Cormier Week 7 Flashcards
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
basic concepts in heritability:
Genetic contribution to disease in a population.
***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
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
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
***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
***Hyercholesterolemia-
autosomal dominant, deficiency in LDL receptors, more severe in homozygotes
***Cystic fibrosis-
autosomal recessive
-mutation in gene encoding for chlorine channels in epithelial cells (deletion of 508F is most common)
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
Locus-
a segment of DNA at a specific location
two alleles that are FUNCTIONALLY identical
Homozygous-
two alleles that are FUNCTIONALLY different
Heterozygous-
two heterogeneous recessive alleles at a particular locus
Compound heterozygotes-
Four basic patterns of single gene inheritance:
Autosomal dominant-
Autosomal recessive-
X-linked dominant-
X-linked recessive-
Pure dominance-
when homozygotes and heterozygotes show identical severity of phenotype
Semidominance-
disease is more severe in homozygotes
Codominant-
variant alleles are expressed together (ie: ABO blood group)
Penetrance-
probability that a mutant gene will have any phenotypic expression (if less than 100%= reduced penetrance)
Expressivity-
severity of expression of the phenotype among individuals with the SAME disease causing genotype
***Allelic heterogeneity-
many loci contain multiple mutant alleles that all manifest as the same clinical phenotype
***Locus Heterogeneity-
same phenotype, different GENES
***Phenotypic heterogeneity-
different mutations in the SAME gene cause DIFFERENT diseases
Sex influenced autosomal recessive-
both sexes develop the disease but one has significantly higher frequency (ie Hemochromatosis: iron metabolism disorder)
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
Huntington disease-
-late age of onset
PKU-
- autosomal recessive, iability to break down phenylalinine
- displays allelic heterogeneity of the PAH gene
retinitis pigmentosa-
shown to have autosomal dominant, autosomal recessive, and X-linked forms (locus heterogeneity)
- photoreceptor degeneration
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
Tay-Sachs-
fatal early childhood neurological disorder involving inability to breakdown gangliosides in the lysosomes
-frequency is 100 times higher in Ashkenazi Jews
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
Duchennes Muscular Dystrophy-
- X-linked recessive
- female carrier can be detected by immunostaining for dystrophin
Rhett Syndrome-
X-linked dominant causing male lethality
-neuro sx begin at 6-18 mo for heterozygous females
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
Haplotypes-
(haploid genotypes) any combination of alleles, loci, or markers on the same chromosome, commonly inherited together.
-SNP haplotypes
-haplotypes blocks
(large sets of SNPs)- large block=recent development
Haplotype maps-
permits the association of phenotypic traits with the presence of specific haplotypes
Haplogroups-
can be used to trace ancestory
***Prader Willi-
region is MATERNALLY imprinted so deletion of the male PW region=PW syndrome
***Angelman Syndrome-
region is PATERNALLY imprinted so deletion of female AS region= Angelman syndrome
BCR-ABL-
Philadelphia chromosome in CML (chronic myelogenous leukemia)
-translocation of chrom22 to chrom9
***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
***Klinefelter Syndrome-
1/1000 males, extra copy of X-chromosome
***Turner’s syndrome-
X-chromosome monosomy 1/5000 females affected
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!
Carrier values of serum creatinine kinase which can overlap normal values are found where?
DMD female carriers
