Genetics quiz 4 study guide PDF

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MULTIFACTORIAL INHERITANCE  

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Genetic + Environmental = Multifactorial inheritance Genetic Disorders o 1) Cystic Fibrosis o 2) Diabetes o 3) Breast Caner Environmental Disorders o 1) Iron-deficiency anemia o 2) Chicken Pox o 3) Lung Cancer Many dzs caused by heritable single-gene mutation o G6PD deficiency OR chromosomal abnormalities o Down syndrome

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Occur w/ low incidence in populations

Mendelian inheritance o Rare = passed down w/in families o Simple Genetics o Unifactorial = mutation in 1 gene o High recurrence rate Multifactorial inheritance o Common o Complex Genetics o Multifactorial = genetics + environment o Low recurrence rate o NOT simple Mendelian inheritance o Still cluster in families o Polygenic o Large # of genetic factors, each making only a small combination to final phenotype o Individual phenotypic variability  Type & # of mutations influence severity o Type:  Common phenotypic traits  Common congenital disorders  Common disease of adulthood Multifactorial inheritance common dzs: Congenital anomalies o Cleft lip/palate o Congenital hip dislocation o Congenital heart defects o Neural tube defects o Pyloric stenosis o Talipes = Club foot Multifactorial inheritance common dzs: Adult onset disorders – acquired o DM o Epilepsy o Glaucoma o HTN o Obesity o CAD o Manic depression o Schizophrenia Characteristics consistent w/ multifactorial inheritance o Trait/condition common in pop o Affected individuals (proband’s) relatives = lower incidence of dz  than for single gene disorders  but have higher risk than general pop

Proband’s siblings & offspring have similar incidence of dz  Risk of siblings similar to offspring o Dz incidence in proband’s relatives decreases rapidly w/ every degree of separation  More distant relatives = more rapid incidence falls o Dz incidence in relatives of proband = higher when proband/index case is of least commonly affected sex  Unequal sex ratio o Dz incidence in proband’s relatives = increases as phenotypic manifestations become more severe in index case o Observed risk increases following birth of 2 affected children  Person have liability factors passing on if more than 2 infected children Continuous/quantitative traits o Quantifiable characteristics – height, body weight, BP, serum cholesterol  determined by small additive effects (polygenic) multiple genes and environmental factors = multiple additive locus model  Clinical clue: 1 organ system affected o Quantitatively measured traits or susceptibility factors whose distribution in populations follows normal Gaussian or bell-shaped curve o Variation centered around average o Each predisposing gene allele – quantitative trait loci – QTL - & environmental factor contributes a small degree to overall expression of the trait o 1’s genetic background can be influenced by one’s environment & lead to variable expression of a trait o Polygenic = many genes o Large # of genetic factors  each making only small contribution to final phenotype o Ex: Susceptibility to CAD = quantitative trait determine by genetic + environmental factors – only some can be controlled o Uncontrollable BUT identifiable OR potential controllable/treatable o

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Bell-shaped curve = average in middle

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Multiple genes + environmental influences

Discontinuous (threshold/dichotomous) traits o All or none expression  have it or don’t o NO quantitative values assigned o Genetic + environmental factors @ play in individuals determines ones “liability” or risk of getting dz  Once reach the “threshold” – build-up of liability factors for that dz trait then have the dz  increased severity of dz manifestation o Expression of these traits does not follow normal Gaussian distribution in populations  Individuals on high end of liability distribution carry more genetic + environmental risk factors = high risk for getting dz o Additive effects of multiple gene alleles + environmental influences accumulate until exceed > threshold = dz phenotype express o Most common multifactorial disorders  Congenital malformations  Cardiovascular dz  Cancer  DM

Enough liability factors >threshold = dz - No Gaussian distribution of trait’s expression - Additive effects of genes +

environment do not lead to variable expression Applies to most multifactorial disorders Threshold may shift depending on FHx Phenotypic severity may be variable beyond threshold  once get beyond threshold see difference in phenotypic severity or specific expression of dz trait present due to types/#’s of dz mutations Liability distribution shifts depending on FHx & degree of relatedness o Relatives of affected distribution curve shift curve right but same threshold  have relatives that share more of those liability factors than average pop. o ALL factor that influence development of multifactorial disorder-genetic or environmental – considered single entity = liability -

