How can it happen?

1. nondisjunction (one or both homologs migrate to the same gamete)

2. lagging homolog (one homolog migrates too slowly into its gamete, and doesn't make it into the nuclear area before the nuclear envelope re-forms. It's left drifting in the cytoplasm.)

Sex Chromosome Aneuploidies

• XO - Turner Syndrome

• XXY - Klinefelter Syndrome

• XYY genotype - taller than average; after about age 35, extra Y often degenerates and is not passed on to offspring.

• XXX genotype - some developmental deficiencies; some instances of mental retardation

normal male - 46 XY

normal female - 46 XX

Aberrations from the normal pattern can be designated by changing the chromosome number and/or the sex chromosome designation, as necessary. For example:

Turner syndrome - 45 X0

Klinefelter - 47XXY

Autosomal Aneuploidies

• Down Syndrome - trisomy 21 - 47 XX +21 (female)

  Using the standard shorthand shown above, changes in a single chromosome can be noted by designating whether the p or the q arm has undergone a mutation. For example:

  If a translocation has occurred in which a piece of the q arm of chromosome 5 breaks off and reattaches to the p arm of chromosome 14, this error in the human in which it occurs is noted like so, in the genotype:

  46 XY, t(5q^-; 14p⁺)
  This says that this is a male with the normal number of chromosomes, but that a piece of the long arm of chromosome 5 has broken off and attached to the short arm of chromosome 14.

More autosomal aneuploidies
Trisomy 18 (Edwards Syndrome)

• most affected are female; generally lethal in males
• generally, death by age 2-3
• severe mental retardation
• very small nose, mouth, receding chin
• no distal flexion creases in fingers
• severe organ malformations
• found in 1/10,000 births

Trisomy 13 (Patau syndrome) 47 XX or XY 13+

• found in 1/20,000 births
• severe mental retardation
• heart and organ defects
• polydactyly
• death by the age of one year

Cri du Chat Syndrome 46 XX or XY, 5p^- (segmental deletion)

• variable expressivity, but traits include...
• wailing, cat-like cry in about 50% of those afflicted due to malformation of the larynx
• microcephaly
• severe mental retardation
• heart and other organ deformities
• essentially, this is a partial monosomy.

Prader-Willi Syndrome

• short stature, obesity, small extremities, poor muscle tone, mental retardation.
• insatiable appetite (non-functioning satiety feedback mechanisms) probably responsible for the obesity.
• caused by the deletion of a specific region of chromosome 15
• unusual expression of this disease is due to a phenomenon known as "parental imprinting" which we will discuss later, when we look at gene regulation/expression.

• some c'somes have what is termed "fragile" sites which are susceptible to breakage, at least in vitro, when subjected to insufficient concentrations of certain chemicals such as folic acid. Some of these regions are thus called "folate sensitive" sites.
• Certain humans have a folate sensitive region on the X c'some.
• This syndrome, the Fragile X syndrome, is the most common inherited form of mental retardation.
• This trait is dominant: a heterozygous female may express the mental retardation, though only about 30% of those affected express the m.r. (variable penetrance) The trait is not fully expressed in all individuals. (variable expressivity)
• About 80% of affected males express m.r.
• Physical traits: long, narrow face w/ protruding chin, large ears, large testicles.
• The responsible gene is FMR-1 (product of this gene is expressed in the brain.

Genetic Anticipation

Mutations at the Single Chromosome Level

How can a chromosome break?

1. Ionizing radiation (production of free radicals, which act like little atomic "cannon balls", blasting through strands of DNA or c'somes.

2. physical trauma

3. chemical insult

AND AS ALWAYS...

Chromosomal Breakage

1. one break, one chromatid
Possible results
a. Restitution (restoration of original chromosome) b. Deletion (loss of acentric fragment)

2. one break, one chromosome (before S phase)

Possible results (after anaphase)
a. restitution
b. one acentric chromosome (this degenerates and is lost) plus one dicentric chromosome (usually inviable)
Possible fates of the dicentric chromosome:

i. pulled apart (separates at "sticky" junction) so that one single-centromere c'some goes to each daughter cell.

ii. pulled apart and broken at a point not at the "sticky" junction; resulting c'somes migrating into each daughter cell are not equal.

The break points of these c'somes are very reactive and unstable; they break and rejoin in many ways. After a few divisions, the cell line carrying this mutation usually dies.

