Basic Genetics & Mutational Mechanisms

Question 1

Mendel’s First Law

Answer 1

The Law of Segregation: During meiosis, each allele of a single gene separates into different gametes

Question 2

Mendel’s Second Law

Answer 2

The Law of Independent Assortment: At meiosis, the segregation of each pair of alleles is independent

Exception: genes linked on the same chromosome

Question 3

Co-dominant traits

Answer 3

Both traits (alleles) are expressed in the heterozygous state

Question 4

Semi-dominant or Incompletely Dominant

Answer 4

Heterozygous phenotype is intermediate between the two homozygous phenotypes

Question 5

4 main categories of Mendelian Inheritance

Answer 5

Autosomal Dominant
Autosomal Recessive
Sex-Linked Dominant
Sex-Linked Recessive

Question 6

Metabolic Disorders are frequently (pattern of inheritance)…

Answer 6

Autosomal Recessive; typically due to loss of function of an important enzyme

Question 7

Penetrance

Answer 7

The fraction of individuals with a trait (genotype) who show manifestations of the disease

100% penetrance: all persons carrying a mutation demonstrate the trait

Question 8

Expressivity

Answer 8

The degree to which a trait is expressed in an individual; a measure of severity

Question 9

Pleiotropy

Answer 9

Multiple phenotypic effects (a syndrome) due to mutation in a single gene

Question 10

Polymorphism

Answer 10

A locus for which at least two relatively common alleles exist within a population

Question 11

Crossing over/meiotic recombination

Answer 11

Exchange of homologous segments of DNA between non-sister chromatids of a pair of homologous chromosomes; during Meiosis I

Question 12

Acrocentric chromsomes

Answer 12

13, 14, 15, 21, 22; centromeres are located near the end of the chromosome; contain distinctive masses of chromatin (satellites) attached to their short arms by narrow stalks (secondary constrictions); stalks contain repetitive DNA sequences that code for rRNA

Question 13

Metacentric chromosomes

Answer 13

The centromere is located in the middle of the chromosome

Question 14

Submetacentric

Answer 14

The centromere is slightly removed from the center of the chromosome

Question 15

Most common mechanism of imprinting

Answer 15

Allele-specific methylation of CpG dinucleotides in the promoter regions of imprinted genes, established and maintained in one of the two germ lines

Question 16

Imprinting Centers

Answer 16

Non-coding DNA sequences that recruit DNA methyltransferase complexes that methylate CpG islands located near the IC on the same chromosome; this is where erasure & resetting of imprinting occurs

Question 17

Chromosomal Microarray (CMA)

Answer 17

Flourescently labeled sample DNA and control DNA are mixed and hybridized to an array; visualization of the array gives information about the spots/color intensities for each probe

Advantages: allows investigation of the whole genome simultaneously and frequently reveals duplications or deletions that cannot be seen by standard cyteogenic techniques

Limitations: detects gains and losses ONLY (cannot detect balanced rearrangements); cannot detect specific mutations or SNPs

Question 18

Heritability

Answer 18

The proportion of total variance in a trait that is due to variation in genes

Question 19

Haplotype

Answer 19

A combination of alleles at different loci on a chromosome that are often inherited together and contribute to a trait or disease status

Question 20

Ex. of incomplete penetrance

Answer 20

Type I Diabetes; 20% of the population carries one of two highest risk haplotypes, but incidence in the general population is only 0.4%

Question 21

Allelic Heterogeneity

Answer 21

Two kinds:

1. Different alleles in the same gene resulting in the same trait
2. Different alleles in the same gene resulting in different traits

Ex: Many mutations in the CFTR gene (alleles) lead to CF; different ‘classes’ of alleles lead to different presentation of disease

Question 22

Locus Heterogeneity

Answer 22

Variants in different genes result in similar clinical presentation

Ex: Early onset Alzheimer’s results from mutations in three separate genes on three different chromosome, which are all involved in the same physiological pathway

Question 23

Phenocopy

Answer 23

An environmentally caused phenotype that mimics the genetic version of the trait

Ex: Thalidomide-induced limb malformation vs. genetically induced

Question 24

Characteristics of Complex Traits

Answer 24

Incomplete Penetrance
Variable Expressivity
Heterogeneity - allele & locus
Presence of phenocopies

Question 25

Lambda S (relative risk)

Answer 25

Risk of disease in siblings of affected / risk of disease in general population

Question 26

Odds Ratio (OR)

Answer 26

Risk of disease given a particular gene variant / Risk of disease not given a particular gene variant

Question 27

Compound heterozygote

Answer 27

An individual who carries two different mutant alleles of the same gene

Ex: HbS/HbC

Question 28

4 mutational mechanisms

Answer 28

Loss of function of the protein
Gain of function of the protein
Acquisition of a novel property by the protein
Perturbed expression of a gene at the wrong time (heterochronic expression) or in the wrong place (ectopic expression)

Question 29

Replicative Segregation

Answer 29

During cell division, the multiple copies of mtDNA in each of the mitochondria in a cell replicate and sort randomly among the newly synthesized mitochondria, which are distributed randomly between the two daughter cells

Question 30

Homoplasmy & Heteroplasmy

Answer 30

Refers to the proportion of mutant and wild-type mitochondrial DNA passed on to a daughter cell during replicative segregation; a daughter cell that receives a pure population of wild type mtDNA is homoplasmic, whereas a daughter cell that receives a mixture of wild type and mutant mtDNA is heteroplasmic

Question 31

Loss of Function Mutations - 5 Examples

Answer 31

Duchenne Muscular Dystrophy - DMD gene, dystrophin
alpha thalassemia - alpha thalassemia gene, a-globin
Turner syndrome - loss of X chromosome
HNPP - PMP-22 gene, peripheral myelin protein
OI Type I - COL1A1 gene, COL1A1 type collagen

Question 32

Gain of Function Mutations - 4 Examples

Answer 32

Hb Kempsey - B-globin gene, missense
Achondroplasia - FGFR3 gene, fibroblast growth factor receptor
Alzheimer Disease in Trisomy 21 - APP gene, amyloid precursor protein
Charcot-Marie-Tooth - PMP22 gene, peripheral myelin protein

Question 33

Novel Property mutations - Examples

Answer 33

Sickle Cell Disease - b-globin gene/protein, missense

Huntington disease: CAG repeats/polyglutamine tracts lead to novel toxicity of protein