Patho - Genes

Explain DNA structure and function

DNA Structure:

• DNA has a double helix shape

• The DNA backbone is made of deoxyribose and phosphate groups

• The rungs of the ladder are made of 4 nitrogen bases: adenine, guanine, thymine, and cytosine

  • Base pairing: Adenine pairs with thymine, and cytosine pairs with guanine

• Weak hydrogen bonds hold the base pairs together

DNA Function:

• Information storage: DNA holds code for making proteins; provides the code for all body protein

• Replication: DNA makes copies of itself so cells can divide and pass traits to new cells

• Carries instructions that cells read and translate into proteins

Explain DNA and RNA interactions as it relates to Replication, Transcription, and Translation

Overarching mechanism: DNA replicates itself and its genetic info is then transcribed into RNA, which then translates the message into a protein that acts in the body

Replication:

• DNA strand will untwist/unzip by a specific enzyme and one of the single strands will serve as a template.

• DNA polymerase then pairs the matching complementary nucleotide base pairs (A-T and C-G)

• DNA polymerase adds new nucleotides and “proofs” the new DNA strand. If the strand is incorrect, then the incorrect nucleotide is removed and replaced

Transcription:

• RNA is synthesized from a DNA template

• RNA polymerase pulls DNA apart at promoter sites

• Results in the formation of messenger RNA (mRNA)

• Transcription occurs until a DNA sequence called the termination sequence is reached, and the newly transcribed mRNA travels to the cytoplasm

Translation:

• After transcription and gene splicing, translation occurs. Here, mRNA directs synthesis of a polypeptide via interaction with transfer RNA (tRNA)

• tRNA carry amino acids to site of protein synthesis - ribosomes

• tRNA translates language of nucleotides into language of amino acids and proteins

Explain chromosomal aberrations including nondisjunction and different types of mutations

Explain elements of formal genetics including domiance, co-dominance, heterozygosity, homozygosity, and recessiveness

Explain karyotypes, genotypes, and phenotypes

Explain common risk factors, gene pedigrees, causes, and clinical presentations for common genetic disorders, including Cri du chat syndrome, cycstic fibrosis, Down syndrome (Trisomy 21), Duchenne muscular dystrophy, and Huntington Disease

Explain differences between single gene disorders (autosomal recessive, autosomal dominant, and sex linked)

Explain concept of penetrance and expressivity and give examples of each

Explain genetic and environmental impact of common diseases having multifactorial traits

The human body has what 2 cell types when it comes to chromosomes?

Somatic cells (body cells) and gametes (sex cells)

What are somatic cells?

All non-reproductive cell types (body cells)

How many chromosomes do somatic cells have?

46 chromosomes (23 pairs or 2 sets of chromosomes, one pair from each parent)

Are somatic cells diploid or haploid?

Diploid

How do somatic cells divide?

Mitosis (diploid cells make identical cells with 46 chromosomes; diploid → diploid)

What are gametes?

Sperm and egg cells only (sex cells; reproductive related cells)

How many chromosomes do gametes have?

23 chromosomes

Are gametes diploid or haploid?

Haploid (they contain one set of chromosomes)

How do gametes divide?

Meiosis (diploid → haploid; diploid cell with 46 chromosomes reduces chromosome count by 1/2 , making haploid cell with 23 chromosomes)

What are autosomes?

Chromosomes 1-22 ; chromosomes that are homologous (The two members of an autosome pair that are structurally identical and are thus said to be homologous)

What are sex chromsomes?

Chromosomes pair #23 (In females, it is a homologous pair - XX. In males, it is a non-homologous pair - XY)

Why is it critical to understand autosomal vs sex-linked diseases?

Critical in understanding where genetic mutations are located, especially in inheritance patterns of diseases

What are the 4 categories of DNA related changes?

• Chromosome issues (macro scale; large scale chromosome changes)

• DNA/Gene issues (small scale changes at level of base pairs or gene coding)

• Mitochondrial DNA issues (DNA that exists only on mitochondria that can change)

• Epigenetic issues (changes in how DNA works rather than changes in its structure)

Macro chromosomal aberations/changes occur in what two types?

Numeric and structural

What are numeric chromosomal aberations?

Chromosomal changes that result in too many/few chromosomes in a cell

• Examples include aneuploidy and polyploidy

What are structural chromosomal aberrations?

These are more commonly called mutations and can happen at organism formation when parent chromosomes combine

• Examples include germline mutations and somatic mutations

What is aneuploidy?

An umbrella term for when someone has an abnormal number of chromosomes (ex: trisomy and monosomy)

What is trisomy?

A cell containing 3 copies of a single chromosome

• Can affect autosomes or sex chromosomes

• Individuals with trisomy 13, 18, or 21 can survive; most others do not

• amount of duplicated material is important in trisomy

  • when smaller ones are duplicated, prognosis is better

What is monosomy?

A cell containing 1 copy of any chromosome

• Can affect autosomes or sex chromosomes

• Typically lethal unless in sex chromosome pair

What are some examples of monosomy aberrations?

