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Yr 2 Sem 1 > Organismal genetics > Flashcards

Organismal genetics Flashcards

1
Q

Yeast as model organism

A

Grown in culture/on agar plates, haploid & diploid stages of life cycle, cheap + easy
- can introduce DNA via plasmid via homologous recombination to create mutant

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2
Q

C. elegans as model organism

A

Worm w/ 4 day life cycle, fast generation, motile, easy identification of defects.
Add DNA via microinjection, reduce gene function via RNAi.

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3
Q

Drosophila as model organism

A

10 day life cycle, transposable elements allow addition/deletion.
Amenable to mutagenesis + chromosomal rearrangements.

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4
Q

A. thaliana as model organism

A

Plant w/ 6 week life cycle. Can be transformed via plasmid in agrobacterium.
Amenable to mutagenesis

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5
Q

Mouse as model organism

A

Similar gene content + physiology to humans.
Amenable to mutagenesis, transgenics, knockouts/knockins, conditional alterations.
Allows for tissue specificity.

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6
Q

Phenylketonuria (PKU)

A

Autosomal recessive, error in metabolism.
Phenylalanine not converted to tyrosine due to deficiency in PAH -> cognitive defects

Newborns can be screened + mutation found using chemical assay, dietary adjustments for improved cognitive development

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7
Q

Autosomal dominance in pedigree charts

A

50% chance transmission, must have affected parent, 2 affected people may have unaffected children, males + females affected equally

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8
Q

Autosomal recessive in pedigree charts

A

Affected person may not have affected parents, all children of 2 affected individuals are affected, males + females affected equally

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9
Q

Penetrance

A

Probability disease will appear when disease allele present (%)

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10
Q

Expressivity

A

Range of symptoms possible for given disease e.g. Marfan syndrome can have mild symptoms so hard to diagnose
Cancer can have age-related onset of expression

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11
Q

Pleiotropy

A

One gene has many functions, can be in many tissues - LoF affects many systems
e.g. Nail-Patella syndrome (NPS), nail abnormalities, absent patella, glaucoma, kidney disease
LMX1B mutation -> multi-tissue expression

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12
Q

Maternal effect

A

Genotype/phenotype mismatch. Phenotype depends on gene expression early in development - mRNA + proteins provided by mother in egg.
In organisms w/ delayed zygotic transcription (not mammals)

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13
Q

Allelic series

A

Different mutations in same gene cause different phenotypes.

e.g. Fibroblast growth factor receptors
receptor domains have many domains + many isoforms due to differential splicing
FGR3 autosomal dominant disease mutations - great phenotypic variation

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14
Q

Locus heterogeneity

A

Mutations in different genes.
e.g. retinitis pigmentosa

e.g. multiple epiphyseal dysplasia
Mainly autosomal dominant, 25% recessive caused by DTDST mutations
Caused by mutations in: COMP (50%), COL9A1, COL9A2, COL9A3, MATN3, DTDST (25%).

-> protein interaction network forms collagen for joint structure development BUT disrupted so abnormal phenotype

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15
Q

Role of COMP in pseudoachondroplasia

A

Autosomal dominant disorder (1:20,000), more severe than epiphyseal dysplasia. Mutation -> structurally abnormal COMP.
-> example of allelic series

COMP expressed in chondrocytes + tendons

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16
Q

Linkage map

A

Based on meiosis recombination. Markers farther apart have more recombination.
Tightly linked markers have less recombination

**recombination hot/cold spots so not always linked to distance

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17
Q

Haplotype analysis

A

Haplotype is combination of alleles present on same chromosome homologue.
- generated from SNP data, SNP combinations inherited + represent individual haplotype

Large scale analysis of haplotypes provides info on regions of DNA differing between populations.
-> disease characteristics

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18
Q

Exome sequencing

A

Captures all exons to then identify variations (disease causing). Exons selected from total genome + hybridised.

e.g. Primary Ciliary Dyskinesia
Abnormal cilia, lack of function, mutation in 14 different genes.
-> exome sequencing on 2 affected individuals + their parents, looked for coding variants
1 unknown in HEATR2 (likely cause), changes conserved Leu to Pro

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19
Q

Limitations of exome sequencing

A
  • only samples known coding regions
  • only identifies sequence changes not chromosomal structure changes
  • many variations in each individual so don’t know which causes phenotype
  • false positives/negatives due to PCR amplification genes
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20
Q

Next gen sequencing

A

Allows sequencing of large number of DNA mols in parallel.
- major modifications so don’t need primers
- rapid generation of large datasets
- alignment to reference genome needed

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21
Q

Polygenic phenotype

A

Phenotype affected by many different genes, linkage more difficult to discover.

