Genomics week 11

winniesmith2's version from 2017-12-11 10:00

Section 1

Question Answer
Inheritance pattern of huntingtons disease autosomal dominant
Why is huntingtons problemtic late onset. Neural degradation, uncontrollabe movements of the limbs, depression, cognitive decline. Intra-nuclear inclusions. No biochemical defect known - prime candidate for linkage analysis.
HD mapping strategy; objective; To find a DNA marker/probe that was linked to HD. The 12th probe called G8 - indicated linkage.
benefit of linkage analysis results from different families can be pooled together.
negative LOD score means no linkage
HD linkage mapping G8 (or D4S10) mapped approx 4cM from HD locus. Localized by in situ hybridization to chromosome region 4p16.3 (tip of p arm)
CAG repeats 11- 34 present and needed in exon. Important! encodes a polyglutamine tract . Main defect is expansion of CAG repeat in exon 1.
What do extra CAG repeats do Cause formation of inclusion bodies. Each generation the number of CAG repeats increase. More copies the earlier you get it/more severe. Triplet repeat diseases.
How can we use this info we can screen people. Use PCR to look at number of repeats.
Current therapies of HD Target individuals repeats so they arent increasing.
Advantages -Uncertainty of gene status removed. -If negative: concerns about self and offspring reduced. -If positive: make plans for the future, arrange surveillance/treatment if any, inform children/decide whether to have children.
Disadvantages -If positive: removes hope, introduces uncertainty (if and when), known risk to offspring, impact on self/partner/family/friends, potential problems with insurance/mortgage. -If negative: expectations of a ‘good’ result, ‘survivor’ guilt.

Section 2

Question Answer
X-linked recessive inheritance-Usually affects males. -Usually born to asymptomatic carrier mothers who may have other affected male relatives. -Females may be affected if the father affected and mother a carrier. -Females may be affected due to non-random X inactivation. -No male to male transmission
Duchenne muscular dystrophy (DMD)Progressive muscle weakness/wastage. Incurable. causing learning difficulties and bone fractures. In wheelchair by age 10 and like lifespan limited to early 20s. Relatively common 1/3000 births. Over 200 types of mutations can cause any one off the forms of MD.
Becker MDless severe. live through 30-40s. less likely to have cognitive impairment.
What does the DMD gene code for encodes for the protein dystrophin, found in muscle cells and some neurons. Cell membrane become permeable. Dystrophin provides strength to muscle cells by linking the internal cytoskeleton to the surface membrane. Without this structural support, the cell membrane becomes permeable.
DMD molecular makeupone of the largest genes 2.2 million base pairs. If defective leads to problems with the anchoring of the proteins.
Mutations which affect the DMD gene-96% are frameshift mutations -30% are new mutations -10-20% of new mutations occur in the gametocyte (sex cell, will be pass on to the next generation). Lead to absence of dystrophin.
Difference between DMD and BMDImpaired dystrophin protein. VS partially function protein.
What happens without dystrophin pg 29
Treatment; cell therapy -Isolate muscle stem cells from healthy donor -Culture MSCs in the lab -Transplant into patients: >Transplanted cells repair muscle >Transplanted cells make dystrophin
Treatment; gene therapy -Dystrophin protein made from new gene -Applicable to ALL patients -Gene is large! -How to get gene into (majority) nuclei of muscle cells? 1) Exon Skipping (missing mutated exons) 2) Stop Codon Readthrough -> full functional protein!
difference between BMD and DMD commonly non synonymous
DMD location Xp21.2
A boy is DMD positive parents aren't, how maternal grandparents