03 - Genes, genetic diseases and epigenetics

Genes

a specific sequence of nucleotides in DNA (or RNA), located on a chromosome. A gene is the functional unit of inheritance controlling the transmission and expression of traits by coding for a particular polypeptide

DNA and RNA are made up by sequences of

bases

DNA bases =

adenine (A),

thymine (T),

guanine (G)

cytosine (C)

RNA bases =

adenine (A),

cytosine (C),

uracil (U)

guanine (G)

Bases form specific pairs:

(A-T, G-C, A-U)

contain the information that codes for specific amino acids (20 different amino acids in the body

Nucleotide

DNA subunit, formed of one deoxyribose

molecule (sugar), one phosphate group, one base

codon

A group of 3 nucleotides is called a codon,

each codon codes for an

amino acid in a

corresponding protein

Polypeptide

chain of many amino acids

Protein

contains one or more polypeptides

Mutation

alteration of genetic information

Base pair substitution

wrong base replaces another

Frameshift mutation:

insertion or deletion of base-pairs of the DNA, thus

altering the amino acid sequence

Two different types of cells:

Gametes

Somatic cells

Gametes

sperm and egg cells)

23 chromosomes (haploid)

Somatic cells

cell that is not a gamete. Is diploid since it has 46

chromosomes arranged in 23 pairs

dna

the structure of dna is similar to a twisted ladder, with base pairs forming the rungs.

genes are composed of dna segments

coiled dna

the dna in each cell would be about 2m long if strecthed out. To fit inside the cell, the dna is tightly coiled

chromosome

one chromosome of every pair is from each parent

nucleus

each nucleus of a somatic cell contains 46 chromosomes arranged in 23 pairs

cells

a nuclesus resides in most human cells

Leading cause of intellectual disability and miscarriage

CHROMOSOMES’ ABNORMALITIES

59% of first-trimester spontaneous abortions have major

chromosome aberrations

chromosome abnormalities in live births

approximately 1 in 150 has a

major diagnosable chromosome

abnormality

Polyploidy

condition in which the diploid

cells have more than two complete sets of

chromosomes

Aneuploidy

presence of an abnormal

number of chromosomes in a cell

triploidity

DOWN SYNDROME

Best-known example of aneuploidy is the trisomy of chromosome 21

1 in 800 live births

risomy 21 means that cells have

3 copies of chromosome 21 instead of two

Chromosome 21 - why is it imp

Chromosome 21 contains 200 to 300 different

genes = many different roles in the body!

down syndrome features - Iq

It usually ranges from 20 to 70 (intellectual disability).

down syndrome features - male/female findings

Virtually all males are sterile; some females can reproduce.

down syndrome features - face

Distinctive features include low nasal bridge, epicanthal folds, protruding tongue, low-set ears.

down syndrome features - musculo-skeletal system

Features include poor muscle tone (hypotonia) and short stature.

down syndrome features - systematic disorders

Features include congenital heart disease (one third to half of cases), reduced ability to fight respiratory tract infections, and increased susceptibility to leukemia-

overall reduced survival rate; by age 40 years usually develop symptoms similar to those of Alzheimer's disease.

down syndrome features - mortality

About 75% of fetuses with Down syndrome abort spontaneously or are stillborn; 20% of infants die before age 10 years; those who live beyond 10 years have life

expectancy of about 60 years.

down syndrome features - causative factors

97% of cases are caused by nondisjunction during formation of one of parent's gametes or during early embryonic development; 3% result from translocations; in 95% of cases, nondisjunction occurs when mother's egg cell is formed; the remainder involve paternal nondisjunction; 1% are mosaics-these have a large number of normal cells, and effects of trisomic cells are attenuated and symptoms are generally less severe.

turner syndrome

1 in 2000 – 2500 females

is on a spectrum so severity of syndrome can vary

Females with part of 1 X chromosome missing, or only 1 X chromosome (not pairedwith another X)

Have 45 chromosomes instead of 46 in certain cells

only seen in females cuz theres 2 x

Some cells might be normal and contain 46

chromosomes

If part or all of the second sex

chrosomosome is lost in most of cells,

individual will develop symptoms of

turner syndrome

turner syndrome features -iq

Individuals with this syndrome are not considered to be intellectually disabled, although the syndrome is associated with some impairment of spatial and

mathematical reasoning ability.

