Define genetics, phenotype, and genotype Discuss dominant and recessive alleles Describe Punnett squares Explain how karyotyping is used to identify chromosomal disorders Create Punnett squares to determine if alleles create genotypes that are homozygous dominant, homozygous recessive, or heterozygous
Phenotype, Genotype-Phenotype Studies, Sickle Cell Disease, Michael DeBaun Created Date: 20111212171909Z
Phenomics: Genotype to Phenotype Based on a NSF-USDA sponsored workshop held 31 March - 2 April 2011 in St Louis, Missouri, USA1 Executive Summary The question of how genetics and environment interact to influence phenotype has a long and important history Recent advances in DNA sequencing and phenotyping technologies, in
genotype, phenotype and environment, in a variety of selective, developmental and assorting situations with complex transmission in which G-(genetic) , F- (phenotypic), E- (environment) inheritance mechanisms operate jointly The transmission rules and development patterns (i e , interactions between
features in plant genotype-phenotype associationanalysis In particular, we investigated (1) whether the geoclimatic fea-tures are predictive of the flowering time phenotype and (2) whether the geoclimatic features are complimentary with the genomic features to improve phenotype predictions and (3) novel computational methods to integrate
say that a phenotype is completely penetrant if all individuals show it and incompletely penetrant if a subset of individuals of a given genotype express the trait Expressivity refers to the severity or degree of expression of a given phenotype If the phenotype shows variable expressivity, the
120 possible to investigate the genotype-phenotype-fitness map by comparing how the fitness 121 effects of many mutations change across a large number of environments The way each 122 mutant’s fitness varies across environments must be related to its phenotype, and thus the way
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The importance of phenotype in genotype-
phenotype studies in sickle cell disease
Michael R. DeBaun MD, MPH
Director of Vanderbilt, Matthew Walker, Meharry
Center of Excellence for Sickle Disease
Objectives
Definitions
Hemoglobin SS, SC,
other
Beta globin Haplotype
Phenotype
Pain
Recommendations
Sickle Cell Disese Genotypyes
SCD Genotypes
Hemoglobin SS
Hemoglobin SC
Hemoglobin S beta thalassemia
Zero no production of hemoglobin A Plus production of hemoglobin (2,30%)
Hemoglobin S Persistent Fetal Hemoglobin
Complications of Sickle Cell Disease
What do families living with
sickle cell disease want health care providers to address?
Topic Suggestions for Future
Events (n= 62 families)
Pain Management
SchoolIntervention
Coping with SCD
Advocacyof Local Events
Financial Resources
CommunityResources
What Does sickle cell anemia look like for a 22 year old? I know that it has been long overdue since we've last talked ,but you knew of any adult hematologists (that you personally approved of) who provides good care. Since I have been here, despite doing everything that I have been told to do (taking hydroxyurea and folic acid "the right way" and even taking oxycontin and oxycodone around the clock, non-stop), I have still been in constant pain. My hemoglobin will not stay up past 3.7 (sometimes lower) for more than a week at a time despite receiving constant blood transfusions and a series of shots every 3 weeks. I feel as though
Vaso-occlusive pain episode
Most generous (Smith et al. Ann Intern Med. 2008 Jan 15;148(2))
Pain that requires opioid treatment at home or
with a physician contact
Limitations
Difficult to quantify because requires a diary
Most conservative (SIT Trial)
Pain that requires hospitalization
Limitations
Most patients with severe pain manage their
pain at home
Lower estimate of the burden of pain
Most Recent Definition of Pain
Comprehensive Sickle Cell Centers
New onset of pain that lasts at least 4 hours for
which there is no explanation other than vaso- occlusion, and which requires therapy with either opioids or ketorolac in a medical setting
Am J Hematol. 2009 Sep; 85(1):6-13.)
Complication
Beta GlobinGenotype
SSSCȕ+
Painful Episodes804040
Incidence of Pain by Genotype
Defined as pain that last for two hours and
requires physician contact-pre HU era
Cooperative Stud of Sickle Cell Disease;
All rates expressed per 100 patient-years
Distribution of pain rates in SS
Platt, NEJM, 1991
Problem
Multiple Modifiers of pain
Hydroxyurea, genotype, age, asthma, therapy
Multiple definitions of pain
Any physician contact-CSSCD
Home diary-Smith et al.
Hospital records -SIT Trial
Duration of evaluation
Lifetime-CSSCD-gold standard
Home diary-6 months
Hospitalization for pain-previous 3 years
Replication Strategies:
The Key to Validating
NCI and NHGRI Workshop
Nature2007;447(7145):655-60.
Three key components
1.Sufficient sample size
2.Independent data set
3.Identical phenotype
ModelCSSCDΏSITTΐ
Chisq(df)P-valueChisq(df)P-value
HbFvsBasic17.9 (1)2.0x10-516.4 (1)5.12x10-5
Genotype vs Basic20.4 (5)0.00112.2 (3)0.0067
Full vsHbF14.4 (5) 0.018.2 (3)0.042
Validation of CSSCD pain models in SITT dataset
Life time pain rate with MD contact versus
3 year retrospective hospitalization for pain
(Lettre et al., PNAS 2008 105 (33): 11869-11874) Basic model: Pain rate* = gender + age registration
HbF model: Pain rate* = basic model + HbF
Genotype model: Pain rate * = basic model + Hb F SNPs Full model: Pain rate* = basic model + HbF + Hb F SNPs
Suggestions for Future Work
Common phenotype definitions for all NIH
funded sickle cell disease trials and observation studies
Central biological repositories for NIH SCD
studies linked to pre-defined common phenotypes
Large consortia for addressing specific
genotype phenotype studies or pathway- phenotype studies
Thank You!
James Casella, Emilly Casella, Pallav Bhatnagar, Dan Arking-Johns
Hopkins; SIT Trial Investigators and Families
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Human Genetics: Phenotype and Genotype