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Disease risk increases w/ affected sibling - Threshold can shift w/in family -

Incidence/recurrence risk greatest amongst relatives of most severely affected individuals

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Affected individual w/in fam. Increases risk

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Recurrence risk = greatest amongst 1st-degree relatives – siblings & offspring – of proband/index case  risk diminishes rapidly in 2nd & 3rd degree relatives

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Increased recurrence risk w/ >1 affected close relative

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Increased recurrence risk w/ increased phenotypic severity of dz in proband

If dz = unequal sex ratio  then 1’s recurrence risk = greater if an affected relative is less commonly affected sex o Due to the lesser affected sex requiring high liability before exceeding threshold for expressing dz phenotype o More predisposing factors likely to be shared w/ close relatives

Family studies of the incidence of cleft lip (+/-) cleft palate Risk/Susceptibility in sibs 8.0

Bilateral CL w/out CP Unilateral CL w/ CP Unilateral CL w/out CP

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6.7 4.9 4.0

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More severed the manifestation of a multifactorial condition = greater probability of recurrence o Phenotypic severity can also increase recurrence of dz trait of relatives in family for multifactorial dz o If have affected index case/proband  risk that person’s siblings is highest w/ most severe phenotype

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**Recurrence risk for 1st degree relatives of a proband of multifactorial dz = calculated by square root of dz incidence

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Cleft lip +/- cleft palate = overall incidence ~1 per 1000 live births o Genes  IRF6  FOXE1  AXIN2 o Environmental  Maternal smoking, hypoxia, alcohol, & anticonvulsant use while pregnant, folic acid deficiency o Sex ratio: 2:1 male to female

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How are recurrence risk determined for genetic factors in complex disease? Evidence from these studies can estimate the heritability of condition  proportion of the cause ascribed to genetic factors rather than environmental factors o Familial risks  Disorder incidence in relatives compared to population? o @ birth so different environments growing up o Twin studies  Monozygotic? Dizygotic? Separated twins?  Identical = 100% - sharing of genome  Fraternal = 50% - sharing of genome o Adoption studies  Disorder incidence in adopted children w/ affected biological parents? o Genetics same – different environments o Population & Migration studies  Incidence in Cases vs. Controls? Incidence in people from particular ancestry group when they move to different geographical area?

Multifactorial inheritance: Factors increasing probability of recurrence in a particular family o Close relationship to proband o High heritability of disorder o Proband of more rarely affected sex o Severe/early onset of dz o Multiple Fx members affect  All these suggest that the Fx has higher liability to disorder  genes of higher effect OR more adverse environmental influences

 Heritability = proportion of total phenotypic variance of condition that is caused by additive genetic variance  Measure of extent to which one’s genetic makeup influences the expression of a trait  Determined by comparing phenotypic concordance (C) b/w MZ & DZ o Have 2 twins  What is the frequency that both twins have same phenotype?  Provide indication of relative importance of genetic factors in its causation  Estimated from degree of resemblance b/w relatives OR using data on concordance rates in monozygotic & dizygotic twins

Heritability (h) = 2 (CMZ – CDZ)

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o Linked genes occur on the same chromosome and are inherited together * Occurrence of linked genes means that NOT all genes are subject to independent assortment To determine if genes are linked  use linkage analysis = determination of how often recombination – mixing of information – crossing over – contained on 2 homologous chromosomes occurs b/w 2 or more genes Genes close together on chromosome = linked > 50% of time Genes on same chromosome can behave as if they were on different chromosomes  because during meiosis, crossing over occurs @ many points along the 2 homologous chromosomes Genes close together = inherited together = linked

Multifactorial sex ratios Disease conditions w/ unequal Sex Ration (male to female) Pyloric stenosis 5:1 Hirschsprung dz

3:1

Congenital dislocation of hip

1:6

Club foot (Talipes)

2:1

Rheumatoid arthritis

1:3

Peptic ulcer

2:1

Cleft lip +/- cleft palate

2:1

Cleft palate only

2:3

What do these unequal ratios tell you about their disease mechanisms? - For some conditions there must be a different “liability” threshold for males & females - Dz threshold = need to have enough genetic + environmental liability factors add up in a person before show affected phenotype o Ex: If males more likely to be affected than females  males must have a lower threshold for dz than females