Most common diseases are polygenic. SNP markers used to generate haplotypes + GWAS can identify regions associated w/ disease using population haplotypes.

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22
Q

GWAS (pros & cons)

A
  • generate haplotype data from affected + unaffected groups
  • evaluate genomic region for association w/ disease

Microarray SNP chip -> Validation -> Replication -> Finemapping -> Functional studies

Advantages: compare large groups + identify regions contributing to variation in phenotype, useful for common disease w/ polygenic basis

Disadvantages: need many people in each group, associated regions often have no genes or unlikely candidates, need functional experiments to demonstrate (association not causation)

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23
Q

What are Mendelian traits?

A

Traits inherited by offspring from their parents, characterized by discrete units

Mendel proposed that traits are determined by alleles, which can be dominant or recessive.

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24
Q

How can you distinguish between Mendelian and Quantitative traits?

A

Mendelian traits follow discrete inheritance patterns, while quantitative traits show continuous variation

Quantitative traits often involve multiple genes and environmental factors.

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25
Q

What does it indicate if a trait disappears in F1 and reappears in 25% of F2?

A

The trait is recessive to the dominant trait

This follows Mendel’s laws of inheritance.

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26
Q

What is the genetic ratio of offspring from a two-trait cross in Mendelian inheritance?

A

9:3:3:1

This ratio represents the expected phenotypic outcomes of a dihybrid cross.

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27
Q

What did Francis Galton contribute to the study of quantitative inheritance?

A

He studied seed size in pea plants and introduced statistical concepts like regression and correlation

Galton’s work laid the groundwork for the biometric approach in genetics.

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28
Q

What is the conflict between Mendelian and biometric approaches?

A

Mendelian focuses on discrete traits, while biometricians emphasize continuous variation in traits

This conflict delayed the integration of genetics with natural selection theory.

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29
Q

What is the modern theory regarding phenotypic control?

A

Some phenotypes are controlled by one gene, while others are influenced by multiple genes and environmental interactions

This complexity reflects the multifactorial nature of many traits.

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30
Q

True or False: All phenotypes are controlled by a single gene.

A

False

Many phenotypes are determined by multiple genes and their interactions.

31
Q

Fill in the blank: The ratio of offspring from a two-trait cross is _______.

A

9:3:3:1

32
Q

What role did Francis Galton play in the eugenics movement?

A

He was a founder of the movement that led to racist policies and forced sterilization programs

Galton’s ideas, while influential in statistics, contributed to harmful social policies.

33
Q

Mendelian vs Biometric approach to the effect of mutants on evolution

A

Mendelians believe variation in discrete characteristics drives evolution (new mutants have large effects)

Biometricians believe that evolution is natural selection acting on continuously distributed characters

34
Q

What are quantitative traits?

A

Phenotypes that vary along a range of values, controlled by interactions between genes and environment.

35
Q

What is quantitative trait inheritance?

A

The inheritance pattern of phenotypes that can be measured on a continuous scale.

36
Q

What is the difference between quantitative trait loci and Mendelian trait inheritance?

A

Quantitative trait loci are genes that cause quantitative traits, while Mendelian traits follow discrete inheritance patterns.

37
Q

What are major genes?

A

Genes that produce a detectable effect on phenotype.

38
Q

How can genes influence phenotypes?

A

Genes can be additive or dominant in their effects.

39
Q

What does it mean for genes to be additive?

A

Each gene contributes equally to the variation in phenotype.

40
Q

What does it mean for genes to be dominant?

A

One gene has a more significant effect on phenotype than other genes.

41
Q

What is heritability test for?

