Genetic Diseases

lecture 6

How many pairs of autosomes are there in humans?

22 pairs

How many pairs of sex chromosomes do humans have (X or Y)?

1

What percent of genome are protein-coding genes?

1.5%

What percent of the genome is transcribed into RNA?

85%

What percent of the genome is devoted to the regulation of gene expression?

80%

What percent of the genome is devoted to the regulation of gene expression?

80%

What is the function of promoters and enhancers?

bind transcription factors

What are promoters and enhancers binding sites for?

DNA-binding proteins that organize and maintain chromatin structure

What are non-coding regulatory RNAs?

genes that are transcribed but not translated

What are microRNAs and long non-coding RNAs examples of?

non-coding regulatory RNAs

What are transposons?

mobile genetic elements

What are telomeres and centromeres?

structural regions of DNA

What are covalent modifications of DNA, post-translational modifications of histones, and 3D chromatin structure?

epigenetic mechanisms

What are SNPs?

single nucleotide positions

Where are SNPs found?

in coding and non-coding regions

What may non-coding SNPs alter?

the regulation of gene expression

What may coding SNPs alter?

sequence of a protein

Do “neutral” SNPs have an effect on gene function or phenotype?

no

Is the effect of individual SNPs on disease susceptibility strong or weak, particularly for complex diseases such as diabetes, heart disease, or cancer?

weak

What are CNVs?

copy number variations

About what percent of CNVs involve coding sequences?

50%

What are duplications, triplications, deletions, and inversions examples of?

copy number variations (CNVs)

What are point mutations?

substitution of a single nucleotide base by a different base

What is a missense point mutation?

changes an amino acid

What is a nonsense point mutation?

creates a stop coding

What are CRISPRs?

clustered regularly interspaced short palindromic repeats

What is CRISPR a form of?

bacterial “immunity”

How does CRISPR gene edit?

uses artificial guide RNAs that target a DNA sequence of interest to introduce mutations

What was the first CRISPR/Cas9-based therapy approved to treat?

sickle cell disease (Casgevy)

What are frameshift mutations?

insertion or deletion of 1-2 base pair alters the reading frame of the DNA strand

What is a wild type protein-coding gene?

mRNA sequence without any mutation

What is a base-pair deletion protein-coding gene?

frameshift causing extensive missense

What is a base-pair insertion protein-coding gene?

frameshift causing immediate nonsense

What is a trinucleotide repeat mutation?

amplification of repeated sequence of 3 bases

What is repeat expansion/amplification?

number of repeats increasing during gametogenesis

What does it mean for a variation to be intra-chromosonal?

within the same chromosome

What does it mean for a variation to be inter-chromosomal?

segments are moved or exchanged between different chromosomes

What are mutations?

changes in DNA sequence

What are epimutations?

changes in epigenetic mechanisms that change gene expression

Through what mechanism does inactivation of tumor suppressor genes occur?

promoter hypermethylation

Through what mechanism does activation of oncogenes occur?

promoter demethylation

What are Mendelian disorders resulting from?

mutations in single genes

What are cytogenetic disease resulting from?

changes in chromosomal number or structure

What are non-mendelian genetic diseases resulting from?

single gene mutations with atypical patterns of expression

What describes an autosomal dominant disorder?

• one copy is sufficient to cause disease

• disease manifests in homozygous state

• does not skip a generation

• male and female are equally likely to be affected

• affected offspring have at least one affected parent

What describes an autosomal recessive disorder?

• two copies are needed to cause disease

• disease manifests in homozygous state

• typically skips a generation

• affected offspring may have unaffected parents

• male and female offspring are equally likely to be affected

What describes X-linked mendelian disorders?

• females can transfer only to sons

• daughter may be carrier

• affected males cannot transmit disorder to son

• typically skips a generation

• male offspring are more likely to be affected

What is a single gene mutation has many phenotypic effects?

pleiotropy

What is multiple genes causing the same trait?

genetic heterogenity

What is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation?

penetrance

What is an example of incomplete penetrance?

BRCA1

What is the degree to which a phenotype is expressed by individuals having a particular genotype?

expressivity

What are Huntington’s disease and Ehler-Danlos syndrome examples of?

autosomal dominant inheritance

What are cystic fibrosis and sickle cell diseases examples of?

autosomal recessive inheritance

What is Fragile X Syndrome an example?

X-linked recessive inheritance

What is the most common life-limiting disease in the US that affects individuals of European descent?

cystic fibrosis

What is the disorder of epithelial ion transport that affects fluid secretion in the lining of the respiratory, GI, and reproductive tracts?

cystic fibrosis

What is characteristic of cystic fibrosis?

• recurrent and chronic pulmonary infections

• pancreatic insufficiency

• male infertility

• high NaCl in sweat

What is the primary defect in CF?

reduced production or abnormal function of CFTR (cystic fibrosis transmembrane regulator), an epithelial chloride and bicarbonate channel protein

What are the five classes of mutations in CTFR?

protein production, protein processing, gating, conduction, and insufficient

What is the most common CF mutation with 90% having it?

F508del (protein processing mutation)

What treatment treats the underlying cause of disease (the defective CTFR) in a majority of the CF population?

Trikafta

What is Trikafta a combination of?

elexacaftor, ivacaftor, and tezacaftor

What is ivacaftor?

chloride channel opener

What is elexacaftor and tezacaftor?

CFTR modulators

What describes when there is an extra copy of chromosome 21?

trisomy 21

What is characteristic of trisomy 21?

• 40% have congenital heart disease

• 10-20 fold increased risk of acute leukemia

• predisposed to serious lung infection and thyroid autoimmunity

• nearly all trisomy 21 patients older than 40 have Alzheimer’s pathology

What is the translocation event between the BCR (chr22) and ABL (chr9) genes?

philadelphia

What involves CGG repeating in the FMR1 gene?

Fragile X Syndrome

What conditions are associated with Fragile X Syndrome?

tremor/ataxia syndrome, primary ovarian insufficiency

What Mendelian disorder primary affects males?

X-linked

What is genetic anticipation?

when clinical features worsen or begin earlier with each successive generation

What is a genetic variant that occurs in at least 1% of the population?

polymorphism