Mendelian genetics and genetic variation Flashcards
Review classes of mutations, including missense, nonsense and frameshift
Most likely outcome of a mutation is full or partial loss of function
- Frameshift=>premature stop codons causing truncation of normal translation
- Splice site mutation=>disrupt normal recognition & joining of exons by the activation of cryptic splice or exon skipping
Define single nucleotide polymorphism (SNP)(6)
- nucleotide substitution with 2 possible alleles (most often)
- millions of SNPs (mostly noncoding) have been identified (more than CNV)
- ubiquitous throughout the genome
- generally assumed to be NEUTRAL POLYMORPHISM but some SNPs may affect gene expression and/or protein function
- framework of the human genetic map
- most abundant throughout the genome (avg variable base every 100-300 basepairs)
Define copy number variation (CNV) (4)
- Segmental duplications: dispersed 1-1000 kb
- 67,000 CNVs identified
>10% of genome may be subject to CNV
- consist of micro- & submicroscopic variants from deletions & duplications (insertions, inversions, translocations)
- Effects very large segments of DNA ~1kb to > 1Mb
-preferentially outside genes but may include genes, may lie within genes, may affect gene expression
- IF IN GENE, THEN WILL ALTER GENE COPY NUMBER
- naturally occurring throughout the human genome and may be pathogenic or benign
What is the largest difference of SNP to CNV?
- CNVs are less numerous than SNPs, but each variant of CNVs alters a very large sequence
Distinguish the scale, large vs small, of genetic variants
CNVs are large scale genetic variants
-If large scale genetic variants occur within the gene then the gene number can be altered
Distinguish the prevalence, common vs rare, of genetic variants
-SNPs and CNVs are very common
Distinguish the disease state, pathogenic vs nonpathogenic, of genetic variants
-CNV can be pathogenic or nonpathogenic
T/F sequence variation is the same as words as mutation, normal variation, polymorphism
True
In sequence variation, what effect does a mutation cause on the phenotype?
-differences in DNA sequence that may cause or predispose to disease which typically alters the protein significantly
In sequence variation, what effect does a normal variation have on the phenotype?
-differences in DNA sequence that account for variation within the normal range which typically encodes minor (common) alterations in protein
In sequence variation, what effect does polymorphism have on the phenotype?
- neutral differences in DNA sequence and abundant throughout the genome
- often genetic markers
- the sequence differences are between polymorphisms vs copy number polymorphisms
Describe the coding sequence of the DNA
-Exons of a gene that directly contribute to the protein product of the gene
Describe the non-coding sequence of the DNA
nucleic acid sequences that do not encode protein that could be any of the following: introns, intragenic regions (everything but exons)
What determines the number of possible genotypes?
-number of alleles
If you have 2 possible alleles (A & a) at a locus, then how many possible genotypes are possible and what are they?
- 3
- A,A; A,a; a,a
If you have 3 possible alleles, (1,2,3) at a locus, then how many possible genotypes and what are they?
-6
1,1; 2,2; 3,3; 1,2; 1,3; 2,3
Regardless of how many different alleles there are, what will determine the observed genotypes?
-individual frequencies
T/F Allele frequency, or gene frequency, is the proportion of an allele at a locus
True
For 2 possible alleles, A & a, if A=0.8, then what is a?
-a=0.2 (must add up to 1.0)
T/F The spectrum of common genetic variation includes single nucleotide polymorphism, insertion and deletion polymorphism, nucleotide repeat polymorphism, and copy number variation, ALL of which may affect coding or non-coding regions of DNA
True
What common genetic variations account for most of the genetic variation in humans?
SNP(single nucleotide polymorphism) and CNV(copy number variation)
Define polymorphism
Neutral differences observed in gene frequency among individuals. Sequence polymorphism consists of a single nucleotide and are very abundant throughout the genome.
Can be Benine or malignant.
Describe the result of the following placement of the SNPs in the genome
in coding sequence
in promoter region
intergenic region
- in coding sequence (exons) => missense mutations
- in promoter regions => expression variation
intergenic regions => polymorphic genetic markers
If you have linked SNPs that are outside the genes, what is the effect?
-no effect on protein production or function
If you have causative SNPs within the gene, what is the result if it is within the non-coding but regulatory region of the gene? coding region?
non-coding => changes amount of protein produced
coding=> changes amino acid sequence
T/F Large-scale copy-number variants are not distributed throughout the genomes of healthy individuals
-False, they are distributed throughout the healthy individuals
T/F Duplicated segments may be dispersed or clustered in the genome
True
What are 3 causative factors along with the clinical significance of CNVs?
- cytochrome P450 genes and drugs response
- 22q deletion syndrome (DiGeorge syndrome)
- Hereditary neuropathies involving PMP22
What are 5 susceptibilities along with the clinical significance of CNVs?
-schizophrenia
Crohn’s disease
Rheumatoid arthritis
type I diabetes
type II diabetes
T/F CNVs are implicated in 10-20% of autism spectrum disorders
True
T/F At the gene level, genetic variation is uniform
-false, genetic variation is diverse
Describe the PMP22 gene as a protein and component of the PNS and effects of the defects in it
- integral membrane protein
- component of myelin in PNS
- defects cause hereditary neuropathies
T/F Each individual genome differs form reference sequence by ~3.5 million CNVs and 1000 large SNPs (>500bp)
-False, 3.5 million SNPs and 1000 large CNVs
T/F A normal, healthy individual is heterozygous for 40-100 disease-associated mutations
True
Is the splice site mutation a change in coding sequence? Explain
-no, change in noncoding sequence that may or may not change the coding capacity of the protein
What are the types of mutations that change the coding sequence indirectly?
-promoter mutation and splice site mutation
In the case of the cytochrome P450 gene with its effect on CYP2D6 and drug metabolism, which person would be more at risk for a toxicity to a standard dose of a drug reacting to CYP2D6, a person with 0 functional CYP2D6 genes, 2 functional CYP2D6 genes, or 13 functional CYP2D6 genes?
-0 functional (greatest risk due to inability to clear the drug) > 2 functional > 13 functional
What percentage of patients have a CNV that causes a disability or anomaly?
-10% diagnostic yield of CNVs
T/F If you have the genotype to have the disease, then the phenotype must show it.
False, if you have the phenotype then you will have the genotype of the trait
What is PMP 22 responsable for?
Myelanation in the peripheral nervous system
What will a defect in PMP 22 cause?
Hereditary neuropathy
How will a sequence number variation in the PMP22 coding region effect expression of the gene
Copy number variants can be benine or pathogenic. A copy number variant in the PMP22 gene are very pathogenic.
What will three to four copies of PMP22 cause? (Clinical Example)
Charcot-Marie type 1A
What will only one genomic copy of PMP22 cause?
(Clinical example)
Hereditary neuropathy