A

To determine if variation in a trait is controlled by genetics, assessing if relatives are more similar than non-relatives.

42
Q

Why is classifying individuals with quantitative traits difficult?

A

Because the effects of many genes are too small to measure individually.

43
Q

Fill in the blank: Quantitative traits are controlled by interactions between _______ and environment.

A

[genes]

44
Q

What are melanosomes?

A

Cellular compartments that store melanin

Melanosomes play a crucial role in determining pigmentation in humans.

45
Q

What types of melanin are identified in human pigmentation?

A
  • Eumelanin - black/brown
  • Pheomelanin - red/yellow

These two types of melanin contribute to the variety of human skin and hair colors.

46
Q

What factors contribute to human pigmentation variation?

A
  • Differences in number of melanosomes
  • Type of melanin
  • Size and shape of melanosomes

These factors are influenced by genetic variants that affect pigmentation.

47
Q

What is the evolutionary function of pigmentation variation?

A
  • Protection against UV radiation
  • Synthesis of vitamin D

Geographic variation in pigmentation serves these important biological functions.

48
Q

What is the significance of selective mouse breeding?

A

It generates strains that are homozygous at all loci and have different genotypes at many loci.

49
Q

What is QTL identification in mice?

A

It involves identifying genomic variations between strains that affect phenotype.

50
Q

What is the role of F1 in genetic studies?

A

F1 is produced by crossing two inbred strains and is heterozygous for all loci.

51
Q

What is a two-bottle choice test in mice used for?

A

To study alcohol preference behaviour by offering one bottle with water and another with ethanol.

-> D2 consumes less than 1g/kg/day while B6 consumes 10g/kg/day.

52
Q

What percentage of individuals are affected by alcoholism?

A

Approximately 5%.

53
Q

What accounts for 50-60% of the variability in alcoholism manifestation?

A

Genetic factors.

54
Q

What does crossing F1 produce?

A

F2 lines, each mouse having different combinations of homozygous DNA.

55
Q

What can be inferred if half of the offspring are grey and half are green?

A

There has been recombination or crossing over.

56
Q

What is linkage analysis?

A

Markers which are polymorphic between strains + have a known chromosomal location used
SSR used, gel electrophoresis to detect SSLP of PCR product -> animals w/ 2 bands are heterozygous.

For SNPs, can detect by sequencing PCR product that amplifies SNP

57
Q

Gene identification

A

Can narrow down scope of investigation depending on study.
e.g. for alcoholism in mice - expressed in brain, synaptic function, gene w/ sequence change that causes functional change to protein (Stxb1)

58
Q

How can you confirm that a gene is causative?

A

Transgenic rescue - add wt allele to mutant & see phenotype disappear

Can use knock-in to generate same sequence change in wt mice + induce same phenotype

59
Q

Epigenetics

A

Study of heritable changes that occur without a modification in DNA sequences of genes

  • histone modification
  • DNA methylation
  • nucleosome remodelling
  • non-coding RNA mediation
60
Q

DNA methylation

A

Addition of methyl group to cytosine (C) - blocks transcription due to tightly packed chromatin.
- methylated genes generally not expressed
- occurs in mammals + plants

Form of ‘imprinting’ , can change depending on parental chromosome

61
Q

What causes Prader willie & Angelman syndromes?

A

Micro-deletions on Chromosome 15.

  • PWS , short stature, impaired cog development, respiratory distress, obesity
    Paternal allele mutated + maternal imprinted (silenced) -> loss of SNRPN expression
  • AS, developmental delay, hyperactivity, impaired cog function, seizures
    Maternal allele mutated + paternal imprinted (UBE3A gene)
62
Q

What is the epigenetic reprogramming cycle?

A
  • imprint establishment in gametes
  • matured and then maintained in fertilisation
  • imprint read into differentiated cells
  • erased in primordial germ cells

Differentiated gametes undergo widespread epigenetic reprogramming

Zygotic genome activated at 2 (mice) or 8 (humans) cell stage.
In mammals - 2 cell lineages of trophectoderm + ICM.
ICM -> forms epiblast & primitive endoderm

ICM + TE have different degree of methylation. ICM forms embryo + TE forms placenta.

