BIO 280 Genetics- Genes and Genetic Diseases

types of epigenetic mechanism?

*DNA methylation *DNA Hydroxymethylation *Chemical modifications that alter the charges of Histone proteins *RNA-based mechanisms

Histone Acetylation

*Diminishes the positive charge of histones *Reduces the strength of their binding to negatively charged DNA *Makes DNA more accessible for transcription

Histone Methylation

*Either increases or decreases the strength of bonding between DNA and histones depending on the specific parts of the histones to which the methyl groups are added

Other diseases caused by epigenetics include:

*Fetal alcohol syndrome *Depression *Posttraumatic stress disorder (PTSD) *Autism-spectrum disorder

Epigenetic mechanisms are responsible for....?

*The phenotype of an individual *the deactivation of the X chromosome when another is present *and are responsible for many different diseases.

Heterochromatic DNA

*a segement of DNA that is bound tightly to its histones - comprises ~7% of your DNA - highly repetitive - gene sparse - cannot be used for production of mRNA

housekeeping genes

*necessary for the function and maintenance of all cells. *These genes escape epigenetic silencing and remain transcriptionally active in all or nearly all cells. *include those encoding histones, DNA and RNA polymerases, and ribosomal RNA genes.

Histones

*positively charged protein molecules around which the negatively charged DNA is tightly coiled in chromatin

Euchromatic DNA

*when DNA is loosely bound to its histones *transcription factors are able to access this and use it for mRNA production

Which percentage of genes are imprinted?

1% *About 1% of genes are known to be imprinted.

Epigenetic steps that happen in utero

1. Fertilization 2. Early embryogenesis 3. DNA replication 4. embryonic cell division 5. implantation in the uterus

The average length of microRNAs (miRNAs) consists of how many nucleotides?

22

Which of the following statements are true? (select one) A- RNA is double stranded. B- DNA is replicated in the cytoplasm C- RNA contains the same bases as DNA D- a mutation is an inherited alteration of DNA

A mutation is an inherited alteration of DNA

Nucleosome

A set of histones and the segment of DNAwound around them.

Imprinting of other genes

A third and smaller subset of autosomes exhibits imprinting of either the maternal copy or the paternal copy. *This means that either the copy inherited through the sperm or the copy inherited through the egg is inactivated and remains in this inactive state in all somatic cells of the individual.

DNA methyltransferase

An enzyme that catalyzes the methylation of DNA.

Phenotype

An organism's physical appearance, or visible traits.

Beck-Wiedemann Syndrome

An over growth condition accompanied by an elevated risk of cancer. Signs: *Large size for gestational age *Neonatal hypoglycemia *A large tongue *Creases on the earlobe *Omphalocele (infant's intestines, liver, or other organs stick outside of the belly through the belly button.) Causes: *by the inheritance of two copies of chromosome 11 from the father, known as uniparental disomy.

Deletion of four million chromosomal base pairs inherited from mother causes ______________, which is characterized by seizures and an ataxic gait.

Angelman syndrome

Severe intellectual disability, seizure, and ataxic gait are the features of

Angelman syndrome.

somatic cells

Any cells in the body other than reproductive cells

Embryonic cell division

As embryonic cell division proceeds in the absence of DNA methyltransferases, cell division continues, eventually yielding cells that have nearly all of their loci in unmethylated, transcriptionally active states.

Which manifestations can be seen in deletion of a region of the long arm of chromosome 15 that is maternally derived?

Ataxia, Seizures and Sever intellectual impairment *Ataxia, seizures, and severe intellectual impairment can be seen in Angelman's syndrome, which is the result of deletion of a region of the long arm of chromosome 15 that is maternally derived.

Which disease is found to have an abnormal methylation of tumor-suppressor genes as part of the progression?

Barrett's Esophagus *Abnormal methylation of tumor-suppressor genes is common in the progression of Barrett's esophagus.

A newborn is assessed at birth and found to have macroglossia (large tongue). Which epigenetic disorder could be responsible for this finding?

Beckwith-Wiedemann Syndrome *Beckwith-Wiedemann syndrome is caused by overproduction of IGF2 and can be associated with macroglossia (a large tongue).

A large tongue, neonatal hypoglycemia, and omphalocele are the features of

Beckwith-Wiedemann syndrome.

DNA methylation in embryonic stem cells

Can also occur at cytosines outside of the CpG context

What are CpG islands?

CpG islands are clusters of CG dinucleotides that are often found at the 5' end of many genes, many of these islands are in promoter elements. These CpG islands are protected from methylation as compared to the 70-80% of CG dinucleotides found in the rest of the genome.

Which epigenetic mechanisms alter the charges of the histone proteins?

DNA Methylation (DNA methylation alters the charge of the histone proteins. By doing so, there is an alteration in histone binding and the rate of transcription.) DNA Hydroxymethylation (DNA hydroxymethylation alters the charge of the histone proteins. By doing so, there is an alteration in histone binding and the rate of transcription)

Which epigenetic mechanism results in anhidrotic ectodermal dysplasis?