turner syndrome features - male/female findings

It is found only in females.

turner syndrome features - musculo skeletal system

Short stature is common; other features are characteristic webbing of neck, widely spaced nipples, and reduced carrying angle at elbow

turner syndrome features - systemic disorders

Features include coarctation (narrowing) of aorta, edema of feet in newborns; females are usually sterile and have gonadal streaks rather than ovaries; streaks are sometimes susceptible to cancer.

turner syndrome features - mortality

About 15-20% of spontaneous abortions with chromosome abnormatities have this karyotype, most common single-chromosome aberration; highly lethal during gestation, only about 0,5% of these conceptions survive to term.

turner syndrome features - causative factors

75% of cases inherit X chromosome from mother, thus caused by meiotic error in father; frequency is low compared with other sex chromosome aneuploidies (2: 5

000 newborn females); 50% have simple monosomy of X chromosome; the remainder have more complex abnormalities; combinations of 45.X cells with XX or XY cells common.

TURNER SYNDROME - Functions of the X chromosome Fertility

• Genes for reproduction are enriched on the X chromosome

• BMP15 gene: involved in folliculogenesis (development of ovulatory

follicles)

TURNER SYNDROME - Skeletal malformations

• Loss of SHOX gene normally present on X chromosome

• SHOX gene plays role in growth and maturation of the skeleton

when you lose can chromosomes what do you look at

you look at the traits and characteristics they impact and you can understand symptoms you will develope

EPIGENETIC MECHANISMS

Biochemical changes that affect gene expression without altering the DNA sequence.

DNA methylation, Histone modifications, microRNA

DNA methylation

methyl group is added to the DNA, which usually silences the gene

Attachment of a methyl group to a cytosine

Histone modifications

alteration of

the structure of chromatin, reducing

or elevating gene expression

microRNA

aberrant miRNA

expression which alters gene

expression at the post-transcriptional level

causes of EPIGENETIC MECHANISMS

• Environmental factors (diet, exposure to certain chemicals)

• Nutritional deprivation

• Transgenerational inheritance of epigenetic modifications

Dense DNA methylation:

insulate the genes, blocks the transcription factors

• Methylated gene is transcriptionally silent

Aberrant DNA methylation:

• Presence of dense methylation where it’s normally absent

• Absence of methylation where it is typically present

• Abnormal methylation is common in cancer: leads to misregulation of tumor-supressor genes and oncogenes

Oncogene

• Can potentially cause cancer

• Mutation/high expression level of normal genes implicated in:

• Cell growth

• Cell proliferation

• Inhibition of apoptosis

her2 receptors

used to measure agressive brest cancer

alot = more agressive

Tumor-supressor genes:

• Can potentially cause cancer

• Abnormal expression leads to loss or reduction of functions, which leads to cells growing abnormally

Tumor-supressor genes categoreis

Caretaker genes

Gatekeeper genes

Landscaper genes

Caretaker genes

stability of genome via

DNA repair

Gatekeeper genes

regulate cell growth by

inhibiting cell cycle or promoting apoptosis

Landscaper genes

regulate cell growth by

their action on the surrounding

environment/stroma

normal vs muatted p53 gene

tumor supressor genes

low level p53 = more cancerous

chromatin

DNA + histones

Histones facilitate the

compaction of

DNA in the nucleus

2 forms of chromatin

Euchromatin

Heterochromatin

Euchromatin

open state where all

genes are transcriptionally active

Heterochromatin

closed state in

which most or all nearby genes are

inactive

Histone modification

addition or deletion of

an acetyl group at the end of the histone

protein

Modification of histones can up or

downregulate nearby gene expression by:

Modifying the tightness of the interaction

between DNA and histones, making DNA

more or less accessible to transcription

factors

Hyperacetylation

disrupts the association

between histone and DNA, leading to

increased accessibility of DNA and increase

gene expression

Hypoacetylation

DNA is more tightly wrapped

around histones, decrease gene expression

HDACs =

histone deacetylases. Enzyme

that removes acetyl groups on histones

HATs =

histone acetyltransferase. Enzyme

that adds acetyl group on histones

RB1 gene

prevents excessive growth, inhibits cell cycle progression

BRCA1 gene

DNA repair

METHYLATION AND CANCER