11/19 Genetics and Genetic testing.

Question 1

what is heritability

Answer 1

the proportion of variation in trait that is based on genes

Question 2

what is the heritability of fat mass?

Answer 2

40-70%

Question 3

why is obesity a mult-factorial trait?

Answer 3

it is affected by a large number of factors and a large number of different genes (probably more than a hundred)

Question 4

What is the relationship between leptin and BMI

Answer 4

Directly related…but leptin doesn’t seem to be as effective in some people.

Question 5

how does nicotine seem to affect appetite?

Answer 5

nicotine-arcuate nucleus nicotinic receptor-POMC neuron - MC4 receptors in secondary neurons reduce food intake and body weight

Question 6

What is one way we can learn about common diseases by looking at small groups that inherit the traits mendilianly

Answer 6

there are many common diseases that have subtypes that have mendilian inheritance, and these can be studied to see what causes the phenotype.

Question 7

what is the relationship between the severity of a disease causing allele and its frequency

Answer 7

inversely related. it seems that the alleles that most severly cause a common disease (the mendelian variations of a disease) are very rare.

Question 8

What is a genome-wide assocation studies

Answer 8

look for varients (SNPs) that different in frequency in the population of cases and in controls…and these SNPs then are probably very close to causal allele.

Question 9

How can you do genome-wide association studies

Answer 9

do DNA microarrays that will compare millions of DNA sequences on single chip!

Question 10

what is the goal of genetic testing?

Answer 10

Detect mutations or other abnormalities that cause genetic disease in order to allow treatment and decision making

Question 11

What Caveats should we consider when we approach genetic testing?

Answer 11

reveal mutaitons, but this does not mean that you will get a disease!! so the specificty is low! and- negative test result does not mean 0% risk of disease! For complex disease sensitivity and specificty are much lower!

Question 12

What do I need to be able to do with genetics as a physician (at a min!)

Answer 12

When and why to order a genetic test and how to interpret the findings

Question 13

how can we detect the transmission and presence of a disease causing allele without actually knowing what the mutation is?

Answer 13

use the principle of linkage with closely linked markers! we can fallow the markers and predict the presence of a mutation!

Question 14

how can we make a direct genetic diagnosis of a patient

Answer 14

Use an electropherogram of a patient to check for the presence and number of an allele, or use a probe hybridization and microarray to check for the presence of a specific allele

Question 15

what are the genes that we use to check for Breast cancer heritablility?

Answer 15

BRCA1 and BRCA2

Question 16

how can we identify a mutation on an electropherogram (sanger sequence?)

Answer 16

look at the comparison of peak sizes and where there is a stark difference in peak height we have a mutation!

Question 17

What is the difference in information that we need for direct vs. indirect genetic diagnosis?

Answer 17

Indirect [family information, errors possible by reombination, markers may be unimformative, can uncover multiple mutations]; Direct [ disease causing mutation must be known]

Question 18

when do we use genetic testing?

Answer 18

prenatal; newborn; carrier testing; presymptomatic; testing for adverse drug reactioins; finding causes of undiagnosed diseases

Question 19

Carrier screeening examples

Answer 19

Sickle-cell disease in African-American population; and Tay Sachs disease in Jewish population

Question 20

How effective was genetic screening for Tay-Sachs in jewish populations?

Answer 20

The number of diseased individuals went to zero!!!

Question 21

how do we undergo prenatal diagnosis of genetic diseases?

Answer 21

ultrasound; amniocentesis; chorionic villus sampling; preimplantation genetic diagnosis; diagnosis of fetal DNA in maternal circulation

Question 22

How can an ultrasound be suggestive of down syndrome?

Answer 22

Nuchal translucency is increased in fetuses with trisomy 21…not diagnostic but suggestive!

Question 23

what can you do with amniocentesis?

Answer 23

do karyotype, DNA testing, Alpha-fetoprotein level.

Question 24

how safe is amniocentesis?

Answer 24

Fetal loss rate 1/500 above background

Question 25

what is CVS for pregancy?

Answer 25

Chorionic vilus sampling: take a piece of Villus tissue and can get karyotype and DNA testing

Question 26

Contrast the information gathered from CVS, Amniocentesis and Maternal Circulation tests

Answer 26

Amnio [Karyotype, DNA testing, Alpha-fetoprotein level]; CVS [Karyotype, DNA testing], [DNA testing, Karyotyping, esp. whole genome sequencing]

Question 27

Constrast when you can perform CVS vs. Amniocentesis

Answer 27

CVS performed at 10-12 weeks gestation; Amniocentesis is performed at 16 weeks gestation.

Question 28

what is the risk of CVS in pregnancy?

Answer 28

it is about 1/100 above background

Question 29

what testing is done on IVF pregnancy?

Answer 29

preimplantation genetic diagnosis after in vitro fertilization. they take a cell from the fertilized embryo when it is only about 8 cells or so. and then can do in situ or SNP array or comparative genomic hybridization or PCR-based methods etc.

Question 30

How can we do fetal DNA testing from the mom’s circulation?

Answer 30

1/1,000,000 cells in maternal circulation are of fetal origin, 5-50% of cel free DNA is of fetal origin. Diagnosis at seven weeks,

Question 31

how effective is fetal DNA in maternal circulation testing for trisomy?

Answer 31

100% detection and 99.5% specificity

Question 32

How much of the genetic information of the baby can we get from mother’s blood

Answer 32

we can do whole-genome sequencing of fetal DNA

Question 33

What is the governments stand on genetic info

Answer 33

GINA prohibits discrimination by insurance companies or employies

Question 34

What would a large jaw, with large ears and large gonads and low IQ suggest for genetic diseases?

Answer 34

it would suggest Fragile X

Question 35

what type of inheritance would show more male affected, with not skipping generations

Answer 35

probably x-linked dominant with incomplete penetrance (fragile X is like this)

Question 36

what is the equation for recombination rate?

Answer 36

with the marker and no disease divided by the #with the marker and with the disease

Question 37

what does the LOD score tell us?

Answer 37

the high LOD means that the marker and the disease gene are probably linked closely together . High LOD is lclose on the same chromosome!

Question 38

what is it called when subsequent generations have more severe symptoms?

Answer 38

antcipation – more and more copies of the disese causing mutation are present.