DNA methylation

Which processes are known as mechanisms of epigenetics?

DNA methylation and hydroxymethylation *DNA methylation and hydroxymethylation, chemical modifications that alter the charges of the histone proteins, and RNA-based mechanisms are all mechanisms of epigenetics.

A newly discovered disease features DNA methylation at cytosines outside of the CpG context. Which cells were most likely involved in this disease process?

Embryonic Stem Cells *In human embryonic stem cells, methylation can occur at cytosines outside of the CpG context.

What are examples of house keeping genes?

Encoding histones, Ribosomal RNA, DNA and RNA polymerases

Russell-Silver Syndrome

Growth retardation, short stature, leg length discrepancy and small triangular face. Causes: *imprinting abnormalities of chromosome 11p15.5 that lead to downregulation of IGF2 and therefore diminished growth. *maternal uniparental disomy (2 copies of a chromosome come from the same parent)

Factor VIII deficiency

Hemophilia A, Non-clotting blood

Which type of DNA segment is bound tightly to its associated histones?

Heterchromatic

Heterochromatization

Highly condensed chromatin, tightly packaged, prevents transcription of these regions Ex: Inactive X chromosome is a heterochromatin

Which structures are responsible for making DNA more compact?

Histones and Protamines *Both histones and protamines make DNA more compact, whereas housekeeping genes code for these as well as other products

Which gene is responsible for the increase in tumors seen in Beckwith-Wiedemann syndrome?

IGF2 Beckwith-Wiedemann syndrome causes increased IGF2, which increases growth and certain tumors.

what is the reason for overgrowth features of beckwit-wiedmann syndrome?

Inheritance of active IGF2 double dose from the father.

Which statement is true about chromatin?

It helps in determining the developmental potential of a cell lineage

Which statement is true about Chromatin?

It is an association of DNA and Histone

which statement is true about uniparental disomy?

It is the inheritance of two copies of a chromosome from the father and none from the mother.

Loci

Location of a gene on a chromosome

DNA replication and Methylation

Methylation is not directly copied by the DNA replication process. Instead, immediately after replication, the methyltransferases read the pattern of methylation on the parent DNA strand, determining which daughter-strand cytosines should be methylated.

What is the cause of hereditary nonpolyposis colorectal cancer?

Methylation of MLH1 gene

noncoding RNA (ncRNA)

Molecules of RNA that do not code for proteins, including transfer RNA, ribosomal RNA, and microRNA.

Which characteristics can be seen when there is a deletion of a region of the long arm of chromosome 15 that is paternally derived?

Obesity, Hypotonia (decreased muscle tone), Short stature, Hypogonadism and others. *This is Prader-Willi Syndrome

DNA methylation In adults

Occurs principally at cytosines that are followed by a guanine base (cytosines in CpG dinucleotides)

Which patient is an increased risk of developing Hepatoblastoma (liver tumor).

Patient with Beckwith-Wiedemann syndrome

Short stature, obesity, and hypogonadism are the features of

Prader-Willi syndrome

Which syndrome is associated with a deletion of four million base pairs of the long arm of chromosome 15, inherited from the father?

Prader-Willi syndrome

Demethylation

Removal of methyl group in CpG site that generally activates transcriptional activity.

Growth, retardation, leg length discrepancy, and a small, triangular face are the features of

Russell-Silver syndrome.

microRNA (miRNA)

Small noncoding RNA that controls gene expression by base-pairing with a specific mRNA to regulate its stability and its translation.

DNA methylation

The addition of methyl groups (—CH3) to the carbon-5 position of a cytosine; may serve as a long-term control of gene expression. *alters the charge of the histone protein

An area of the genome that is normally densely methylated is found to be largely devoid of DNA methylation. What would be the effect on expression of the associated genes in this area?

There would be an increase in their expression *Because DNA methylation decreases gene expression, areas where there is less DNA methylation would have an increase in expression.

DNA hydroxymethylation

This involves a hydroxymethyl group being affixed to the C5 of cytosine. *results in a change in histone charge similar to the resultant change in histone charge that occurs with DNA methylation.

Which sources are most likely responsible for the presence of large numbers of Tet enzymes in sample cells?

Tumor *Tet enzymes are known to be responsible for the translocations found in certain types of leukemias Embryo *During implantation of the embryo, there is an abundance of methylation loss that is mediated by the Tet enzyme.