Turner syndrome (single X chromosome) and Cri du chat (“cry of the cat”)

What is an example of a non-lethal monosomy in humans?

Cri du chat - this is a partial monosomy caused by deletion on short arm of chromosome 5. It is characterized by severe cognitive impairment

What partial monosomy is a deletion that occurs on the short arm of chromosome 1?

1P36

What are some mechanisms of aneuploidy?

Disjunction and nondisjunction

What is disjunction?

Normal separation of chromosomes during cell division

What is nondisjunction?

Failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis. It is usually the cause of aneuploidy

What are some other forms of aneuploidy that aren’t trisomy and monosomy?

Partial trisomy and chromosomal mosaics

What is partial trisomy?

When only an extra portion of a chromosomes is present in each cell — an individual has an extra copy of only a specific segment of a chromosome instead of an entire extra chromosome

• Not as severe trisomies

What are chromosomal mosaics?

Trisomies that occur in only some cells of the body. The body has two or more different cell lines, each of which has a different karyotype — occurs when a person has two or more genetically different sets of cells in his or her body

Are abnormalities of chromosome structure macro or micro issues?

Macro

True or false: Effects of abnormalities of chromosome structure may or may not have serious consequences depending on severity

True

When chromosome breaks occur, the break is usually repaired with no damage. What can be used to repair it?

DNA polymerase

With chromosomal breakage, breaks can persist or heal in a way that alters the structure of the chromosome. What does this in turn alter?

In turn alters protein that should be produced

Mutations fall under the structural category chromosomal issues. Germline mutations and somatic mutations are common. What are germline mutations?

Congenital anomalies that are present in original embryo cells

What are somatic mutations?

Age/environment-related changes. Mutations that occur during lifetime of individual and that occur as a result of living, age, etc.

What are some examples of abnormalities of chromosome structure?

Deletions, Duplications, Inversion, and Reciprocal Translocation

What are deletions?

Chromosome breakage or loss of DNA not repaired by DNA polymerase

What is an example of a deletion syndrome?

22q11.2 deletion syndrome (DiGeorge/Velocardiofacial syndrome - microdeletion in embryonic period resulting in heart defects, immune system problems, cleft palate)

What are duplications?

Excess genetic material. These usually have less serious consequences

What is an inversion?

Chromosomal rearrangement in which a chromosome segment is inverted. ABCDEFG becomes ABEDCFG.

• All genetic data is retained but not in original origin. Person produces games and donations are rearranged. Offspring may not receive full complement of chromosome

• Usually affects offspring but usually doesn’t affect carrier

Inversion chromosomal structural abnormalities usually affect offspring or the carrier?

Offspring

What is a reciprocal translocation?

When breaks take place in two different chromosomes and the material is exchanged

• 5% of down syndrome cases caused by reciprocal translocation rather than nondisjunction

What are some micro scale DNA/gene issues?

Single-Gene/Monogenic/Medelian Disorders and Multifactorial/Polygenic/Complex Disorders

What are Single-Gene/Monogenic/Mendelian Disorders?

Specific DNA error affecting only 1 gene - these form predictable patterns of inheritance; often clinical targets for genetic counseling or cancer testing for genetic disorders

What are some examples of Single-Gene/Monogenic/Mendelian Disorders?

• Cystic Fibrosis

• PKU

• Sickle Cell Disease

• Tay-Sachs Disease

What are Multifactorial/Polygenic/Complex disorders?

Health conditions caused by a combination of multiple genetic variations and external lifestyle or environmental factors, rather than a mutation in a single gene

What are some types of Multifactorial/Polygenic/Complex disorders?

Gene-Environment Interactions and Multi-gene Disorders

What do gene-environment interactions result from?

Result from various two-hit hypotheses where a person has susceptible genetic variation that’s altered by an interaction with something in the environment \

• notable in common cancers, asthma, cleft lip/palate

What are some conditions that multi-gene disorders result in?

Heart disease, Alzheimer’s, Rheumatoid arthritis

Small scale changes are usually referred to as what?

MutationsW

What are mutations?

Any alteration of genetic material

• Chromosome aberrations (breakage, etc.)

What is a base pair substitution?

A genetic mutation where one base pair (one nucleotide pair) is substituted for another

What is a silent substitution?

A base pair substitution that may not alter the function of the affected gene

• Substitution that does not result in an amino acid change

• These are possible because multiple codon sequences can code for the same amino acid

What is a frameshift mutation?

Involves the insertion or deletion of one or more base pairs to the DNA molecule and alters the first stop codon encountered in a sequence. The resulting polypeptide could be abnormally short/long and most likely not functional

What are mitochondrial (mtDNA) inheritance issues?

Genetic disorders caused by damage to mitochondrial DNA

Mitochondrial inheritance issues are transmitted maternally or paternally?

Maternally

What is the transmission rate for Mitochondrial Inheritance Issues?

100%

Mitochondrial Inheritance Issues impact what kind of organs?

