Genetics of Common Disorders with Complex Inheritance and Personalized Medicine Flashcards Preview

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Flashcards in Genetics of Common Disorders with Complex Inheritance and Personalized Medicine Deck (66):
1

What percent of the genome is identical between individuals?

99%

2

1% of the DNA sequence between individuals is different. These DNA differences are called

Polymorphisms

3

Can be small insertions/deletions, differences in the number of repeats, or single nucleotide differences (SNPs)

Polymorphisms

4

Most polymorphisms are silent, meaning they exert no functional

Difference

5

The entire genome is equivalent to a book, each chromosome is equivalent to a chapter, each gene is equivalent to a paragraph, and each nucleotide is equivalent to a

Letter

6

A DNA change that severely alters the activity or expression of a gene

Mutation

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Silent change in the DNA that does not alter the
expression or activity of the gene.

Polymorphism

8

Subtle changes that alter the levels or activity of a gene, but the gene is still in NORMAL range

Functional Polymorphism

9

How do we find relative risk?

Prevalence in affected / prevalence in unaffected

10

The variance within pairs of dizygotic (DZ) twins will be similar to that seen within monozygotic (MZ) twins, and heritability (h^2) will approach 0 if the variability of the trait is determined chiefly by the

Environment

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If the variability is determined chiefly by the environment, the heritability will approach

0

12

If the variability is determined exclusively by genetic makeup, than the variance of MZ pairs is 0 and the heritability is

1

13

A single gene disorder named after Gregor Mendel

Mendelian Disorder

14

What are the three modes of inheritance for the Mendelian disorder?

1.) Recessive
2.) Dominant
3.) semi-dominant

15

To identify the causative gene, we want to sequence all the genes in the region and look for a mutation that segregates with disease in all

Pedigrees

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To find the causative gene, we want to look for the presence of different mutations in different

Families

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To identify the causative gene, we want to confirm that the mutation affects expression or activity of a

Gene

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Deep sequencing, the next generation of sequencing, allows for sequencing the entire genome in a cheap and relatively fast manner. We can sequence the

Genome, Exome, or Transcriptome

19

Neural crest defect for cells that go on to form the enteric nervous system of the intestines

-leads to enlarged colon

Hirschsprung's disease (HSCR)

20

The frequency of HSCR is

1/5000

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Does not follow a simple recessive or dominant inheritance pattern

HSCR

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The relative risk for siblings to get HSCR is about

-Monozygotic twins do not show perfect concordance

200

23

How much more likely are males within the family to get HSCR than females?

2x

24

HSCR is caused by a mutation in the tyrosine kinase receptor needed for neural crest migration known as

RET

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Scanning of the genome for 67 siblings that both have HSCR showed that 55/67 siblings shared alleles at

10q11.2 (RET), 3p21, and 19q12

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Are major health concerns and therefore understanding the biological basis of these disorders so new treatments can be developed is necessary

Common diseases

27

The phenotypic overlap of Multiple sclerosis (MS), type 1 diabetes, and survival bone marrow transplant is

Autoimmunity

28

The phenotypic overlap of schizophrenia, bipolar disorder, and autism is

Neurodevelopmental disorder

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Refers to inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes, or interaction with the environment, or both

Multi-factorial inheritance

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A character determined by the combined action of a number of genetic loci

Polygenic

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Caused by mutations in single genes

-ex: Cystic fibrosis and Duchene Muscular Dystrophy

Monogenic (Mendelian) disorders

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Do not follow simple recessive or dominant inheritance patterns

Multi-factorial diseases

33

What are the risks for common diseases

1.) Genetic
2.) Epigenetic
3.) Non-genetic environmental factors

34

What are two types of genetic risks for common diseases?

Functional polymorphisms (common variants) and mutations (rare variants)

35

Hormones, diet, or infections that alter cell biological pathways

Non-genetic environmental factors

36

Common diseases occur frequently in the population; some of the genetic susceptibility alleles are then likely to be

Common (>5%)

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Are likely to have less of a phenotypic effect per individual but would affect more individuals within the population

Common variants (functional polymorphisms)

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Would have a significant phenotypic effect per
individual but contribute less to general population

Rare variants (mutations)

39

If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the A polymorphism should be inherited more frequently in

Affected individuals

40

If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the G polymorphism should be inherited more frequently in

Unaffected individuals

41

The previous polymorphism example was an example of an

Association study

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SNPs are co-inherited as blocks or bins. Panels are created with tagged SNPs for each bin. Thousands of people with the disease are recruited and their DNA is isolated and genotyped for their whole genome

Genome Wide Association Analysis (GWAS)

43

Once the recruits have been genotypes, we then do statistical analysis to identify the

SNP alleles co-inherited with disease

44

What are some problems with GWAS?

Reproducibility and functionality

45

49% of variants in individuals affected with ASD are

Common inherited (A)

46

Seeks to identify all functional elements in the human genome

ENCODE

47

Identified protein coding regions contained in approximately 20,000 genes

-discovered that protein coding regions made up only 1% of genomeq

Human genome project

48

Aims to characterize other functional DNA elements

ENCODE

49

ENCODE discovered that what percent of the genome is involved in at least one biochemical event?

>80%

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ENCODE discovered that 95% of the genome is within 8kb of a

DNA protein interaction

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What percent of the genome is within 1.7kb of an ENCODE identified event?

99%

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A substantial proportion of variants are annotated as having predicted functional effects in the

Non-coding category

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Affects the epigenome, transcriptome, proteome, and metabolome

Environment

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Says that risks of commmon diseases are due to epimutations

Epigenetic hypothesis

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Changes in the epigenetic signature

-affects gene regulation

Epimutation

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Contribute to non-genetic components of diseases

Epimutations

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Epimutations provide an interface between environmental factors and

Gene expression

58

For many common diseases cause by epimutations, phenotypes are very

Heterogeneous

59

The metabolic state of a cell is not invariant and is directly linked to

Cellular function

60

The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.

Warburg effect

61

What most human diseases are, where if you get one allele, you have a certain clinical phenotype, but if you get two mutant alleles, you have a much worse phenotype

Semi-dominant

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Looks like AD, but may appear to skip a generation

Incomplete penetrence

63

Identifying pieces of DNA that are co-inherited with the mutation

Genetic linkage

64

A handful of mutations cause these diseases as opposed to just one

-Ex: HSCR

Simple complex disorders

65

Pose less individual risk, but more population risk

Common varaints

66

Tell us how the cell is functioning

Metabolites

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