DNA Methylation and Cancer

Tumor cells often exhibit decreased methylation genome-wide that can increase the activity of oncogenes. *This tends to continue as tumors progress from benign neoplasms to malignancy.

genomic imprinting

Variation in phenotype depending on whether an allele is inherited from the male or female parent. *can be Biallelic or monoallelic expression

Color blindness is an example of

X-linked disorders

Barrett's esophagus

a condition that occurs when the cells in the epithelial tissue of the esophagus are damaged by chronic acid exposure

Pander-Willi syndrome

a congenital metabolic condition characterized by hypotonia, hyperphagia, marked obesity, hypogonadism, and mental retardation. *Deletion of the long arm of Chromosome 15, inherited from the father

Beckwith-Wiedemann syndrome is characterized by

a large tongue, creases on the earlobe, omphalocele, and neonatal hypoglycemia.

monoallelic expression

a mechanism of gene expression that inactivates one gene of a pair of alleles and allows the other gene of the pair to be expressed.

facioscapulohumeral muscular dystrophy (FSHD)

a mild form of slowly progressing, autosomal dominant muscular dystrophy that affects males and females equally.

Inheritance of two X chromosomes carrying a normal and mutant allele results in anhidrotic ectodermal dysplasia, which is characterized by

a patchy appearance of skin and absence of sweat glands.

Colon cancer is associated with

abnormal DNA methylation of the promoter gene MLH1.

Angelman Syndrome

an autosomal-recessive syndrome characterized by jerky puppetlike movements, frequent laughter, mental and motor retardation, a peculiar open-mouthed facial expression, and seizures. *It can be caused by a deletion on chromosome 15 inherited from the mother.

onocogenes

cancer causing genes

Chromatin helps in determining the

development potential of a cell lineage and undergoes major changes during organismal development

Protamines

enable sperm DNA to wind into a more compact state.

Cytosine DNA methylation

epigenetic mechanism, occurs through the attachment of a methyl group (CH3) to a cytosine.

Fascioscapulohumeral muscular dystrophy (FSHMD) is a

genetic-epigenetic disease that occurs through loss of normal methylation.

About one third of the Russell-Silver syndrome cases are caused by the

imprinting abnormalities of chromosome 11p15.5 that lead to down regulation.

Beckwith-Wiedemann syndrome is a well-known example of

imprinting that is identified at birth. A glucose level of 60 mg/dL indicates hypoglycemia.

Early embryogenesis

is characterized by rapid fluctuation in genome-wide DNA methylation densities.

Why is epigenetic modification important?

it helps with differentiation of embryonic stem cells, and the inactivation of one of the X chromosomes in females.

Russell-Silver syndrome is characterized by

leg length discrepancy and a small, triangular face.

biallelic expression

meaning that both the maternally and the paternally inherited copies contribute to offspring phenotype.

Oncomirs

miRNAs that stimulate cancer development and progression

Somatic mosaicism

mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs

Congenital heart disease is associated with

mutations in genes that encode histone-modifying proteins

A newborn with Beckwith-Wiedemann syndrome has

neonatal hypoglycemia, a large tongue, creases on the ear lobe, and an omphalocele, which is birth defect of the infant's intestines

Anhidrotic ectodermal dysplasia is a condition seen in females who have

one X chromosome bearing a normal allele and one X chromosome bearing a mutant allele at the X-encoded locus.

Aberrant DNA methylation

patterns and aberrant histone modifications are found in human cancer cells

Histones are

proteins, which facilitate compaction of genomic DNA into the nucleus of a cell.

Fragile X syndrome involves a

reduced IQ and a set of behavioral abnormalities.

DNA methylation states are a common feature of...?

several human cancers, including those of the colon and breast.

The symptom of FSHMD include adverse impacts on

skeletal musculature such as the eyes, mouth, face, shoulders, lower legs, and upper arms. When the patient's skeletal musculature gets affected, he or she has difficulty whistling, closing the eyes, pronouncing certain words, and has an unusual smile.

TET enzymes

ten-eleven translocation *These proteins may promote DNA demethylation by binding to CpG rich regions to prevent unwanted DNA methyltransferase activity,

implantation in the uterus

the DNA methyltransferases become active again, permitting establishment of the cell lineage-specific marks required for the establishment of organ systems.

Totipotency

the ability of a cell, particularly a zygote, to differentiate into any of a number of specialized cells and thus form a new organism or regenerate a body part

Fertilization

the action or process of fertilizing an egg, involving the fusion of male and female gametes to form a zygote. *triggers a global loss of DNA methylation at most loci in both sex cells, accomplished in part by suppression of the DNA methyltransferases

Down regulation of insulin like growth factor 2 (IGF2) is responsible for

the diminished growth of children seen in Russell-Silver syndrome.

Housekeeping genes are essential for

the functioning and maintenance of all cells.

Epigenetics

the study of influences on gene expression that occur without a DNA change *how a given set of genomic information is expressed. *Epigenetics is currently a focus of preventative efforts and pharmaceutical interventions.

Ribosomal RNA (rRNA)

type of RNA that makes up the major part of ribosomes

Inheritance of two copies of chromosomes from the father and no copy from the mother is known as

uniparental disomy, which may cause Beckwith-Wiedemann syndrome.