Molecular Genetics Test 5: Chapter 16
Trisomy-21 or Down's syndrome
-3 copies of Chromosome 21 -3510 per 1 x 10^6 conceptions -1430 per 1 x 10^6 live births
Chromosomal Mutations and Human Reproduction
1. 50 % of spontaneous abortions contain chromosomal mutations.
Types of Chromosomal Mutations
1. Can arise spontaneously or be induced experimentally by chemical or radiation mutagen
Types of Chromosomal Mutations
2. Can be detected in both prokaryotes and eukaryotes by genetic analysis, i.e., by changes in linkage arrangement of genes.
Chromosomal Mutations and Human Reproduction
2. Visible chromosomal mutations occur in 6 out of 1000 live births.
Types of Chromosomal Mutations
3. In eukaryotes chromosomal mutations can often be detected cytologically during mitosis and meiosis.
Chromosomal Mutations and Human Reproduction
3. One in seven fertilizations ends in spontaneous abortions.
Chromosomal Mutations and Human Reproduction
4. Therefore, it is estimated that about 15 % of all conceptions contain chromosomal mutations.
Fragile Sites and Fragile X Syndrome
40 such sites have been identified thus far.
Chromosomal Mutations and Human Reproduction
5. Eleven percent of infertile men have chromosomal mutations.
Chromosomal Mutations and Human Reproduction
6. Six percent of people institutionalized for mental deficiencies have chromosomal mutations.
Examples of Human Translocations:
90 % of patients have a chromosomal mutation called the Philadelphia chromosome (discovered in the city of Philadelphia).
Inversion
A chromosome mutation that results when a segment of a chromosome is excised and then reintegrated in an orientation 180 degrees from the original orientation.
Translocation
A translocation is a chromosomal mutation in which there is a change in position of chromosome segments and the gene sequence they contain.
Fragile Sites and Fragile X Syndrome
After Down's syndrome Fragile X Syndrome is the leading cause of mental retardation in the USA -1 in 1250 males -1 in 2500 females
Chromosome 2
All Members of Hominidae except Humans have 24 sets of Chromosomes.
Changes in the parts of chromosome rather than changes in the numbers of chromosomes.
All four mutations depend on a break in chromosome. Broken ends of chromosomes are sticky and can adhere to other chromosomes.
Hemoglobin consist of two copies of two different subunits.
Alpha-globin is found as a cluster of genes on one chromosome.
Chromosome rearrangements that alter gene expression.
Amplification leads to increase synthesis of gene product.
Duplication in Drosophila
Bar mutant on the X-chromosome resembles incomplete dominance. Cytological studies show that the trait is a result of a duplication of a small segment of X chromosome. It is due to unequal crossing-over event.
Hemoglobin consist of two copies of two different subunits.
Beta-globin is also found as a cluster of genes on another chromosome.
Deletions:
Can be induced either by heat, radiation, viruses, chemicals, transposable elements or by errors in recombination.
Changes in the parts of chromosome rather than changes in the numbers of chromosomes.
Change in arrangement of Chromosome segment: -Inversions
Changes in the parts of chromosome rather than changes in the numbers of chromosomes.
Change in location of chromosome segment: -Translocation
Changes in the parts of chromosome rather than changes in the numbers of chromosomes.
Changes in the amount of DNA per chromosome: -Deletions and Duplications
Polytene Chromosomes (Drosophila)
Chromocenter: is a proteinaceous structure joining all the Polytene Chromosomes at their centromere.
Polytene Chromosomes (Drosophila)
Chromosomal mutations are easily seen in polytene chromosomes of Drosophila salivary glands.
Chromosomal Mutations:
Chromosomal mutations are variations from the wild-type condition in either chromosomal structure or chromosomal number.
Deletions:
Chromosomal mutations involving loss of a chromosome segment.
