BIL 104 - Lecture 14

PHENOTYPIC EFFECTS OF ABNORMAL CHROMOSOME NUMBER We've already discussed aneuploidies: too few or too many of a particular homologous pair. But how can these mutations of chromosomal number happen?

nondisjunction

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.)

Functional aneuploidies can also occur when chromosomes break and either lose pieces, or re-attach in unusual ways. THE PHYSICAL RESULTS OF ANEUPLOIDIES 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

Standard nomenclature for human genotypes: genotypes can be written with a standard, shorthand format, as follows:

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 The consequences of these are much worse than sex c'some 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 (short) or the q (long) arm of a chromosome 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 c'some 5 has broken off and attached to the short arm of c'some 14.
More autosomal aneuploidies:
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)

wailing, cat-like cry in about 50% of those afflicted
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.

Fragile X syndrome (Martin-Bell syndrome)

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.
The gene consists of many TRINUCLEOTIDE REPEATS.
(this is also seen in the Huntington's disease gene)
normal - 50 repeats; carrier - 50 - 200 repeats; expressor - 200 or more repeats.
This is a case of GENETIC ANTICIPATION. In Genetic Anticipation, the severity of the disorder increases with succeeding generations, due to the ever-increasing number of repeats. (It's possible that the presence of the repeats actually fosters more repeats during replication.)

MUTATIONS AT THE SINGLE CHROMOSOME LEVEL Some mutations are caused by the breakage of a chromosome, resulting in either a loss of a broken fragment, or its translocation to another, aberrent location. Before we discuss this, let's consider...

How can a chromosome break?

2. physical trauma

3. chemical insult

Remember: we're talking about mutations that happen in the gonads, where gametes are being formed. Otherwise they will not have evolutionary consequences!

Also note that the time in the cell cycle that the insult happens is also important to the results of the mutation:

Breaks which occur before S phase will affect both newly formed chromatids.
Breaks which occur when the c'some is in dyad form may affect only one c'tid. (Thereafter, only the progeny of the broken c'tid carrying cell will be affected.)

Break points of c'somes are highly reactive ("sticky"), whereas normal ends of c'somes are capped by telomeres, which do not readily bond to other molecules.

AND AS ALWAYS...

Mitotic mutations are not evolutionarily significant in animals, but can be in plants and fungi (Review your life cycles!).

Meiotic mutations, if not lethal, can have profound evolutionary impact.

Some types of chromosomal mutations: (Let's do some drawings) 1. deletion - part of a chromosome is omitted and lost

2. duplication - part of a chromosome is doubled

3. translocation - part of one chromosome breaks off and reattaches to a different chromosome

4. inversion - a double break results in a piece of a chromosome being excised, flipped around backwards and reattached

POSITION EFFECT

In some translocation mutations, the new position of the gene can affect the rate of its transcription and translation.

For example, if a highly-transcribed gene is translocated to a region close to tightly coiled, inactive heterochromatin, it can sometimes be partially engulfed by that heterochromatin. This will result in a failure of the gene to be expressed in the cells where the heterochromatin coils over the translocated gene.

5. Robertsonian fusion - two telocentric chromosomes fuse at the centromere, making one large chromosome

6. centromere fission - one chromosome breaks at the centromere, creating two new telocentric chromosomes.