BIMS 320 Exam 3

Mutation

detectable & heritable change in DNA; heritable change in the nucleotide sequence or chromosome

the ultimate source of all genetic variation in humans & other organisms

mutations

How can mutations occur?

• spontaneously because of errors in DNA replication

• exposure to environmental factors such as radiation or chemicals

Somatic Mutations

occur in cells of the body that do not form gametes; not transmitted to future generations

Germ-Line Mutations

occur in cells that produce gametes; transmitted to future generations-inherited

Genome Mutations

aneuploidy, monoploidy, etc.

Chromosomal Aberrations

translocations, inversions, deletions, etc.

Gene Mutations

• Base-pair substitutions

• transition mutation

• transversion mutation

• missense mutation

• sense mutation

• nonsense mutation

• neutral mutation

• silent mutation

Spontaneous Mutation

low level of genetic changes that occur through time; can be due to transposable elements, DNA replication errors, & naturally occurring mutagens or natural radiation; led to the idea of Genetic Clock

Genetic Clock/Molecular Clock

average rate at which a species genome accumulates mutations, used to measure their evolutionary divergence & in other calculations

How can mutations be observed?

• pattern of inheritance

• phenotype

• biochemistry

• degrees of lethality

Identification of Dominant Mutations

easiest to detect; expressed in heterozygous condition; sudden appearance in a family can be observed in a single generation

Identification of a Recessive Mutation

more difficult to detect; can be detected only in the homozygous condition; extremely difficult to identify the origin of the mutation

Identification of Sex-Linked Recessive Mutations

even more difficult to determine, but generally, they only appears in males in a family

What was the cause of the end of the royal family concerning Queen Victoria & Hemophilia?

an x-linked recessive trait

Mutation Rates

number of event that produce mutated alleles per locus per generation; different for different genes; range from 1 in 1,000 to 1 in 1,000,000

What do accurate measurement of mutation rates depend on?

• frequency at which heritable changes in DNA occur

• rate at which mutations are detected & repaired by cells

• whether the mutation results in a recognizable phenotype

Under what conditions can mutation rates for dominant alleles be measured?

• mutant phenotype must never be produced by recessive alleles

• mutant phenotype must always be fully expressed & completely penetrant

• paternity must be clearly established

• phenotype must never be produced by non-genetic agents

• phenotype must be produced by mutation of only a single gene

What factors influence mutation rates?

• Size of the Gene: larger genes have higher mutation rates

• Nucleotide Sequence: presence of nucleotide repeats are associated with higher mutation rates

• Spontaneous Chemical Changes: C/G base pairs are more likely to mutate than A/T pairs

Radiation

process by which electromagnetic energy travels through space or a medium such as air

Ionizing Radiation

radiation that produces ions during interaction with other matter, including molecules in cells

Background Radiation

radiation in the environment that contributes to radiation exposure

Rem

unit of radiation exposure used to measure radiation damage in humans

Mutagens

chemicals that cause mutations; some can cause nucleotide substitutions or change the number of nucleotides in DNA

Base Analogs

mutagenic chemicals that structurally resemble nucleotides & are incorporated into DNA or RNA during synthesis

Intercalating Agents

chemicals that insert themselves into DNA; produce frameshift mutations; ex. Agent Orange

Irradiated Food

may produce mutations & cancer-causing compounds in food; could result in radiation-resistent microorganism

Nucleotide Substitutions

involve replacing one or more nucleotides in a DNA molecule with other nucleotides

Frameshift Mutations

a number of bases are added to or removed from DNA, causing a shift in the codon reading frame

Missense Mutation

cause the substitution of one amino acid for another in a protein

Sense Mutations

mutations in a single nucleotide can change a termination codon into one that codes for an amino acid producing elongated proteins

Nonsense Mutation

change an amino acid specifying a codon to one of three termination codons

Insertions

change the reading frame, changing the amino acids in the protein

Trinucleotide Repeats

a three-base pair repeating sequence

Allelic Expansions

increase in gene size caused by an increase in the number of trinucleotide sequences

Disorder due to expanded trinucleotide repeats

Huntington Disease

Fragile-X Syndrome

#1 leading cause of male mental retardation; FMR-1 gene mutated

Anticipation

onset of a genetic disorder at earlier ages & with increasing severity in successive generations due to increasing number of repeats