Duplication
Chromosomal mutations that cause a doubling of a chromosome segment. These mutations have played an important role in the evolution of gene families, such as alpha-and beta-globin in hemoglobin.
Chromosome rearrangements that alter gene expression.
Chromosomal rearrangements occur in nature as mechanisms of altering gene expression.
Chromosome 2 Fusion in one of our hominid ancestors:
Chromosome 2 of humans has DNA sequence nearly identical to two Chromosomes of our closest relative, chimpanzees. -Humans have Vestigial Centromere in 2.1 -Humans have Vestigial Telomeres in 1.3
Types of Chromosomal Mutations
Chromosome Rearrangements that Alter Gene -Expression -Amplification or deletion of genes -Inversions that alter gene expression -Transpositions that alter gene expression
Examples of Human Translocations:
Chronic Myelogenous Leukemia (CML) is a fatal cancer that involves uncontrolled replication of myeloblast (stem cells for white blood cells).
Deletion in Humans:
Cri-du-chat syndrome (french for "Cry of the cat") ---1 infant in 50,000 live births: 1. Severe mental retardation 2. Physical abnormalities 3. Cry of the baby sounds like the mew of a cat.
Chromosomal Mutations:
Cytogenetics: The study of chromosomal behavior in normal cells and how this behavior is altered in cells with chromosomal mutations. Both genetics and cytological methods are used in this type of study.
Chromosome rearrangements that alter gene expression.
Deletion: If gene is deleted, expression is abolished. If a regulatory region of the gene is deleted, the gene expression can either be up-regulated or down-regulated.
Changes in the parts of chromosome rather than changes in the numbers of chromosomes.
Duplications, inversions and translocations can change back to wild-type. However, deletion mutations cannot revert due to the loss of DNA.
Trisomy-18
Edward's syndrome---most die within 6 months.
Position Effect---It is a change in the phenotypic expression of a gene (or more genes) because of a change in its position in the genome. For example:
Euchromatin is the regions of a chromosome that are condensed during division but become uncoiled during interphase.
Chromosomal Mutations:
Found in prokaryotes, eukaryotes and viruses.
Fragile Sites and Fragile X Syndrome
Fragile X syndrome---the long arm of the chromosome is prone to breakage.
Hemoglobin consist of two copies of two different subunits.
Genes are expressed at different times during an organisms development.
Position Effect---It is a change in the phenotypic expression of a gene (or more genes) because of a change in its position in the genome. For example:
Heterochromatin is those regions of a chromosome that remain condensed during division and interphase.
Duplication
Heterozygous duplication results in unpaired loops and may be detected with amicroscope.
Unequal Crossing-over
Homologous chromosomes pair inaccurately, which is possibly due to similar DNA segments in neighboring regions of the chromosome.
Translocations and Human Tumors
However, it is not always clear if the chromosomal mutations caused the tumor or is a result of the tumor.
Deletions:
If deficiency is large enough, we can see deletions as mismatched pair of homologous chromosome or by unpaired loops of DNA.
Translocations and Human Tumors
In some cases, once a chromosomal mutation has occurred in the early stages of a tumor other mutations will occur that correlate with a progression to an uncontrolled growth state.
Two kinds of translocations occur;
Interchromosomal Translocation—transfer of a chromosome segment from one chromosome into a nonhomologous chromosome.
Two kinds of translocations occur;
Intrachromosomal Translocation—chromosomal segment changes position within the same chromosome
Inversions that alter gene expression
Inversions that regulate gene expression are rare.
Polytene Chromosomes (Drosophila)
Its large size enables cytogeneticist to identify segments of chromosome and to look at banding patterns after staining.
Molecular basis of Fragile X syndrome:
Male and females with Fragile X syndrome have 200 to 1300 CGG repeats in the FMR-1 gene. -Indicates that there is threshold for phenotypic expression. -Individuals who are clinically normal have < 200 CGG repeats. -Individuals who have clinical symptoms have > 200 CGG repeats. -The amplification of repeats occurs only in females.
