Genetics Exam 2

Two checkpoints in interphase

(G1/S and G2/M)

Intercalary deletion/interstitial deletion

- a deletion that occurs from the interior of a chromosome.

Terminal deletion

- a deletion that occurs towards the end of a chromosome.

Micro-deletion

- a relatively small amount of deletion (up to 5Mb that could include a dozen genes; next lecture).

Silent Mutation

- alters a codon into one that codes for the same amino acid. - Recall codon degeneracy

the G2/M checkpoint

- checking for potential DNA damage to ensure the cell is ready for mitosis. Also known as postreplication checkpoint

Metaphase

- chromosome align at the cell equator

Prophase

- chromosomes condense and become visible

Telophase

- chromosomes decondense and are enclosed in two nuclei

the G1/S checkpoint

- making the key decision of whether the cell should divide, delay division, or enter a resting stage. All necessary enzymes are synthesized. Also known as restriction point.

Anaphase

- sister chromatids separate and move to opposite poles

Prometaphase

- spindle forms and sister chromatids attach to microtubules from opposite centrosomes

G2 phase

- synthesis of proteins required for mitosis

Robertsonian Translocation(or Fusion)

-a translocation that occurs in maternal germ line cells and joins the long arms of two acrocentric chromosomes and creates a single large chromosome. The short arms become lost. -Can result in familial Down syndrome in children of carriers

3- Simple sequence repeats (SSRs)

1-10 base sequence repeated 15-100 times in tandem i.e. repetition of one or more nucleotides directly adjacent to each others

Four categories of genetic variation

1. Single nucleotide substitutions (polymorphisms/mutations) One base pair changes 2.Deletion-insertion polymorphisms (DIPs) Short insertions or deletions of a single or a few base pairs 3. Simple sequence repeats (SSRs) 1-10 base sequence repeated 15-100 times in tandem 4. Copy number variants (CNVs) Large blocks of duplication or deletion with population frequency of < 1%

1- Genetic Variation through Random Distribution of Chromosomes in Meiosis

2^n = 2^3 Independent assortment of nonhomologs creates different combinations of alleles Even without considering crossing over, in humans meiosis alone can generate 223 (about 8.4 million) genetically different gametes.

Radical and conservative substitution

A DNA mutation in a protein coding gene which causes an amino acid change can be classified as "conservative" or "radical" depending on the magnitude of the physicochemical difference between the two amino acids: radical mutations involve larger changes than conservative mutations -a neutral mutation is a mutation that occurs in an amino acid codon but it has no impact

The MTOC is made up of a pair of centrioles at its center, and is surrounded by pericentriolar material (PCM) that is important for microtubule nucleation.

A centriole is a cylindrical cell structure composed mainly of a protein called tubulin.

2-Deletion- polymorphisms (DIPs)/Mutations

A deletion changes the number of DNA bases by removing a piece of DNA (a single or a few base pairs)

Polymorphism - Mutation

A mutation is defined as any change in a DNA sequence away from normal. This implies there is a normal allele that is prevalent in the population and that the mutation changes this to a rare and abnormal variant. In contrast, a polymorphism is a DNA sequence variation that is common in the population.

Molecular mechanisms of mitosis in cell cycle

A precise chromosome distribution The consequences of a single error are grim Cells with abnormal number of chromosomes are either non-viable or, worse, they can become the first step on the road to cancerous transformation. Mitotic spindle Centrosomes Kinetochore

Ring chromosome

A ring chromosome is an aberrant chromosome whose ends have fused together to form a ring.

Centrosome

A structure in animal cells containing centrioles from which the spindle fibers develop.

Mutation suppressor

A suppressor mutation is a genetic change that hides or suppresses the effect of another mutation.

Mutations are caused several natural and unnatural factors

A.Spontaneous replication errors B.Spontaneous chemical changes Chemically-induced mutations

SNP or mutation?

About 90 percent of all human genome variation comes in the form of SNPs 1 bps in 1000 bps

Missense Mutation

Alters a codon so that it specifies a different amino acid in a protein (amino acid substitution).

Mutagen

An environmental agent that significantly increase the rate of mutation

2-insertion polymorphisms (DIPs)/Mutations

An insertion changes the number of DNA bases in a gene by adding a piece of DNA (a single or a few base pairs).

Isochromosome

An isochromosome is an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other

3- SSRs: Huntington disease, an example

Autosomal dominant disorder Normal allele has < 34 CAG repeats Disease-causing alleles have 42 or more CAG repeats

Nonsense Mutation: Cystic Fibrosis, an example

CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). About 10% of CF results from a premature stop codon in the DNA (G542X) This leads to an early termination of mRNA synthesis Degradation of nascent mRNA or production of truncated protein.