Fates of cells with accumulated DNA damage:

• dormancy (good - cell stops replicating)

• apoptosis (best case scenario - cell dies)

• cancer (bad)

DNA polymerase

proofreads DNA sequence during DNA replication & repair DNA damage caused by UV light

Xeroderma pigmentsoum

condition caused by a genetic disorder affecting DNA repair systems

Thymine dimers

caused by UV light damage to DNA

Action of the enzyme photolyase

• requires light energy (320-370nm, blue light)

• does not remove any nucleotides

• repairs dimer formation by splitting the T=T bonds

Fanconi anemia

impaired removal of DNA interstrand cross-links such as those caused by the antibiotic mitomycin-C

Ataxia telangiectasia

sensitive to ionizing radiation

Bloom Syndrome

high frequency of chromosome breakage

Cystic Fibrosis

>1300 mutations of the CFTR gene (trans-cell membrane protein)

Epigenetics

study of chemical modifications of DNA & its associated proteins; alter gene expression without changing the nucleotide sequence of DNA

Epigenetic Trait

phenotype that is produced by epigenetic changes to DNA

Epigenome

epigenetic state of a cell; can change multiple times over the lifespan of the cell, depending on the environment

Promoter

regulatory region located at the beginning of a gene; very easy to make an epigenetic gene by blocking this

Methylation

addition of a methyl group to a DNA base or a protein

Genetic Imprinting

selective expression of a gene depending on whether it is inherited from the mother or the father; does not affect all genes

Prader-Willi Syndrome

(SNRPN & NDN genes) imprinted maternal copy & deletion on the paternal copy results in no functional gene; autosomal recessive inheritance; obesity, uncontrollable appetite & mental retardation

Angelman Syndrome

(UBA3A gene) imprinted paternal copy & the maternal UBE3A gene is absent or not functioning normally; autosomal recessive inheritance; severe mental retardation, uncontrollable puppet-like movements & seizures of laughter

Beckwith-Wiedmann syndrome (BWS)

caused by abnormal patterns of imprinting that in turn are caused by improper epigenetic modifications of certain genes located in clusters on chromosome 1; genetic disorder but not caused by a gene mutation

Is genetic imprinting reversible?

Yes, because it is an epigenetic change where in each generation the previous imprinting is erased & the gene is reimprinted

Carcinogen

a substance capable of inducing cancer in an organism

Clastogen

substance that causes chromosome abnormalities

Teratogens

an agent that increases the incidence of congenital malformations

What did Theodor Boveri propose?

a link between genetics & cancer in the nineteenth century

• predisposition to more than 50 forms of cancer is inherited to one degree or another

• most chemicals that cause cancer cause mutations

• some viruses carry genes that promote & maintain the growth of cancer in infected cells

• specific chromosomal changes are found in certain forms of cancer

What is cancer?

genetic disorder of somatic cells

• malignant tumors

What is the primary risk factor for cancer?

age

What pattern of inheritance do heritable predispositions to cancer usually show?

dominant pattern

What are the two characteristics of cancer?

uncontrolled cell division

• noncancerous (benign) tumors

the ability of cancer cells to spread to other parts of the body

• cancerous (malignant) tumors

Where does cancer begin? & how does it change from there?

single cell; cancer cells become a clonal descendent of that mutant cells; that cell accumulates mutations overtime & escapes the cell cycle beginning uncontrolled division

Metastasis

process by which cells detach from the primary tumor & move to other sites in the body, forming new malignant tumors

• ability to invade new tissues results from new mutations in cancer cells

Inherited Cancer

inherited genes cause a predisposition to cancer; mutations are carried in all cells

Sporadic Cancer

cancer caused by accumulation of a number of mutations in somatic cells; mutation occurs in a single somatic cell

What causes the abnormal shape in cancer cells?

uncontrolled cell division

Tumor suppressor genes

decrease cell division; genes encoding proteins that regulate the cell cycle; act at G1/S or G2/M during the cell cycle; deletion or inactivation of these products cause cells to divide continuously

