Cormier Week 7

Question 1

define linkage analysis***

Answer 1

• linkage analysis uses statistics to determine whether two genes, loci or the markers they are based on, are likely to lie near one another, estimated by the frequency that they are transmitted together, as an intact unit, during meiosis
• 2 genetic loci are linked if they are transmitted together from parent to offspring more often than expected under independent inheritance
• linkage analysis is used to study families to determine if two genes demonstrate linkage when passed from one generation to another
• the closer two genes or markers are to each other the less likely they will be separated during meiotic recombination. The likelihood of separation is called the recombination frequency (RF). A RF of ≥ 50% means two genes or a gene and marker are unlinked; < 50% means they are linked
• RF of 1% = 1 centiMorgan (cM), unit of genetic distance that corresponds to ~ 2 MB of sequence

Question 2

basic concepts in heritability:

Answer 2

Genetic contribution to disease in a population.

Question 3

***alpha-1 antitrypsin-

Answer 3

inhibits leukocytes’ proteolytic elastase damaging lung connective tissue if not downregulated.

• 5 major alleles (ZZ homozygotes the worst off)
• highest frequency of Z among Danish population
• also increases risk of liver disease

Question 4

Beta-globin locus-

Answer 4

sickle cell anemia when homozygous, usually fatal
-heterozygous is selected for (heterozygous advantage) in pops of w Africa because it creates immunity to malaria which increases reproductive fitness

Question 5

HARDY-WEINBERG:

Answer 5

p2 + 2pq + q2
P2= probability of AA genotype
2pq= probability of Aa
q2= probability of aa 
Assumption:
1.	population is large
2.	matings are random
3.	allele frequencies remain constant→no mutations, negative selection, genetic influx

Question 6

***I-cell disease-

Answer 6

autosomal recessive lysosomal storage disease caused by a defect in protein trafficking
-no mannose 6-P= sent out of cell instead of to lysosome

Question 7

***Hyercholesterolemia-

Answer 7

autosomal dominant, deficiency in LDL receptors, more severe in homozygotes

Question 8

***Cystic fibrosis-

Answer 8

autosomal recessive

-mutation in gene encoding for chlorine channels in epithelial cells (deletion of 508F is most common)

Question 9

Determining Phase:

• the polymorphic marker linked to the disease
• need at least 3 generations to determine

Answer 9

• the polymorphic marker linked to the disease

- need at least 3 generations to determine

Question 10

Locus-

Answer 10

a segment of DNA at a specific location

Question 11

two alleles that are FUNCTIONALLY identical

Answer 11

Homozygous-

Question 12

two alleles that are FUNCTIONALLY different

Answer 12

Heterozygous-

Question 13

two heterogeneous recessive alleles at a particular locus

Answer 13

Compound heterozygotes-

Question 14

Four basic patterns of single gene inheritance:

Answer 14

Autosomal dominant-
Autosomal recessive-
X-linked dominant-
X-linked recessive-

Question 15

Pure dominance-

Answer 15

when homozygotes and heterozygotes show identical severity of phenotype

Question 16

Semidominance-

Answer 16

disease is more severe in homozygotes

Question 17

Codominant-

Answer 17

variant alleles are expressed together (ie: ABO blood group)

Question 18

Penetrance-

Answer 18

probability that a mutant gene will have any phenotypic expression (if less than 100%= reduced penetrance)

Question 19

Expressivity-

Answer 19

severity of expression of the phenotype among individuals with the SAME disease causing genotype

Question 20

***Allelic heterogeneity-

Answer 20

many loci contain multiple mutant alleles that all manifest as the same clinical phenotype

Question 21

***Locus Heterogeneity-

Answer 21

same phenotype, different GENES

Question 22

***Phenotypic heterogeneity-

Answer 22

different mutations in the SAME gene cause DIFFERENT diseases

Question 23

Sex influenced autosomal recessive-

Answer 23

both sexes develop the disease but one has significantly higher frequency (ie Hemochromatosis: iron metabolism disorder)

