GENETICS OF COMPLEX DISEASES

Question 1

how common are single gene mutations in disease?

Answer 1

rare

Question 2

what are single gene mutations in disease?

Answer 2

Mutations in a gene Dominant/recessive pedigree patterns

Structural proteins, enzymes, receptors, TF

Question 3

how common are Multifactorial/Complex?

Answer 3

common

Question 4

how many genes are affected in Multifactorial/Complex?

Answer 4

> 1 gene affected, gene variants

Question 5

how common are Chromosomal changes?

Answer 5

common

Question 6

how many genes are affected Chromosomal changes?

Answer 6

100’s of genes affected, e.g. gain/loss of chromosome

Question 7

how common do Environmental factors affect disease?

Answer 7

very common

Question 8

give examples of environmental factors that effect disease?

Answer 8

Includes viral/bacterial infections, affect disease penetrance

Question 9

what is multifactorial inheritance?

Answer 9

The inheritance and expression of a phenotype being determined by the cumulative action of multiple genes at multiple loci.

Question 10

what effect do the genes have in multifactorial inheritance?

Answer 10

Each gene contributes a small amount to a final phenotype that is also significantly influenced by environmental factors.

Question 11

what is the effect of each gene contributing to the phenotype in multifactorial inheritance?

Answer 11

As a result these multiple genes are not viewed as being dominant or recessive to each other.

Question 12

how are the genes arranged in multifactorial inheritance?

Answer 12

These multiple genes do segregate in a Mendelian manner, but the phenotype does not.

Question 13

what are monogenic diseases?

Answer 13

Have a single strong highly penetrant phenotype

Question 14

how common are monogenic diseases?

Answer 14

very rare

Question 15

what are modifiers?

Answer 15

Other genes that affect phenotype severity (e.g. regulate expression of the disease allele) but the primary gene dominates

Question 16

how common are polygenic diseases?

Answer 16

very common

Question 17

what are polygenic diseases?

Answer 17

Have lower penetrant phenotypes
Not dominated by one gene though a genetic locus could have a predominant effect (e.g. BRCA1/2 genes in breast/ovarian cancers)

Question 18

what effect does environmental contribution have on polygenic diseases?

Answer 18

reduces penetrance

Question 19

what are pedigrees?

Answer 19

more complex

Question 20

what is penetrance?

Answer 20

the fraction of cases carrying a given gene that manifests in a specified phenotype

Question 21

what are the 2 factors that cause any trait?

Answer 21

genetics

environment

Question 22

give examples of polygenic complex diseases?

Answer 22

Obesity, Schizophrenia, Alzheimer’s, Asthma, Multiple sclerosis, Autism, Cancer

Question 23

Why study genetics of multifactorial disease?

Answer 23

Identify individuals with an increased risk of disease
Understanding may identify targets for better therapy
Untangle complexity of gene-environment interactions

Question 24

why is complex inheritance the underlying factor for most common human diseases?

Answer 24

Multifaceted interactions of genotypes at multiple loci

Environmental factors that trigger, accelerate or worsen disease development

Question 25

what is polygenic inheritance?

Answer 25

Traits are usually quantified by measurement | >= 2 genes contribute to the phenotype

Question 26

does phenotypic variation in polygenic inheritance vary?

Answer 26

yes across a wide range

Question 27

how is polygenic inheritance best analysed?

Answer 27

in populations rather than individuals

Question 28

what does the interaction of genes with the environment produce?

Answer 28

a wide range of phenotypes

Question 29

give an example of polygenic inheritance

Answer 29

adult male height

Question 30

what are the 2 methods to study multifactorial traits?

Answer 30

Threshold model | Recurrence risk

Question 31

what is the threshold model?

Answer 31

Frequency of disorder among relatives is compared with the frequency of the disorder in the general population

Question 32

what is the recurrence risk?

Answer 32

Estimates the risk that the disease will recur

Question 33

what is the liability threshold?

Answer 33

Measure of the disease state of an individual When alleles push the distribution towards the liability threshold they are termed ‘risk alleles’ or susceptibility alleles

Question 34

are all alleles additive?

Answer 34

not all of them | some are dominant, epistatic (=modifier genes), protective

Question 35

what is heritability?

Answer 35

the proportion of disease variation due to genetic variation

Question 36

what is monozygotic twins?

Answer 36

Single fertilization | Genetically identical

Question 37

what is dizygotic twins?

Answer 37

Independent fertilization events | Share approximately half their genes

Question 38

what is concordance?

Answer 38

probability (%) that twins (identical or non-identical) will both have the disease, given that one of the pair has the disease

Question 39

how do you estimate heritability?

Answer 39

Difference between the % concordance in dizygotic twins versus monozygotic twins

Question 40

how do you estimate the genetic, shared environment and non-shared environment contributions?

Answer 40

By looking at the concordance and discordance between mono- and dizygotic twins

Question 41

how is familial breast cancer caused?

Answer 41

Known genes (e.g. BRCA1&2) involved in familial breast cancer account for <30% of the familial risk

Question 42

what is autism?

Answer 42

characterized by great difficulty in communicating, forming relationships and in using language and abstract concepts Known to be strongly influenced by genetics

Question 43

what is an allele?

Answer 43

one of a number of alternative forms of the same gene

Question 44

how are disorders inherited?

Answer 44

Studies have shown that an individuals risk of inheriting certain disorders correlates to the relatedness of affected family members (e.g. schizophrenia)

Question 45

what are Single Nucleotide Polymorphisms | (SNPs)?

Answer 45

DNA sequence variations that occur when a single nucleotide in the genome sequence is altered at the same genetic location between different chromosomes

Question 46

how are variations considered a SNP?

Answer 46

variation must occur in >= 1% of the population

Question 47

what do SNPs act as?

Answer 47

While most have no effect on protein function, it is believed they can act as biological markers, helping us identify genes associated with disease

Question 48

what do SNPs help to understand?

Answer 48

widely differing susceptibilities to complex yet common diseases

Question 49

what are SNPs used as?

Answer 49

to map haplotypes

Question 50

what are haplocytes?

Answer 50

disease-linked genomic loci that are physically linked on a chromosome and segregate together

Question 51

what are GWAS?

Answer 51

genome-wide association study

Question 52

how many genes are involved in chromosomal disorders?

Answer 52

thousands

Question 53

what is aneuploidy?

Answer 53

presence of an abnormal number of chromosomes in a cell | Humans should have 46 chromosomes

Question 54

give examples of aneuploidy affecting sex chromosomes?

Answer 54

``` Triple-X syndrome (47,XXX) Klinefelter syndrome (47,XXY) XYY syndrome (47,XYY) Turner syndrome (45,X0) ```

Question 55

why is aneuploidy nearly always deleterious?

Answer 55

because of genetic imbalance

Question 56

give examples of autosomal chromosomes?

Answer 56

Trisomy 21, Down syndrome Trisomy 18, Edward syndrome Trisomy 13, Patau syndrome

Question 57

what is DiGeorge Syndrome?

Answer 57

Deletion of band 11.2 on long arm of chr 22

Question 58

what are the symptoms of DiGeorge Syndrome?

Answer 58

Congenital cardiac defects, facial dysmorphia, thymic aplasia, cleft palate, hypocalcemia, learning disabilities, T-cell immunodeficiency

Question 59

what causes down's syndrome?

Answer 59

Meiotic non-disjunction

Question 60

what is non-disjunction?

Answer 60

failure of chromatids to separate into 2 chromosomes

Question 61

what effect does non-disjunction have on age?

Answer 61

increases with maternal age