Oncogenes

increase cell division

Proto-oncogenes

initiate or maintain cell division; may become cancer genes (oncogenes) by mutation

Retinoblastoma

malignant tumor of the eye arising in retinoblasts; tumor usually only occurs in children; associated with a deletion in the long arm of chromosome 13

Familial retinoblastoma

individuals inherit one mutant copy of RB1 gene

• 85-95% chance of developing the disease

Sporadic retinoblastoma

mutation of both copies of RB1 gene occur in a single cell

RB1 gene

tumor-suppressing protein pRB controls the G1/S transition in the cell cycle

• without pRB, cell division is uncontrolled

How do proto-oncogenes become oncogenes?

a single base change can produce an altered gene product; mutations can increase the number of copies of a normal gene

What do mutations in BRCA1 & BRCA2 genes cause?

predisposition to breast & ovarian cancer in women

BRCA1 protein

found only in the nucleus & is activated when DNA is damaged; stops DNA replication & binds to Rap80 protein to identify DNA damage & initiate repair

What is the risk associated with mutations in BRCA1 & BRCA2 genes?

account for about 20% of all breast cancers & women who carry one of these mutant genes have up to a 85% risk of breast cancer by age 70

Male Breast Cancer

very rare; approximately 2,000 cases per year; men who inherit mutant BRCA1 or BRCA2 have an 80-fold elevated risk of breast & prostate cancers

Knudson hypothesis (aka multiple-hit hypothesis)

hypothesis that cancer is the result of accumulated mutations to a cell’s DNA; study of colon cancer provides insight into the number & order of steps involved in transforming normal cells into cancel cells

How does colon cancer origniate?

• starts as a benign tumor that later becomes malignant

  • six or more mutations required to initiate cancer

What are the two pathways to colon cancer related to genetic predispositions?

• familial adenomatous polyposis (FAP)

• hereditary nonpolyposis colon cancer (HNPCC)

Familial adenomatous polyposis (FAP)

autosomal dominant trait resulting in the development of polyps & benign growths in the colon; polyps often develop into malignant growths & cause cancer of the colon &/or rectum

Colon Polyps

small clusters of dividing cells on the lining of the colon

what are the 3 steps of FAP associated colon cancer?

1, mutation in the APC gene on chromosome 5

2. mutation of one copy of the k-ras proto-oncogene in a polyp cell transforms the polyp into an adenoma

3. mutations in both alleles of the p53 gene on chromosome 17 cause the late-stage adenomas to become cancerous

Hereditary nonpolyposis colon cancer (HNPCC)

autosomal dominant trait associated with genomic instability of micro-satellite DNA sequences & a form of colon cancer

• mutations in MSH2 or MLH1 genes destabilize the genome causing mutations in DNA micro satellites

• clusters are called short sequence repeats (SSRs) or short tandem repeats (STRs)

Gatekeeper Genes

genes that regulate cell growth & passage through the cell cycle; ex. tumor suppressor genes

Caretaker genes

genes that help maintain the integrity of the genome; ex. DNA repair genes

What is common in cancer cells?

changes in the number & structure of chromosomes

What are some disorders associated with?

high rates of cancer; may result from the presence of an initial mutation or genetic imbalance that moves cells closer to a cancerous state

What do translocation events cause? & what are examples of cancers associated?

creates hybrid genes that activate cell division; chronic myelogenous leukemia; Philadelphia chromosome

What cancers are associated with specific chromosomal abnormalities?

myeloblastic leukemia, Burkitt’s lymphoma, multiple myeloma

Chronic myelogenous leukemia (CML)

C-ABL gene (chromosome 9) is moved next to the BCR gene (chromosome 22)

• hybrid gene encodes an abnormal protein that signals CML cells to divide

Philadelphia Chromsome

abnormal chromosome produced by translocation between the long arms of chromsomes 9 & 22; linked to chronic myelogenous leukemia (CML)

The Cancer Genoma Atlas

to employ large scale genome sequencing of cancer cells to catalog genetic changes & identify new genes

Gleevac

inactivates the BCR-ABL protein; cancer cell stops dividing

Epidemiology

study of factors that control the presence, absence, or frequency of a disease; provides statistical correlation between the environment & diseases such as cancer