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Pyloric stenosis = multifactorial etiology  5 X MORE common in MALES than females o Hypertrophy & thickening (stenosis) of pylorus muscle  blocks food from entering small intestine from stomach  Starting @ 3-5 weeks o Vomiting, constipation, weight loss, & electrolyte imbalance o Gene + Environmental  Maternal smoking, bottle feeding during 1st 4 months (bottle or formula), & some abxs

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Dz risk RISES if affected relative is LESS often affected sex Need less liability factors to give expression of trait

Relationship

Frequency %

Male relatives of male pt Female relatives of male pt

5% 2% 17%

Male relatives of female pt Female relatives of a female pt

Acquired more liability factors before become affected  anyone related to them share more Increase on general population risk fo liability factors than male same sex X 10 X 20 X 35

1%

Frequency of pyloric stenosis in relatives  For a female to be affected w/ pyloric stenosis, she must have particularly strong genetic susceptibility Degrees of Relationship First degree

Second degree

Parents

Uncles & Aunts

1st cousins

Siblings

Nephews & Nieces.

Great-grandparents

Children

Grandparents

Great-grandchildren

Grandchildren

Third degree

X 70

½ siblings

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 Monogenic (single gene/Mendelian) disorders = observed phenotype caused by mutation/abnormal function of single gene OR locus  Non-syndromic = Abnormal phenotype occurs in absence of additional phenotypic anomalies  Syndromic (single & contiguous genes) = additional phenotypic anomalies accompany abnormal phenotype  Complex/Multifactorial (Non-Mendelian contributions to phenotype from multiple loci) = Contributions from small # of genes = oligogenic = w/ LARGE effects/LARGE # genes = polygenic w/ SMALL effects across populations  Continuous/Quantitative traits = measurable trait differences amongst individuals w/ multiple underlying genetic influences = quantitative trait loci (QTLs)  Discontinuous/Threshold traits = accumulation of liability factors beyond threshold to cause expression of trait/phenotype  Ethnicity:  Population-specific genetic variants  Dz susceptibility  Tay Sachs dz = Ashkenazi Jews  Increasing potential for personalized medicine  Monogenic dz gene identification  1) Enriched protein levels in specific cells/tissues  Hemophilia A - Clotting factor VII deficiency  increased protein levels in blood  α−¿ β - Thalassemia - Reduced synthesis of alpha/beta globin genes  measure protein levels to diagnose dz  2) Candidate gene approach  Knowledge of biology of dz or phenotypic similarities = locus heterogeneity (ex.)  take what you know about dz or similar dz w/ similar gene  3) Position-dependent & position-independent strategies  Dependent = require you to have info about position of various genetic markers w/in genome & define region of chromosome that contains mutation & then looking there for dz gene mutations  Independent = look everywhere quickly to find mutations  Linkage analysis & positional cloning  1) Identification of chromosomal region – & eventually gene   associated w/ expression of trait/dz phenotype using informative polymorphic genetic markers to track heritability w/in family pedigree  2) Linkage requires large families w/ multiple affected individuals   (10-20 informative meioses) OR combination of many SMALL families affected w/ same dz  Multiple affected  link to dz phenotype  3) Positional cloning =  Strategy for dz gene identification that benefits from identification of an initial genetic location before starting to screen for mutations

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Start from scratch NOT knowing where gene mutation is Use genetic mapping  narrow region down to SMALL interval that ONLY has SMALL # of genes & screen for dz causing agent

 Position-dependent strategies= rely on identification of chromosomal location associated w/ disorder 

1) Linkage analysis= use informative polymorphic genetic markers from across genome to track inheritance of nearby dz genes that segregate w/ affected individuals w/in family  Polymorphic marker = normal variation in nucleotide sequence composition @ genomic locus  Know position of sequence w/in genome w/in certain chromosome  Informative marker = 2 parental chromosomes carry different alleles of genetic marker  MORE alleles per marker = the BETTER  More = better  Informative markers = establish linkage phase  chromosome haplotype is associated w/ dz-causing mutation  @ 1 locus can have multiple alleles affecting chromosome  Informative meiosis = parental allele combinations @ known genetic marker(s) allows inheritance of parental chromosome w/in pedigree to be inferred  Use genetic markers to know which chromosome being passed along pedigree  Genotype = individual’s allelic composition @ given genetic marker locus 

