Genetics 11 - Genetic Diversity and Complex Genetic Diseases Flashcards

Question

heavy chain DNA rearrangement

Answer 1

1. LVDJ spliced to be contiguous with C_mu 2. LVDJ spliced to be contiguous with C_delta expression of IgM heavy chain or IgD heavy chain

Answer 2

Goes to ER and leader sequence is cleaved off

Answer 3

recombination signal sequences non-coding DNA sequences that are found directly adjacent to the points at which recombination takes place (VDJ) function as signals for the recombination process that rearranges the gene segments located 3' side of each V segment, 5' side of each J segment and both sides of D segments

Answer 4

nonmer heptamer 1 (12 bp) or 2 (23 bp) turn signals Rag-1 and Rag-2 - Cleave out introns and exons in between

Answer 5

ONLY between a 1 and 2 turn signal - 12/23 rule **_κ light chains_** a 1 turn signal downstream (3') of V a 2 turn signal upstream (5') of J so κ V and J can join, but V won't join to another V **_λ light chains_** a 2 turn signal downstream (3') of V a 1 turn signal upstream (5') of J so λ V and J can join, but V won't join to another V **_heavy chains - 2-1-1-2_** a 2 turn signal downstream (3') of the V gene 1 turn signals on each side of the D exon a 2 turn signal upstream (5') of the J exon only 2 to 1 and 1 to 2 recombination is permitted V cannot recombine directly to J

Answer 6

catalysed by Rag-1 and Rag-2 (also involved with TCRs) mutations in the genes for these proteins results in severe combined immunodeficiency disease (SCID) as the recombination mechanisms are also involved in generation of TCRs

Answer 7

randomly inserts nucleotides at the junction between D and J further diversity in this hypervariable region - junctional diversity result = 10⁷ - 10⁸idiotypes of Ig

Answer 8

Heavy chain expressed first Recombination - in frame - go on to form heavy chain - pre b cell (either maternal or paternal) B cell is diploid - only 1 allele expressed so whatever allele makes a heavy chain first is going to be expressed

Answer 9

a process of affinity maturation of the V segments which occurs in the subset of B cells that can bind to a specific foreign antigen post-stimulation involves activation-induced deaminase (AID) mutation rate increase to 10³ per bp per generation some Igs have high affinity binding and B cells with these Igs are selected and proliferate extensively result = population of mature plasma cells secreting highly specific Ig

Answer 10

excision of introns and somatic hypermutation constitutes irreversible somatic genetic change considerable element of random recombination and mutation Fred and George - almost certainly end up with a different repertoire of their 10¹⁰ - 10¹¹ idiotypes of Ig similarly different TCR idiotypes and olfactory receptors

Answer 11

for most of maternal chr 1 the sequence in both monozygotic twins are identical for CNV loci the number of copies at a given locus on maternal chr 1 may differ between the 2 twins in a twin with a duplication of the CNV on mat chr 1 the 2nd/duplicate copy (paralogous sequence) may differ slightly from the original copy

Answer 12

if twin A develops complex disease and twin B does not - regions of the genome with CNV can be investigated further changes in CNV may identify whether a missing gene, or multiple copies of a gene, are implicated in disease onset pathogenic CNVs are particularly enriched for genes involved in development link to dosage sensitivity and neurodevelopmental disorders

Answer 13

bi-allelic expression is usual - from both maternal and paternal some genes normal physiological function requires full gene dose - 2 functional alleles individual with only 1 functional allele is haploinsufficient may be because of: heterozygous with 1 functional and 1 non-functional (null) allele OR hemizyogus (del) - allele deleted on 1 chr e.g. CNV microdeletion syndrome - Smith-Magennis syndrome (SMS) - haploinsufficiency of RAI1. microdel 17p11.2

Answer 14

genes - mendelian characters (phenotype) - never entirely Mendelian environmental influence genetic interactions chance (stochastic) events \* Penetrance and Expressivity

Answer 15

traits/disorders showing familial clustering, but no recognised Mendelian inheritance pattern determined by the additive effects of many genes at different loci (polygenic), combined with effects of environmental factors e.g. height, T2DM, hypertension, CV disease, schizophrenia, Alzheimer's disease

Answer 16

a useful framework for considering the inheritance patterns of traits/disorders that rely on the interaction of a large number of genetic factors, each of which make a small contribution to overall phenotype