Question 24

Neurofibromatosis (NF1)-

Answer 24

• autosomal dominant
• nervous system- expressed in a wide range of tissues (pleiotropy)
• 100% penetrance
• Variable expressivity due to different mutations in the NF1 gene

Question 25

Huntington disease-

Answer 25

-late age of onset

Question 26

PKU-

Answer 26

• autosomal recessive, iability to break down phenylalinine

- displays allelic heterogeneity of the PAH gene

Question 27

retinitis pigmentosa-

Answer 27

shown to have autosomal dominant, autosomal recessive, and X-linked forms (locus heterogeneity)
- photoreceptor degeneration

Question 28

RET gene-

Answer 28

encodes receptor tyrosine kinase; 3 separate mutations

• dominantly inherited failure to develop colonic ganglia, leads to defective colon motility and chronic constipation (Hirschsprung disease)
• dominantly inherited cancer of the thyroid and adrenal glands (multiple endocrine neoplasia type 2A and 2B)
• a third separate mutation can cause both
• example of Phenotypic heterogeneity

Question 29

Tay-Sachs-

Answer 29

fatal early childhood neurological disorder involving inability to breakdown gangliosides in the lysosomes
-frequency is 100 times higher in Ashkenazi Jews

Question 30

Male limited precocious puberty-

Answer 30

adolescent growth spurt at 4 yo

• autosomal dominant but sex limited
• difficult to distinguish from X-linked, need father-son transmission

Question 31

Duchennes Muscular Dystrophy-

Answer 31

• X-linked recessive

- female carrier can be detected by immunostaining for dystrophin

Question 32

Rhett Syndrome-

Answer 32

X-linked dominant causing male lethality

-neuro sx begin at 6-18 mo for heterozygous females

Question 33

RFLP-

Answer 33

restriction fragment length polymorphism (insertion or deletion), used to distinguish between two chromosomes

• usually just a biomarker and not a cause of dysfunction
• can be analyzed by southern blotting or PCR

Question 34

Haplotypes-

Answer 34

(haploid genotypes) any combination of alleles, loci, or markers on the same chromosome, commonly inherited together.
-SNP haplotypes

Question 35

-haplotypes blocks

Answer 35

(large sets of SNPs)- large block=recent development

Question 36

Haplotype maps-

Answer 36

permits the association of phenotypic traits with the presence of specific haplotypes

Question 37

Haplogroups-

Answer 37

can be used to trace ancestory

Question 38

***Prader Willi-

Answer 38

region is MATERNALLY imprinted so deletion of the male PW region=PW syndrome

Question 39

***Angelman Syndrome-

Answer 39

region is PATERNALLY imprinted so deletion of female AS region= Angelman syndrome

Question 40

BCR-ABL-

Answer 40

Philadelphia chromosome in CML (chronic myelogenous leukemia)
-translocation of chrom22 to chrom9

Question 41

***Down’s Syndrome-

Answer 41

trisomy 21

• rate increases to 1/15 in women over 45
• 8-fold increase risk of recurrence (1/100 from original baseline of 1/800)
• most common chromosomal birth defect

Question 42

***Klinefelter Syndrome-

Answer 42

1/1000 males, extra copy of X-chromosome

Question 43

***Turner’s syndrome-

Answer 43

X-chromosome monosomy 1/5000 females affected

Question 44

MSS-

Answer 44

Maternal serum screening:
First Trimester: Indicates greater chance of trisomy21
Nuchal translucency- UP
PAPP-A- DOWN
Free B-hCG- UP
Second trimester:
uE3- DOWN
AFP- DOWN
Free b-hCG- UP
Inhibin A- UP
**AFP→up in 2nd tri=neural tube defects
***NOT DEFINITIVE***
values can overlap!

Question 45

Carrier values of serum creatinine kinase which can overlap normal values are found where?

Answer 45

DMD female carriers