63
Q

Describe the process of comatic cell nuclear transfer

A

Cloning e.g. Dolly the Sheep

Nucleus removed from adult cell, oocyte transferred w/ no nucleus.
Implant it into host mother -> nucleus/DNA supplied from adult w/ imprint in place
- electric current applied so nucleus fuses w/ empty egg

4% results in birth of live young

64
Q

How does large offspring syndrome arise?

A

Often unhealthy live young from cloning.
- respiratory distress, 2-fold increase in birth weight
- skeletal, immunological + placental defects

Caused by improper placental development due to imprinting defect.
- abnormal X chrom inactivation in females + imprinting (far less methylation) defects both genders

65
Q

Is epigenetics the cause of clone abnormalities?

A

Cloned animals used in natural mating -> offspring do not show defects (LOS)

They have same genotype but not same epigenetic imprinting SO yes.
Gene expression changed -> determines survival & phenotype

66
Q

Histone modifications

A

Chromatin organisation formulates gene expression pattern.
Epigenetic signatures vary by cell type & in disease.

Chromatin & miRNA environment dictates cellular gene expression

67
Q

What was Barkers impact on epigenetic inheritance?

A

Mapped areas of infant mortality + low birthweight in UK 1910s, analysed death rates due to Cardiovascular + type II diabetes 1970s -> correlation w/ deprivation

Hypothesised nutrient conditions during pregnancy affect health in adult life (thrifty phenotype)
Programming - caused persistent physiological + metabolic changes which cannot be compensated by adequate nutrition after birth

68
Q

How did the Dutch Hunger Winter (1944-45) support Barker’s hypothesis?

A

Maternal starvation during pregnancy limits intrauterine growth of offspring -> higher CV + diabetes rates
-> placental abnormalities + maternal stress

Offspring had children w/ low birthweights -> not found w/ siblings not born in famine

69
Q

What are the epigenetic changes linked to early development during a famine?

A

Individuals exposed to famine in gestation -> reduced methylation of IGF2 gene at age 60.
Vs siblings not conceived in famine had higher levels of IGF2 methylation

SO uterine environment encodes epigenetic state during development
- maternal obesity increases risk type II diabetes in child
monozygotic twins discordant for type II diabetes

70
Q

What are the effects of diet on epigenetic state in rats?

A

Fed normal and low protein (LP) diet during gestation + lactation.

  • Hnf4a polymorphisms confer type II diabetes risk
  • Hnf4a expression reduced in LP diet rats - persists throughout life
  • Hnf4a levels normally decrease in old age

LP diet induces DNA methylation + histone acetylation on Hnf4a enhancer region -> changes expression throughout life

71
Q

Transgenerational inheritance

A

Refers to altered phenotypes in offspring through beyond F2 generation to F3.
- need to eliminate effect on gametes to confirm
- offspring exist as germ cells in grandmothers pregnancy
- can study w/ animal models

Multigenerational exposure can be seen in grandchildren (F2) but no further.

72
Q

What is the experimental evidence for transgenerational inheritance?

A

Folate deficiency - folate is carrier of methyl groups needed for cellular metabolism.
Mttr gene needed for normal metabolism of folate + methionine

Mttr mutation (gt) - insertion leads to folate metabolism deficiency

Analysed gt heterozygote intercrosses:
- phenotypes did not correlate w/ maternal or offspring phenotypes
- 45% zygotes showed abnormal phenotype in development
- abnormal phenotypes present in all offspring genotypes equally (F2)

SO hypothesised maternal + grandparental genotype might correlate w/ offspring

73
Q

How did they determine if Mttr mutation is an example of transgenerational inheritance?

A

Analysed pedigree charts - pregnancies w/ abnormal litters always had mutant grandparents
- global DNA methylation levels disrupted in mutant adult livers
- Wt littermates show disrupted methylation levels in adult liver

Wt pre-implantation embryos w/ mutant maternal grandparent transferred to wt female for development
Wt embryos w/o mutant maternal grandparents used as controls
-> found congenital defects only in offspring w/ mutant maternal grandparent

Defects persisted for at least 5 generations -> transgenerational

Yr 2 Sem 1 (3 decks)

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