3. Two breaks on one chromatid
Possible results:
a. restitution
b. deletion
c. inversion
possible results of an inversion:

i. new linkage arrangements

ii. change in gene order can cause position effects (which can change gene expression)

Chromosomal Rearrangements: The Mystery of the Inversion Heterozygote

Inversion of a chromosome can cause position effects, but in many cases, if individual essential genes are not disrupted by the break and inversion, the inversion may not produce any noticeable phenotypic effects. All loci on the wild type will be present in the inversion heterozygote. Some inversion heterozygote individuals may exhibit position effects in the phenotype, but others may look entirely normal (wild type). In this case, the inversion mutation is, at least at the level of the individual carrying it, phenotypically neutral.

It is only when this individual begins manufacturing gametes that the inversion will make itself known in the form of semisterility of the inversion heterozygote.

Semisterility in an Inversion Heterozygote
When this organism (say, a fruitfly) undergoes meiosis in its own little gonads, very strange things begin to happen during synapsis...

• Inversion loop forms when homologous loci line up. This results in crossover suppression.
  • the two outer chromatids in this mess don't undergo crossing over. (one resulting c'some will be normal, one will contain the inversion section.)

  • the internal c'tids in the loop mess will undergo crossing over to produce one acentric chromosome and one dicentric chromosome, with all their resultant bad baggage (as seen in the double break c'some previously).

  • If gametes carrying the acentric and dicentric c'somes undergo fertilization with a normal mate's gametes, the resulting zygotes are invariably inviable.

  • Hence, flies carrying an inversion mutation are said to be semisterile, since half of their offspring die before ever leaving mom's cloaca.

(Pericentric inversion crossover results in two nonrecombinant c'somes (one without mutation, one with mutation), and two imbalanced c'somes, each carrying double of half the original loci.

Inversion Mutations and Evolution

• Organisms carrying an inversion tend to undergo little crossing over in the inversion region in both inversion and non-inversion chromosomes.

• If these loci affect a single trait (or suite of related traits), this means they'll be inherited together generation after generation in a very long chain and be unlikely to undergo further mutation.

• Such a suite of tightly bound loci which affect a single trait is collectively known as a supergene.

  e.g. - mimicry coloration in some species of butterflies

  snail shell color pattern (some species)

• Because supergenes behave like a single locus (little change or mutation), they are fairly fixed and stable. This can be great in a stable environment where the trait is beneficial.

• ...but if conditions change, and the trait becomes a liability, there is little room for modification. The supergene will be rapidly removed from the population.

More Chromosomal Rearrangements:
The Mystery of the Translocation Heterozygote

• Two breaks, two non-homologous chromosomes
  Possible results:
  a. restitution b. deletions c. reciprocal translocations

• If a reciprocal translocation occurs, the two chromosomes switch segments.
• The organism that inherits a translocation chromosome set is known as a translocation heterozygote.
• During meiosis, the translocations produce a characteristic synaptic pattern, in which both tetrads line up to form a "cross shaped" octad, with homologous loci lined up together.
• As with an inversion heterozygote, a translocation heterozygote may exhibit position effects, but in some cases the mutation will be phenotypically neutral, and the fly will appear as a wild type. Only when it manufactures gametes does the translocation manifest, causing semisterility for a slightly different reason.

  Semisterility of the Translocation Heterozygote
  

• Three different chromosome segretation patterns can occur:

  1. Alternate segregation (#1 and #4 plus #2 and #3)
  All gametes are viable, though half carry the translocation mutation.

  2. Adjacent 1 segregation (#1 and #3 plus #2 and #4)
  All gametes have a duplication error, and are inviable.

  3. Adjacent 2 segregation (#1 and #2 plus #3 and #4)
  All gametes have a duplication error, and are inviable.

  This, once again, has created partial sterility in the translocation heterozygote who originally inherited the mutation from its parent.

The Practical Side of Inversions and Translocations

By identifying individuals who all share a genetic disorder, screening can be done to see if mutants all share a translocation in a common gene region. This information can be used to localize a particular gene and, ultimately, to understand its function. (The gene responsible for neurofibromatosis in humans was found this way, and is now known to be located on chromosome 17.)

Because translocations and inversions result in the deletion of small segments of chromosomes, these can be used in the laboratory to induce such changes to note their effects.