High-energy organs like the brain, nerves and muscles

What is an example of a mitochondrial inheritance disease?

Myoclonic Epilepsy with Ragged-Red Fibers (MERRF) - a rare multi-system genetic disorder that affects the nervous system and muscles

What are Epigenetic issues?

Conditions caused by changes in how genes are expressed, rather than changes in DNA sequencing

• Relates to functional rather than structural changes

• Affect how genes are expressed, they don’t change DNA sequence

What are the three known types of epigenetic modification?

1. DNA methylation

2. Histone modification

3. Non-coding RNA/silencing (least common)

What happens in the epigenetic modification DNA methylation?

Methyl group attaches to DNA structure and silences gene in that area

What happens in the epigenetic modification histone modification?

Cause DNA segments to be too tight or too loose that either silences or over-activates gene activity

What are some examples of epigenetic conditions?

Angelman syndrome and Prader-Wili Syndrome (also examples of genetic/genomic imprinting - means parent of origin of silenced chromosome matters)

If genetic mom’s chromosome is silenced, this leads to?

Angelman syndrome

If genetic dad’s chromosome is silenced, this leads to?

Prader-willi syndrome

What is Angelman syndrome?

Neurodevelopmental disorder caused by loss of maternal gene expression on chromosome 15

What is Prader-willi syndrome?

Neurodevelopmental disorder caused by loss of paternal gene expression on chromosome 15

What is a point mutation?

A genetic change where a single nucleotide base in a DNA or RNA sequence is changed, added, or deleted

• Generally fall into three main categories: basepair substitutions (one base is swapped for another), insertions (extra base pair is added), or deletions (a base pair is removed)

A basepair substitution is an example of what kind of mutation?

Point mutation

Sickle cell disease is an example of what kind of mutation?

A basepair substitution, which is a type of point mutation

Describe the mechanism behind the development of sickle cell disease.

In people with sickle cell, a single amino acid, glutamic acid, replaces valene in the amino acid beta chain

• This single amino acid substitution changes the shape of the hemoglobin molecule, causing it to form rigid/stiff fibers when releasing oxygen

• This rigidity shapes red blood cells into a sickle shape, reducing oxygen carrying capacity

Humans inherit one hemoglobin gene from mom and one from dad. If both inherited genese are the hg s allele, what happens?

Person would have sickle cell disease

If a person inherits one hg s allele and one hg a allele, what happens?

Person would have smaller portion of hg (hemoglobin) that’s type s, and would be considered to have sickle cell trait rather than the full blown disease

Sickle cell is an ______ ______ condition

autosomal recessive

What is an example of an autosomal aneuploidy?

Down syndrome - trisomy of chromosome 21 (denoted as karyotype 47, +21)

• Manifestations: cognitive challenges, low nasal bridge, epicanthal folds, protruding tongue, flat and low set ears. Increased risk of congenital heart disease, respiratory infections, and leukemia

What is the most common cause of down syndrome?

Maternal nondisjunction (risk of down syndrome increases with maternal age)

What is an example of of a sex chromosome aneuploidy?

Trisomy X (denoted as karyotype 47, XXX)

What is Trisomy X?

Describes females with 3 or more X chromosomes

• Symptoms are variable and include sterility, menstrual irregularity, and/or cognitive deficits

• Symptoms worsen with each additional X chromosome

What are some examples of sex chromosome aneuploidies other than Trisomy X?

Turner syndrome and Klinefelter syndrome

Which of the following is a sex chromosome aneuploidy that is a monosomy?

Turner syndrome

What is Turner Syndrome?

A sex chromosome monosomy where individuals have only one X chromosome (denoted as karyotype 45, X)

What typically causes Turner Syndrome?

Typically caused when sperm doesn’t contain expected X chromosome

What are some characteristics of Turner Syndrome

• Absence of ovaries

• short stature

• webbing of the neck

• widely spaced nipples

• high number of aborted fetuses

• X chromosome that is usually inherited from the mother

• Have phenotypical female body shape and insufficient estrogen

What do teenagers with Turner Syndrome typically receive to promote development of sex characteristics and prevent osteoporosis?

Estrogen

What is Klinefelter Syndrome?

A sex chromosome aneuploidy where individuals have at least one Y chromosome and at least two X chromosomes (karyotype denoted by 47, XXY)

What is the most common sex chromosomal disorder in males?

Klinefelter syndrome

What are some characteristics of Klinefelter Syndrome?

• Male appearance

• Female-like breasts

• Small testes

• Sparse body hair

• Some individuals can be XXXY and XXXXY; will have male appearance; abnormalities will increase with each X; can also have an extra Y chromosome, but need at LEAST one Y and two Xs

• Risk increases with mother’s age

True or False: point mutations and frameshift mutations are small-scale (molecular mutations rather than structural (chromosomal) mutations

True

What is chromatin?

Material that makes up the actual chromosome; consists of Both DNA and proteins

What is the major protein in chromatin?

Histones