Pericentric Inversion Figure 16.9
Meiotic products resulting from a single crossover within a heterozygous, pericentric inversion loop. Crossing-over occurs at the four-strand stage involving two nonsister homologous chromatids.
Consequences of a paracentric inversion. Figure 16.8
Meiotic products resulting from a single crossover within a heterozygous, paracentric inversion loop. Crossing-over occurs at the four-strand stage involving two nonsister homologous chromatids.
Changes in complete sets of chromosomes.
Monoploidy---1 set of chromosomes instead of two sets. Because of lethal recessive alleles, many do not survive.
Changes in complete sets of chromosomes.
Most common type in humans is Triploidy (3 sets), which is lethal in humans. -15 to 20 % of spontaneous abortions -1 in 10,000 live births ( most die within a month)
Translocation
Nonreciprocal translocation—transfer of a segment in one direction from one chromosome to another.
Molecular basis of Fragile X syndrome:
On average, there are 29 CGG repeats (range from 6 to 54) located in the FMR-1 gene. Phenotypically normal transmitting males, their daughters, and some carrier females have a large number of CGG repeats (55-200 repeats).
Trisomy-13
Patau syndrome---most die by 3 months
Changes in complete sets of chromosomes.
Polyploidy---more than the normal set of chromosomes.
Chromosome rearrangements that alter gene expression.
Programmed amplification or deletions of genes are found widely in nature. -Amplification or Deletion can involve are large part of the genome or a small set of genes.
Translocation
Reciprocal translocation—exchange of segments between the two chromosomes.
Molecular basis of Fragile X syndrome:
Repeated 3-base-pair sequence CGG GCC or CGG repeat
Robertsonian Translocation
Segregation pattern for a heterozygous Robertsonian translocation. Chromosomes 14 and 21
Translocations and Human Tumors
Several human tumors have been shown to have chromosomal mutations.
Fragile Sites and Fragile X Syndrome
Since the X-chromosome is the site of breakage, males with the disease are predominant.
Fragile Sites and Fragile X Syndrome
The X chromosomes of Human cells in culture will sometimes develop narrowing or gaps call fragile sites.
Robertsonian Translocation
The long arms of two homologous acrocentric chromosomes have a reciprocal translocation.
Translocation
There is no gain or loss of genetic material involved.
Changes in complete sets of chromosomes.
These changes are lethal in most animals but tolerated by plants.
Hemoglobin consist of two copies of two different subunits.
These genes are believed to be derived from an ancestral gene that underwent duplication and subsequent sequence divergence.
Polytene Chromosomes (Drosophila)
They consist of chromatid bundles resulting from repeated cycles of replication without nuclear or cell division.
Molecular basis of Fragile X syndrome:
This is located in a gene called FMR-1 (fragile X mental retardation), whose function is that of an RNA-binding protein, which binds to certain mRNAs in the cell and thus blocking protein synthesis. Data suggest it is active at regulating the strength of neural synapses in the brain.
Robertsonian Translocation
This type of translocation can cause Down's syndrome.
Polytene Chromosomes (Drosophila)
Tightly fused pair of homologous Chromosomes. Observed number of Polytene Chromosomes is half the diploid number.
Types of Chromosomal Mutations
Translocation -Position Effect -Fragile sites and fragile X syndrome
Types of Chromosomal Mutations
Variations in Chromosomal Number -Changes in one or a few chromosomes -Changes in complete sets of chromosome
Types of Chromosomal Mutations
Variations in Chromosomal Structure: -Deletion -Duplication -Inversion
Chromosomal Mutations:
We will focus on eukaryotes and discuss human disease syndromes associated with chromosomal mutations. Note: Not all genetic defects result from mutations of a single gene.
Chromothripsis:
Where one or more chromosomes explode into countless small pieces and are somehow put back together with missing fragments and in the wrong order.
