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Flashcards in Cormier Week 7 Deck (45):
1

define linkage analysis*******

• 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

2

basic concepts in heritability:

Genetic contribution to disease in a population.

3

***alpha-1 antitrypsin-

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

4

Beta-globin locus-

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

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HARDY-WEINBERG:

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

6

***I-cell disease-

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

7

***Hyercholesterolemia-

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

8

***Cystic fibrosis-

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

9

Determining Phase:
-the polymorphic marker linked to the disease
-need at least 3 generations to determine

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

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Locus-

a segment of DNA at a specific location

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two alleles that are FUNCTIONALLY identical

Homozygous-

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two alleles that are FUNCTIONALLY different

Heterozygous-

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two heterogeneous recessive alleles at a particular locus

Compound heterozygotes-

14

Four basic patterns of single gene inheritance:

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

15

Pure dominance-

when homozygotes and heterozygotes show identical severity of phenotype

16

Semidominance-

disease is more severe in homozygotes

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Codominant-

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

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Penetrance-

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

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Expressivity-

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

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***Allelic heterogeneity-

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

21

***Locus Heterogeneity-

same phenotype, different GENES

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***Phenotypic heterogeneity-

different mutations in the SAME gene cause DIFFERENT diseases

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Sex influenced autosomal recessive-

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

24

Neurofibromatosis (NF1)-

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

25

Huntington disease-

-late age of onset

26

PKU-

-autosomal recessive, iability to break down phenylalinine
-displays allelic heterogeneity of the PAH gene

27

retinitis pigmentosa-

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

28

RET gene-

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

29

Tay-Sachs-

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

30

Male limited precocious puberty-

adolescent growth spurt at 4 yo
-autosomal dominant but sex limited
-difficult to distinguish from X-linked, need father-son transmission

31

Duchennes Muscular Dystrophy-

-X-linked recessive
-female carrier can be detected by immunostaining for dystrophin

32

Rhett Syndrome-

X-linked dominant causing male lethality
-neuro sx begin at 6-18 mo for heterozygous females

33

RFLP-

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

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Haplotypes-

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

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-haplotypes blocks

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

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Haplotype maps-

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

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Haplogroups-

can be used to trace ancestory

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***Prader Willi-

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

39

***Angelman Syndrome-

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

40

BCR-ABL-

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

41

*******Down’s Syndrome-

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

42

***Klinefelter Syndrome-

1/1000 males, extra copy of X-chromosome

43

***Turner’s syndrome-

X-chromosome monosomy 1/5000 females affected

44

MSS-

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!

45

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

DMD female carriers