A. Types of genetic markers  1) * Microsatellite/short tandem repeat (STR) polymorphism  2) * Single nucleotide polymorphism (SNP)  3) Restriction fragment length polymorphism (RFLP)

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Genetic Markers: 1) Microsatellite/short tandem repeat (STR) polymorphism  Normal variation in copy # of short tandem repeat sequence  Look for differences & use those as genotype and mapping study  Ex: (CA)n OR (GATA)n  HIGHLY polymorphic = many possible alleles per locus  1 per 1000 bp average  but mapped density = 1 per 500 kb Genetic Markers: 2) Single nucleotide polymorphism (SNP):  Sequence variant @ single nucleotide position in genome  Occur FREQUENTLY – found often in genome  Know near a gene of SNP is linked or SNPs across entire genome  LESS polymorphic  because ONLY 4 allele possibilities (A, G, C, OR T) per locus  1 per 100-300 bp, but mapped density ~ 1 per 700 bp  Single marker vs. automated whole-genome arrays (open to automated genotyping technologies) Genetic Markers: 3) Restriction fragment length polymorphism (RFLP)  Sequence variant creates/destroys restriction enzyme cut site  Sequence difference w/in family interferes w/ normal restriction enzyme  LOW frequency, ONLY 2 alleles  not used as much anymore

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Polymorphic markers  Mapped to chromosomes by nucleotide sequences to create genetic map  Genotype info & potential gene linkage of dz on potential chromosome to find genes in region that cause dz

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B. Principles of linkage  Alleles @ markers in close proximity on a chromosome are co-inherited more frequently because the frequency of meiotic recombination events b/w them is low  These alleles = linked  Further away 2 markers are  more likely for recombination to occur b/w them  complicates genetic analysis  Haplotype = series of alleles @ 2 or more neighboring genetic markers on single chromosome/region  Allele 1 @ 1 marker & allele 2 @ another marker & another allele @ marker 1 Haplotype: 1,2,1 each chromosome  Meiotic recombination = homologous human chromosomes often split by recombination into 2-7 segments via crossing over during prophase I  Create new haplotypes  new combinations of alleles can be formed  Frequency of crossover increases as distance increases b/w 2 markers  Crossover frequency INCREASES = as distance INCREASES  Increase genetic diversity

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 Crossing over of non-sister chromatids  Recombination frequency = % of informative meioses in which recombination occurs b/w 2 markers  If in large # of informative meioses studied in families, recombination b/w alleles of 2 markers = occurs 5% of time  recombination frequency = 5%  Have 2 genetic markers, if recombination @ 1 of them  100% = 1 in every 100 gametes Concept of linkage:  Have dz causing mutation somewhere in genome & genetic marker that is really close & never recombines away from that  so can use this marker to follow through pedigree where dz causes mutation

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Genetic distance in centimorgans (cM) = 1 cm = 1% recombination frequency  1 in every 100 gametes show recombination

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Mendel’s law of independent assortment = random segregation of parental chromosomes into gametes/offspring  50% change of passing 1 parental chromosome & 50% chance of passing the other  So, 2 markers on same chromosome separated by >50 cM = NOT “linked” AND segregate randomly because recombination occurs b/w them w/ >50% frequency  62-284 cM (smallest-largest) rangesize for chromosomes  Chance of recombination b/w 2 markers = chance of no recombination b/w them  Recombination = 50% of time, so when individual passes along a chromosome  50% time alleles on chromosome will cross over NOT associated together @ HIGHER frequency  LARGER # of recombination events that can occur on LARGER chromosomes that can actually break haplotypes into 7 different fragments  Linkage = observed b/w alleles of 2 genetic markers OR marker & dz phenotype IF the recombination frequency b/w them = Unaffected 

D. Determination of significant linkage: Candidate region vs. genome-wide  Likelihood of the odds (LOD score)  = considers likelihood that 2 loci (genetic markers OR dz mutations) are linked @ recombination frequency vs. likelihood that 2 loci ARE NOT linked  recom. Freq. = 50%  Statistical significance = likelihood of the odds (LOD) score  measures the chance that 2 loci (genetic markers or dz loci) are linked @ recombinatio...