Detection of deletion (or deficiency) loops through cytogenetic analysis of meiotic chromosomes (Fig.8-15c)

• Useful for mapping; mapping distance is smaller

Duplications

Description: Duplicated genetic material.

• Duplications arise as the result of unequal crossing over during meiosis or through a replication error (re-replication) during S-phase (this tends to be smaller in scale).

Consequences of gene duplications

• May be deleterious, neutral or advantageous

  • Can’t predict; depends on the extent of the duplication

  • Copy number variants may play crucial roles in human traits and disease

• Provides increased gene dosage relative to other genes (e.g., duplications led to the increase in rRNA genes)

• A second copy of gene is free to undergo modification to acquire new functions (e.g., rhodopsin genes, globin gene amplification; steroid hormone receptor gene amplification).

Detected as loops during synapsis in meiosis

Inversions

Definition: Flipping a segment of a chromosome

Consequences

• A change in the order of genes

• No loss of genetic information

  • Gene order is different along the chromosome

  • However, if the break point is within a gene or changes expression of a gene (e.g., an oncogene), then there are consequences

• Generally speaking, no effect on viability but decreased fertility

• But inversion loops are formed during the pairing of homologous chromosomes during meiosis

  • Recombination results in inviable offspring

  • Inversions “suppress recombination” (e.g., evolution of Y from X)

• Detection

  • A change in the order of genes (change in linkage)

  • Inversion loops

  • Reduction in isolating recombinants; partial sterility

Two kinds of inversions

Paracentric: para - outside of (not including) the centromere, recombinant chromosomes: dicentric (2 chomosomes) and acentric fragment (no centromere)

Pericentric: peri - including the centromere, both recombinants inviable

Recombination during meiosis

If there are no crossovers within the inverted sequences, then the meiotic products will be viable (all cross-overs are outside of the inverted region).

• Half will be normal and half will carry the inversion

However, if there are crossovers in the inverted region, then not all of the meiotic products will be viable.

• For pericentric inversions, half will be viable (normal plus the inversion carrier), and half will be nonviable (contain duplicated and deleted genetic material).

• For paracentric inversions, half will be viable (normal and the inversion carrier), and half will be nonviable (dicentric or acentric with duplicated and deleted genetic material).

Inversions

During Meiosis 1 segregation

• Bridges break

• Acentric lost

• Recombinant chromosomes → large deletions, inviable

• Only parentals obtained

• Maps like deletion

• Note: Can recover DCOs

• Inversions “suppress” recombination

Translocations

Definition: Fusion of two different chromosomes

• These can be reciprocal or nonreciprocal

Consequences

• A change in the order of genes

• No loss of genetic information

  • Genes are on different chromosomes (linked to different centromeres)

  • However, if the break point is within a gene or changes expression of a gene (e.g., an oncogene), then there are consequences

• Consequences can vary; generally, no effect on viability but decreased fertility.

Recognized by

• Pairs of synapsed chromosomes during meiosis (cytological)

  • Unusual synapsis between that includes different homolog pairs

• Genes show linkage to the genes and the centromere from another different chromosome

• Semi-sterility (half of the meiotic products are non viable)