Answer 17

HERITABILITY estimates how much of differences between populations are down to their genes THRESHOLDS explains how dichotomous characters can be polygenic

Answer 18

proportion of total phenotypic variance that is attributable to genetic variance in a population how much of differences between people in a group are down to genetic differences between them, and how much is down to differences in their environments nature (genes) vs nurture (environment) heritability is not about individuals - relates to populations

Answer 19

compares incidence in relatives of affected individual vs incidence in general population heritability of 0.5 does not mean that a trait is 50% caused by genetic factors - it means that 50% of variability in the trait in a population is due to genetic differences among people e.g. heritability of religion is 0 intelligence is somewhere between 0 and 1

Answer 20

caused by mutations in the PAH gene - phenylalanine hydroxylase mutations prevent conversion of the AA phenylalanine to other compounds builds up toxic levels, affecting nerve cells - brain damage

Answer 21

as we screen for PKU now, heritability of PKU is close to 0 - diet adjusted

Answer 22

co twin also affected higher rate with monozygotic twins

Answer 23

co twin unaffected higher rate in fraternal (dizygotic) twins - share 50% of genes - siblings

Answer 24

weaker evidence as family environment is shared and so could be responsible for the effect

Answer 25

stronger evidence than family studies as separates the effects of genes and family environment

Answer 26

rare, but very strong evidence as genetics are matched and family environment is different

Answer 27

explains how dichotomous characters can be polygenic susceptibility to a disease is a continuous character that depends on combined effect of many genes if your susceptibility exceeds a threshold you will manifest the disease - all or nothing relatives will therefore be more likely to also manifest the disease, than the general population explains why complex diseases tend to run in families

Answer 28

Julie Already have 2 children with cleft palate - threshold is low - a lot of susceptibility genes

Answer 29

polygenic threshold characters run in families parents with several affected children have more high risk alleles than parents with one affected RECURRENCE RISK RULES the more seriously affected, the higher the risk for siblings the more affected children you have, the higher risk of recurrence the closer the relative to the index case, the higher the risk of recurrence

Answer 30

hypertonic pyloric stenosis projectile vomiting and failure to thrive 5x more common in males must be higher threshold for girls than boys

Answer 31

offspring of affected females As females have higher threshold, she must have a lot of susceptibility genes for this disorder so more likely to pass on gene

Answer 32

higher recurrence risk if the index case is of the less commonly affected sex e.g. HPS - Male - lower threshold Most likely to have it - a male child of an affected female

Answer 33

linkage analyses - microsatellites association candidate gene testing - gene you think might be involved - haplotyping genome-wide association studies (GWAS)

Answer 34

relationship between loci not alleles specifically genetic phenomenon linkage analysis looks at physical chunks of the genome of related individuals with the phenotype and associates them with given traits PRINCIPLE if we find a common genetic marker (e.g. microsatellite, SNP) we assume that the gene that causes the disease is somewhere in the same area

Answer 35

purely statistical phenomenon and not specifically genetic GOAL = identify 1 or more allels within a population that co-occur with a particular phenotypic trait more often than would be expected by chance METHOD = gather some people with a disease (cases) and some people without a disease (controls) in a population and look to see what alleles are present more in cases than controls association is not causation - may be on same haplotype, or by chance present in higher frequency in subgroup with the disease - Gene involved - but molecular investigation must prove it

Answer 36

targets can be informed by: knowledge of the disease apthology (functional cloning) - quicker, but need prior knowledge to make an educated guess linkage and association testing (positional cloning)

Answer 37

scans all genes in genome no prior knowledge needed high resolution SNP chips used WGS also used

Answer 38

HYPERGLYCAEMIA \> 7mmol/L fasting \> 11 mmol/L non fasting TYPE 1 = sudden onset in youth related to autoimmune pancreatitis TYPE 2 = gradual onset in middle/later years associated with obesity and inactivity (diabetes epidemic)

Answer 39

mature onset diabetes of the young autosomal dominant pattern of inheritance not associated with obesity or sedentary lifestyle 7 different single gene defects identified

Answer 40

severe single gene defects some associated with deafness

Answer 41

ethnic differences family and twin studies - 2.4x risk for families 15-25% of first degree relatives develop impaired glucose tolerance or T2D \> 30 genes with susceptibility alleles (linkage/GWAS studies)