2-Deletion-insertion polymorphisms (DIPs)/Mutations; BRCA1 an example

Change the length of the DNA molecule Disrupt the reading frame BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT frameshift

2- Genetic Variation Through Crossing Over

Crossing-over between homologs creates different combinations of alleles within each chromosome Recombination helps a population get rid of deleterious mutations. Increase organismal fitness Fast adaptations to the fluctuating environment

S phase

DNA replication - duplication of chromosome into sister chromatids

B. Spontaneous chemical changes

Depurination Deamination

Nondisjunction in Mitosis(somatic mutation)

Euploid: chromosome number is the exact multiple of the haploid number, 2n in humans Aneuploid: chromosome number is NOT the exact multiple of the haploid number Examples in human: Monosomy (2n - 1), Trisomy (2n + 1)

Interphase includes

G1 phase, S phase, G2 phase

Crossing over in meiosis I

Homologs pair, cross over, and then segregate Sister chromatids remain intact throughout meiosis I Maternal and paternal homologs recombine and create new combinations of alleles (segregate in different daughter cells)

4- Unequal crossing-over produces new alleles of copy number variants (CNVs)

Large blocks of duplication or deletion with population frequency of < 1%

Loss-of-function and gain-of-function mutations

Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). Gain-of-function Mutation. A type of mutation in which the altered gene product possesses a new molecular function or a new pattern of gene expression.

C. Chemically-induced mutations

Mutagen Base analog Alkylating agent:

Mitotic spindle:

Newt lung cells fixed and stained for microtubules (green) and DNA (blue) Arrays of microtubules organized by centrosomes (left) to metaphase stage (right)

Single nucleotide substitutions (polymorphisms/mutations)

One base pair substitutes Genome variations include mutations and polymorphisms. Single nucleotide polymorphisms, or SNPs (pronounced "snips") or Mutations

Stable or steady state phase (G0)

Period in the cell cycle where cells exist in a inactive state. Typical for cells that do not divide often or ever, e.g., neurons, heart muscle cells

Anomalous base-pairing:

Rare tautomeric form can mispair during replication

Point mutations in noncoding DNA

Regulatory regions (response elements) Enhancer, silencer and insulators miRs and siRNA sequences Introns splice sites

Somatic vs germline mutations

Somatic mutations - occur in a single body cell and cannot be inherited (only tissues derived from mutated cell are affected) Germline mutations - occur in gametes and can be passed onto offspring (every cell in the entire organism will be affected)

A. Spontaneous replication errors

Tautomeric shift Anomalous base-pairing

Kinetochore

The kinetochore is the protein structure (complex) on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart

Depurination:

The loss of a purine base (A or G) from the nucleotide

Deamination

The loss of an amino group (NH2) from the nucleotide Spontaneous or chemically-induced (Nitrous acid)

Microtubule organization and polarity

The plus end can grow by addition of tubulin subunits (polymerization) or shrink by the loss of tubulin subunits (depolymerization) from the plus end

Missense Mutation; Sickle-cell disease (SCD), an example

The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function

Tautomeric shift:

The spontaneous isomerization of a nitrogen base to an alternative hydrogen-bonding form

Human Karyotyping

Trisomy Monosomy Deletions Duplications Translocations Genetic Rearrangement

Eukaryotic reproduction at the cellular level: MEIOSIS

Two rounds of cell division Chromosomes duplicate once; nuclei divide twice Meiosis I reduces the chromosomes from 2n to n.

Chromosomal Translocation

When part of one chromosome breaks off and attaches to another non homologous, chromosome.

chromosomal inversion

When part of the chromosome becomes oriented in the reverse of its usual direction

mutation

a change from one hereditary state to another

Gene Fusion

a structure created by joining together segments of two separate genes, in particular when the regulatory region of one gene is joined to the coding region of a reporter gene

Point mutations

changes in a single gene at the molecular level.

Chromosomal mutations

changes in the number and structure of chromosomes.

Base analog:

chemical mutagens consist of base analog chemical structures similar to any of the four bases.

Alkylating agent:

chemicals that donate alkyl groups such as methyl, ethyl etc. (EMS: ethyl methyl sulfonate)

Dicentric chromosome

chromosome with two centromeres

Nonsense Mutation

converts an amino-acid-specifying codon into a stop codon

nonreciprocal translocation

genetic material moves from one chromosome to another without any reciprocal exchange

kinetochore microtubules attach to the

kinetochore of a chromosome.

Chromosomal Deletion

loss of a portion of a chromosome

In cells, the minus ends of microtubules are anchored in structures called

microtubule organizing centers (MTOCs). The primary MTOC in a cell is called the centrosome, and it is usually located adjacent to the nucleus.

The microtubules from opposite poles that do not attach to the kinetochores but do overlap at the

midpoint between the two poles are referred to as polar microtubules.

Mitosis has five stages that have distinct cytological characteristics

prophase, prometaphase, metaphase, anaphase, telophase

The aster microtubules point away from the

spindle equator.

G1 phase

stage of interphase in which cell grows and performs its normal functions - chromosomes are not duplicating or dividing Length of time varies in different cell types

p53 plays an important role in triggering

the control mechanisms at both G1/S and G2/M checkpoints.

spindle microtubules

the filaments responsible for moving chromosomes during cell division.