Recall that position effect occurs when a portion of a chromosome is moved to a new area where it is closer to or engulfed in heterochromatin. This property was invaluable in determining the nature of the variegation seen in Drosophila eyes caused by position effect resulting from translocations.

Cancers are most often caused by mutations in the coding or regulatory sequences of genes that regulate either cell proliferation or programmed cell death. Chromosomal rearrangements are often found to be the source of carcinogenic mutations to these genes. The translocation can either...
• move a proto-oncogene close to a different regulatory element
  In Burkitt lymphoma, a proto-oncogene that normally encodes proteins used only when the c ell is preparing to proliferate is accidentally translocated next to a gene that encodes constitutively transcribed immunoglobins. The result: cell proliferation genes are constantly activated, and the cells proliferate without control.
• form a hybrid gene that promotes cancer
  Chronic Myelogenous Leukemia (CML) is caused by a translocation that forms a hybrid of two proto-oncogenes, bcr1 and abl. The abl gene encodes a kinase responsible for passing along a transduction signal initiated by a growth factor. In normal cells, this leads to proliferation. In hybrid form, the gene encodes constant transcrioption of the kinase, so the signal is passed along constantly, even in the absence of the initiating growth factor.

Other Errors Involving a Single Chromosome

Result: same gene loci, but fewer chromsomes!

There is often evidence of this occurrence in closely related species. How to tell if this has happened in closely related species? Compare the NF (fundamental number): the number of chromosome arms visible at metaphase.

Centromere fission. In this case, the chromosome splits at the centromere, creating two chromosomes from one.

Result: same number of gene loci, but MORE chromosomes.

Aneuploidy vs. Polyploidy: Gene Balance

Synteny

Aberrent Euploidy: Changes at the Level of Chromosome Set

In most animals, polyploidy is usually lethal (it is known in a few reptiles, fish and invertebrates, but it's always lethal in mammals and birds, as far as we know). Haploidy is normal in some species, such as honeybees (drones)--where it takes part in sex determination--but it is not common.

In plants, polyploidy is an important mechanism for speciation. Three general ways this can happen:

1. Autopolyploidy (all chromosome sets from the same species)

2. Allopolyploidy(chromosome sets from different species) - two forms of this type.

Note: usually, a polyploid plant is much bigger, more robust and healthy than its parental diploid stock!

Allopolyploidy

In such cases, if the parental chromosome sets differ in number, the hybrid offspring will have two separate sets of chromosomes, each member lacking a matching homolog. Each chromosome in the hybrid is said to be univalent, and cannot undergo normal meiosis without that homologous partner. The chromosomes do not undergo synapsis, and there is no crossing over. There may be random segregation of chromosomes during meiosis, resulting in inviable gametes.

However, viable, fertile hybrids have been produced in the laboratory, and it's possible that they could occur in similar fashion in natural situations. Here's an example of such an artificially produced hybrid that is fertile, and can self-cross.

Brassica oleracea (cabbage) x Raphanus sativa (radish)

• Both species 2n = 18; n = 9

• Breeding between the two species produces an allodiploid F1 generation in which 2n = 18 (but actually is 9 + 9, since the chromosomes are not homologous).

• But if somatic doubling (i.e. nondisjunction) occurs in a meristematic cell. Result: 2n = 36. In effect, each parental chromosome set has "created" its own homologous set and migrated with it into a new cell.

• The cell is said to be allotetraploid.

• At this point, normal meiosis, complete with synapsis and crossing over, can take place. Because these plants are usually self-fertile, they can produce offspring, even if there is only one such amphidiploid individual in the poplation. This "new genus/species" was named Raphanobrassica.
• In most cases where such a hybrid is artificially produced, a new scientific name is not assigned, since it is not truly a new (wild) species, but an artificially bred domestic one.
• Backtracking through natural matings of other species, one can see how new species may be produced via the non-finicky mating habits of some species, particularly plants.

Some animals can produce allopolyploids

• horse x donkey yields a mule, but these are sterile, with extremely rare exceptions.
• lion x tiger yields a liger or tigon

Why are animal allopolyploids so rare?

• Animals have chromosomally determined sex, and polyploidy interferes with this.

• Animals have multiple biological isolating mechanisms (geographic, temporal, behavioral etc.) which tend to prevent natural interbreeding between species.