Mendelian genetics and genetic variation

Question 1

Review classes of mutations, including missense, nonsense and frameshift

Answer 1

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

Question 2

Define single nucleotide polymorphism (SNP)(6)

Answer 2

• 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)

Question 3

Define copy number variation (CNV) (4)

Answer 3

• 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

Question 4

What is the largest difference of SNP to CNV?

Answer 4

• CNVs are less numerous than SNPs, but each variant of CNVs alters a very large sequence

Question 5

Distinguish the scale, large vs small, of genetic variants

Answer 5

CNVs are large scale genetic variants
-If large scale genetic variants occur within the gene then the gene number can be altered

Question 6

Distinguish the prevalence, common vs rare, of genetic variants

Answer 6

-SNPs and CNVs are very common

Question 7

Distinguish the disease state, pathogenic vs nonpathogenic, of genetic variants

Answer 7

-CNV can be pathogenic or nonpathogenic

Question 8

T/F sequence variation is the same as words as mutation, normal variation, polymorphism

Answer 8

True

Question 9

In sequence variation, what effect does a mutation cause on the phenotype?

Answer 9

-differences in DNA sequence that may cause or predispose to disease which typically alters the protein significantly

Question 10

In sequence variation, what effect does a normal variation have on the phenotype?

Answer 10

-differences in DNA sequence that account for variation within the normal range which typically encodes minor (common) alterations in protein

Question 11

In sequence variation, what effect does polymorphism have on the phenotype?

Answer 11

• neutral differences in DNA sequence and abundant throughout the genome
• often genetic markers
• the sequence differences are between polymorphisms vs copy number polymorphisms

Question 12

Describe the coding sequence of the DNA

Answer 12

-Exons of a gene that directly contribute to the protein product of the gene

Question 13

Describe the non-coding sequence of the DNA

Answer 13

nucleic acid sequences that do not encode protein that could be any of the following: introns, intragenic regions (everything but exons)

Question 14

What determines the number of possible genotypes?

Answer 14

-number of alleles

Question 15

If you have 2 possible alleles (A & a) at a locus, then how many possible genotypes are possible and what are they?

Answer 15

• 3
• A,A; A,a; a,a

Question 16

If you have 3 possible alleles, (1,2,3) at a locus, then how many possible genotypes and what are they?

Answer 16

-6

1,1; 2,2; 3,3; 1,2; 1,3; 2,3

Question 17

Regardless of how many different alleles there are, what will determine the observed genotypes?

Answer 17

-individual frequencies

Question 18

T/F Allele frequency, or gene frequency, is the proportion of an allele at a locus

Answer 18

True

Question 19

For 2 possible alleles, A & a, if A=0.8, then what is a?

Answer 19

-a=0.2 (must add up to 1.0)

Question 20

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

Answer 20

True

Question 21

What common genetic variations account for most of the genetic variation in humans?

Answer 21

SNP(single nucleotide polymorphism) and CNV(copy number variation)

Question 22

Define polymorphism

Answer 22

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.

Question 23

Describe the result of the following placement of the SNPs in the genome

in coding sequence

in promoter region

intergenic region

Answer 23

• in coding sequence (exons) => missense mutations
• in promoter regions => expression variation

intergenic regions => polymorphic genetic markers

Question 24

If you have linked SNPs that are outside the genes, what is the effect?

Answer 24

-no effect on protein production or function

Question 25

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?

Answer 25

non-coding => changes amount of protein produced
coding=> changes amino acid sequence

Question 26

T/F Large-scale copy-number variants are not distributed throughout the genomes of healthy individuals

Answer 26

-False, they are distributed throughout the healthy individuals

Question 27

T/F Duplicated segments may be dispersed or clustered in the genome

Answer 27

True

Question 28

What are 3 causative factors along with the clinical significance of CNVs?

Answer 28

• cytochrome P450 genes and drugs response
• 22q deletion syndrome (DiGeorge syndrome)
• Hereditary neuropathies involving PMP22

Question 29

What are 5 susceptibilities along with the clinical significance of CNVs?

Answer 29

-schizophrenia
Crohn’s disease
Rheumatoid arthritis
type I diabetes
type II diabetes

Question 30

T/F CNVs are implicated in 10-20% of autism spectrum disorders

Answer 30

True

Question 31

T/F At the gene level, genetic variation is uniform

Answer 31

-false, genetic variation is diverse

Question 32

Describe the PMP22 gene as a protein and component of the PNS and effects of the defects in it

Answer 32

• integral membrane protein
• component of myelin in PNS
• defects cause hereditary neuropathies

Question 33

T/F Each individual genome differs form reference sequence by ~3.5 million CNVs and 1000 large SNPs (>500bp)

Answer 33

-False, 3.5 million SNPs and 1000 large CNVs

Question 34

T/F A normal, healthy individual is heterozygous for 40-100 disease-associated mutations

Answer 34

True

Question 35

Is the splice site mutation a change in coding sequence? Explain

Answer 35

-no, change in noncoding sequence that may or may not change the coding capacity of the protein

Question 36

What are the types of mutations that change the coding sequence indirectly?

Answer 36

-promoter mutation and splice site mutation

Question 37

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?

Answer 37

-0 functional (greatest risk due to inability to clear the drug) > 2 functional > 13 functional

Question 38

What percentage of patients have a CNV that causes a disability or anomaly?

Answer 38

-10% diagnostic yield of CNVs

Question 39

T/F If you have the genotype to have the disease, then the phenotype must show it.

Answer 39

False, if you have the phenotype then you will have the genotype of the trait

Question 40

What is PMP 22 responsable for?

Answer 40

Myelanation in the peripheral nervous system

Question 41

What will a defect in PMP 22 cause?

Answer 41

Hereditary neuropathy

Question 42

How will a sequence number variation in the PMP22 coding region effect expression of the gene

Answer 42

Copy number variants can be benine or pathogenic. A copy number variant in the PMP22 gene are very pathogenic.

Question 43

What will three to four copies of PMP22 cause? (Clinical Example)

Answer 43

Charcot-Marie type 1A

Question 44

What will only one genomic copy of PMP22 cause?

(Clinical example)

Answer 44

Hereditary neuropathy